Objetos metálicos de la Edad del Bronce de Chipre - metal procedente de Anatolia y el Mediterráneo Occidental

Hundreds of Bronze Age metal artefacts excavated on archaeological sites in Cyprus have been analysed for their lead isotope and elemental composition in the Isotrace Laboratory, University of Oxford, in the years 1982-2002. In parallel, but in particular after 1995, hundreds of samples of minerals and slags collected from the mines and smelting sites around the Troodos Mountains were also analysed. Most of the results were published in various articles over the years, but the interpretation of some of the lead isotope data needs a current revision in view of new research conducted in Spain, Sardinia and southern France. It has been known that the lead isotope data for metal artefacts from the Cypriot Bronze Age sites shows that not all of the copper is consistent with origin from the Cypriot ores. In addition, the lead and silver artefacts found there must have been imported, because there are no lead or silver ores on Cyprus. The re-evaluation of the data shows that about 11 % of the analysed metal artefacts are consistent with the origin from the deposits in the Aegean and Turkey, while about 14 % with sources in the Western Mediterranean. This paper discusses in detail the current interpretation of the research into the sources of imported metal found in the Bronze Age context on Cyprus.Cientos de objetos de metal de la Edad del Bronce excavados en yacimientos de Chipre han sido analizados para conocer su composición elemental y sus isótopos de plomo en el Isotrace Laboratory de la Universidad de Oxford entre los años 1982 y 2002. Especialmente con posterioridad a 1995 cientos de muestras de minerales y escorias recogidas de minas y sitios de reducción de minerales localizadas en el entorno de las montañas de Troodos también fueron analizadas. La mayoría de los resultados fueron publicados en varios artículos a lo largo del tiempo, pero la interpretación de algunos análisis de isótopos de plomo necesitan de una revisión a la vista de las nuevas investigaciones realizadas en España, Cerdeña y Sur de Francia. Es sabido que los datos de isótopos de plomo de objetos metálicos de yacimientos chipriotas de la Edad del Bronce muestran que no todo el cobre es consistente con un origen de minerales de Chipre. Además, los objetos de plomo y plata debieron ser importados debido a que no existen minerales de plomo o plata en la isla. La re-evaluación de los datos muestra que alrededor del 11 % de los objetos de metal analizados son consistentes con un origen en los depósitos del Egeo y Turquía, mientras que un 14 % lo son con minerales del Mediterráneo Occidental. Este artículo discute en detalle la interpretación actual de la investigación sobre el metal importado recuperado en contextos de la Edad del Bronce en Chipre

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.

Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy.This article is freely available via Open Access

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). Interpretation: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Lead isotope studies - Sardinia and the Mediterranean: Provenance studies of artefacts found in Sardinia

It has been a principal aim of research at the Isotrace Laboratory in Oxford to establish Bronze Age trading patterns in the Mediterranean, especially for metals. The metals copper and tin, together with silver, lead and gold, were the metals which constituted the ‘trade’ in metals in the Late Bronze Age Mediterranean. Archaeology per se had failed to establish these trading patterns, as had scientific methods using chemical analyses. However it was established by the Isotrace Laboratory in 1982 that comparative lead isotope analyses of metal ores and artefacts could be extended from the study of lead and silver to provide a method to establish trading patterns for copper. A principal form in which copper was traded around the Mediterranean region in the period roughly between 1600 BC and 1100 BC was in the form of the so called copper oxhide ingots, weighing on average about 30 kilograms. The present paper proves that the large number of copper oxhide ingots found on Sardinia were not made of copper from Sardinian ore deposits, as surmised by some archaeologists, but were instead made from copper from the Apliki mining region deposits in Cyprus, in common with all other analysed copper oxhide ingots from around the LBA Mediterranean, including the ingots excavated from the LBA shipwreck of Cape Gelidonya. It is also proved that copper alloy artefacts excavated from nuragic contexts on Sardinia are consistent with having been made of copper from Sardinian ore deposits.Citation: Gale, N. H. (2006). 'Lead isotope studies - Sardinia and the Mediterranean - Provenance studies of artefacts found in Sardinia', Instrumentum 23, 29-34

Bronze Age metal artefacts found on Cyprus - metal from Anatolia and the Western Mediterranean

Hundreds of Bronze Age metal artefacts excavated on archaeological sites in Cyprus have been analysed for their lead isotope and elemental composition in the Isotrace Laboratory, University of Oxford, in the years 1982-2002. In parallel, but in particular after 1995, hundreds of samples of minerals and slags collected from the mines and smelting sites around the Troodos Mountains were also analysed. Most of the results were published in various articles over the years, but the interpretation of some of the lead isotope data needs a current revision in view of new research conducted in Spain, Sardinia and southern France. It has been known that the lead isotope data for metal artefacts from the Cypriot Bronze Age sites shows that not all of the copper is consistent with origin from the Cypriot ores. In addition, the lead and silver artefacts found there must have been imported, because there are no lead or silver ores on Cyprus. The re-evaluation of the data shows that about 11 % of the analysed metal artefacts are consistent with the origin from the deposits in the Aegean and Turkey, while about 14 % with sources in the Western Mediterranean. This paper discusses in detail the current interpretation of the research into the sources of imported metal found in the Bronze Age context on Cyprus.<br><br>Cientos de objetos de metal de la Edad del Bronce excavados en yacimientos de Chipre han sido analizados para conocer su composición elemental y sus isótopos de plomo en el Isotrace Laboratory de la Universidad de Oxford entre los años 1982 y 2002. Especialmente con posterioridad a 1995 cientos de muestras de minerales y escorias recogidas de minas y sitios de reducción de minerales localizadas en el entorno de las montañas de Troodos también fueron analizadas. La mayoría de los resultados fueron publicados en varios artículos a lo largo del tiempo, pero la interpretación de algunos análisis de isótopos de plomo necesitan de una revisión a la vista de las nuevas investigaciones realizadas en España, Cerdeña y Sur de Francia. Es sabido que los datos de isótopos de plomo de objetos metálicos de yacimientos chipriotas de la Edad del Bronce muestran que no todo el cobre es consistente con un origen de minerales de Chipre. Además, los objetos de plomo y plata debieron ser importados debido a que no existen minerales de plomo o plata en la isla. La re-evaluación de los datos muestra que alrededor del 11 % de los objetos de metal analizados son consistentes con un origen en los depósitos del Egeo y Turquía, mientras que un 14 % lo son con minerales del Mediterráneo Occidental. Este artículo discute en detalle la interpretación actual de la investigación sobre el metal importado recuperado en contextos de la Edad del Bronce en Chipre