Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27

Baseline patient and tumor characteristics differentially affected type of death in the MA.17 placebo-controlled letrozole trial where cardiovascular death was not separately identified. The MA.27 trial allowed competing risks analysis of breast cancer (BC), cardiovascular, and other type (OT) of death. MA.27 was a phase III adjuvant breast cancer trial of exemestane versus anastrozole. Effects of baseline patient and tumor characteristics were tested for whether factors were associated with (1) all cause mortality and (2) cause-specific mortality. We also fit step-wise forward cause-specific-adjusted models. 7576 women (median age 64 years; 5417 (72 %) < 70 years and 2159 (28 %) ≥ 70 years) were enrolled and followed for median 4.1 years. The 432 deaths comprised 187 (43 %) BC, 66 (15 %) cardiovascular, and 179 (41 %) OT. Five baseline factors were differentially associated with type of death. Older patients had greater BC (p = 0.03), cardiovascular (p < 0.001), and other types (p < 0.001) of mortality. Patients with pre-existing cardiovascular history had worse cardiovascular mortality (p < 0.001); those with worse ECOG performance status had worse OT mortality (p < 0.001). Patients with T1 tumors (p < 0.001) and progesterone receptor positive had less BC mortality (p < 0.001). Fewer BC deaths occurred with node-negative disease (p < 0.001), estrogen receptor-positive tumors (p = 0.001), and without adjuvant chemotherapy (p = 0.005); worse cardiovascular mortality (p = 0.01), with trastuzumab; worse OT mortality, for non-whites (p = 0.03) and without adjuvant radiotherapy (p = 0.003). Overall, 57 % of deaths in MA.27 AI-treated patients were non-breast cancer related. Baseline patient and tumor characteristics differentially affected type of death with women 70 or older experiencing more non-breast cancer death

Anterior eye health recording.

AIMS: To survey eye care practitioners from around the world regarding their current practice for anterior eye health recording to inform guidelines on best practice. METHODS: The on-line survey examined the reported use of: word descriptions, sketching, grading scales or photographs; paper or computerised record cards and whether these were guided by proforma headings; grading scale choice, signs graded, level of precision, regional grading; and how much time eye care practitioners spent on average on anterior eye health recording. RESULTS: Eight hundred and nine eye care practitioners from across the world completed the survey. Word description (p<0.001), sketches (p=0.002) and grading scales (p<0.001) were used more for recording the anterior eye health of contact lens patients than other patients, but photography was used similarly (p=0.132). Of the respondents, 84.5% used a grading scale, 13.5% using two, with the original Efron (51.6%) and CCLRU/Brien-Holden-Vision-Institute (48.5%) being the most popular. The median features graded was 11 (range 1-23), frequency from 91.6% (bulbar hyperaemia) to 19.6% (endothelial blebs), with most practitioners grading to the nearest unit (47.4%) and just 14.7% to one decimal place. The average time taken to report anterior eye health was reported to be 6.8±5.7 min, with the maximum time available 14.0±11 min. CONCLUSIONS: Developed practice and research evidence allows best practice guidelines for anterior eye health recording to be recommended. It is recommended to: record which grading scale is used; always grade to one decimal place, record what you see live rather than based on how you intend to manage a condition; grade bulbar and limbal hyperaemia, limbal neovascularisation, conjunctival papillary redness and roughness (in white light to assess colouration with fluorescein instilled to aid visualisation of papillae/follicles), blepharitis, meibomian gland dysfunction and sketch staining (both corneal and conjunctival) at every visit. Record other anterior eye features only if they are remarkable, but indicate that the key tissue which have been examined

The Genetic Structure of Pacific Islanders

Human genetic diversity in the Pacific has not been adequately sampled, particularly in Melanesia. As a result, population relationships there have been open to debate. A genome scan of autosomal markers (687 microsatellites and 203 insertions/deletions) on 952 individuals from 41 Pacific populations now provides the basis for understanding the remarkable nature of Melanesian variation, and for a more accurate comparison of these Pacific populations with previously studied groups from other regions. It also shows how textured human population variation can be in particular circumstances. Genetic diversity within individual Pacific populations is shown to be very low, while differentiation among Melanesian groups is high. Melanesian differentiation varies not only between islands, but also by island size and topographical complexity. The greatest distinctions are among the isolated groups in large island interiors, which are also the most internally homogeneous. The pattern loosely tracks language distinctions. Papuan-speaking groups are the most differentiated, and Austronesian or Oceanic-speaking groups, which tend to live along the coastlines, are more intermixed. A small “Austronesian” genetic signature (always <20%) was detected in less than half the Melanesian groups that speak Austronesian languages, and is entirely lacking in Papuan-speaking groups. Although the Polynesians are also distinctive, they tend to cluster with Micronesians, Taiwan Aborigines, and East Asians, and not Melanesians. These findings contribute to a resolution to the debates over Polynesian origins and their past interactions with Melanesians. With regard to genetics, the earlier studies had heavily relied on the evidence from single locus mitochondrial DNA or Y chromosome variation. Neither of these provided an unequivocal signal of phylogenetic relations or population intermixture proportions in the Pacific. Our analysis indicates the ancestors of Polynesians moved through Melanesia relatively rapidly and only intermixed to a very modest degree with the indigenous populations there

Increasing the reference populations for the 55 AISNP panel: the need and benefits

Ancestry inference for an individual can only be as good as the reference populations with allele frequency data on the SNPs being used. If the most relevant ancestral population(s) does not have data available for the SNPs studied, then analyses based on DNA evidence may indicate a quite distantly related population, albeit one among the more closely related of the existing reference populations. We have added reference population allele frequencies for 14 additional population samples (with >1100 individuals studied) to the 125 population samples previously published for the Kidd Lab 55 AISNP panel. Allele frequencies are now publicly available for all 55 SNPs in ALFRED and FROG-kb for a total of 139 population samples. This Kidd Lab panel of 55 ancestry informative SNPs has been incorporated in commercial kits by both ThermoFisher Scientific and Illumina for massively parallel sequencing. Researchers employing those kits will find the enhanced set of reference populations useful

POT1 mutations predispose to familial melanoma

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.D.J.A., C.D.R.-E., Z.D., J.Z.L., J.C.T., M.P. and T.M.K. were supported by Cancer Research UK and the Wellcome Trust (WT098051). C.D.R.-E. was also supported by the Consejo Nacional de Ciencia y Tecnología of Mexico. K.A.P. and A.M.D. were supported by Cancer Research UK (grants C1287/A9540 and C8197/A10123) and by the Isaac Newton Trust. N.K.H. was supported by a fellowship from the National Health and Medical Research Council of Australia (NHMRC). L.G.A. was supported by an Australia and New Zealand Banking Group Limited Trustees PhD scholarship. A.L.P. is supported by Cure Cancer Australia. The work was funded in part by the NHMRC and Cancer Council Queensland. The work of N.A.G. was in part supported by the Dutch Cancer Society (UL 2012-5489). M.H., J.A.N.-B. and D.T.B. were supported by Cancer Research UK (programme awards C588/A4994 and C588/A10589 and the Genomics Initiative). C.L.-O., A.J.R. and V.Q. are funded by the Spanish Ministry of Economy and Competitiveness through the Instituto de Salud Carlos III (ISCIII), the Red Temática de Investigación del Cáncer (RTICC) del ISCIII and the Consolider-Ingenio RNAREG Consortium. C.L.-O. is an investigator with the Botín Foundation.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.294

Improving the immunogenicity of native-like HIV-1 envelope trimers by hyperstabilization

The production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 SOSIP.664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp)120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation. The resulting next-generation SOSIP.v5 trimers induce strong autologous tier-2 neutralizing antibody (NAb) responses in rabbits. In addition, the BG505 SOSIP.v6 trimers induced weak heterologous NAb responses against a subset of tier-2 viruses that were not elicited by the prototype BG505 SOSIP.664. These stabilization methods can be applied to trimers from multiple genotypes as components of multivalent vaccines aimed at inducing broadly NAbs (bNAbs)

Il sito web dell'Osservatorio Vesuviano

L'Osservatorio Vesuviano ha di recente realizzato una radicale ristrutturazione del proprio sito Web, attivo dalla seconda metà del 1997, al fine di adeguarlo alla sua nuova configurazione giuridica. Infatti, dal 10 gennaio 2001 è entrato a far parte dell'Istituto Nazionale di Geofisica e Vulcanologia (INGV), un ente nazionale di nuova formazione in cui sono confluiti i maggiori enti ed istituzioni di ricerca operanti nel campo della geofisica e della vulcanologia in Italia. Con la nascita dell'INGV si è posta un'esigenza di coordinamento tra i siti web di dette istituzioni, che si configurano attualmente come sezioni del nuovo ente nazionale. Inoltre, è sorta la necessità di creare delle pagine comuni, relative all'ente nella sua totalità, che introducessero i visitatori alle pagine delle singole sezioni ed eventualmente a specifici tematismi riguardanti le attività dell'ente. A tal fine, è stato istituito un gruppo di Coordinamento Nazionale per il Web che comprende personale afferente alle diverse sezioni. Parallelamente sono stati istituiti gruppi di lavoro locali per la ristrutturazione dei siti delle sezioni. Nell'ambito di questa riorganizzazione, presso l'Osservatorio Vesuviano, con Decreto Direttoriale N. 6, del 30 gennaio 2002, è stato istituito un gruppo di lavoro con il compito di curare la progettazione e lo sviluppo del nuovo sito web della sezione. Nello svolgimento di questa attività il gruppo di lavoro si è posto come obbiettivi prioritari l'usabilità e l'accessibilità del sito, in ottemperanza alle indicazioni espresse dalla più recente normativa apparsa in materia. Per perseguire a pieno questi obbiettivi e garantire la massima fruibilità delle informazioni è stata prevista, fin dalla fase progettuale, la realizzazione del sito anche in versione inglese, che attualmente è in allestimento. Il nuovo sito web dell'Osservatorio Vesuviano è stato messo in linea il 22 maggio 2002 ed è visitabile all'indirizzo http://www.ov.ingv.it. Nel seguito del presente rapporto sono introdotte sinteticamente le finalità istituzionali e le principali attività dell'Osservatorio Vesuviano e sono descritte le fasi di progettazione e sviluppo del sito, con particolare dettaglio sulla strutturazione dei contenuti, definita nell'ambito delle linee dettate dal decreto di istituzione del gruppo di lavoro, e sulle scelte tecnologiche adottate

Introduction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67161/2/10.1177_0308275X9301300401.pd