Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Combining qualitative and quantitative methods to analyze serious games outcomes: A pilot study for a new cognitive screening tool

Computer games for a serious purpose - so called serious games can provide additional information for the screening and diagnosis of cognitive impairment. Moreover, they have the advantage of being an ecological tool by involving daily living tasks. However, there is a need for better comprehensive designs regarding the acceptance of this technology, as the target population is older adults that are not used to interact with novel technologies. Moreover given the complexity of the diagnosis and the need for precise assessment, an evaluation of the best approach to analyze the performance data is required. The present study examines the usability of a new screening tool and proposes several new outlines for data analysis.

Peri-implant bone loss of dental implants with platform-switching design after 5 years of loading: a cross-sectional study

OBJECTIVE The aim of this cross-sectional study was to estimate bone loss of implants with platform-switching design and analyze possible risk indicators after 5 years of loading in a multi-centered private practice network. METHOD AND MATERIALS Peri-implant bone loss was measured radiographically as the distance from the implant shoulder to the mesial and distal alveolar crest, respectively. Risk factor analysis for marginal bone loss included type of implant prosthetic treatment concept and dental status of the opposite arch. RESULTS A total of 316 implants in 98 study patients after 5 years of loading were examined. The overall mean value for radiographic bone loss was 1.02 mm (SD ± 1.25 mm, 95% CI 0.90- 1.14). Correlation analyses indicated a strong association of peri-implant bone loss > 2 mm for removable implant-retained prostheses with an odds ratio of 53.8. CONCLUSION The 5-year-results of the study show clinically acceptable values of mean bone loss after 5 years of loading. Implant-supported removable prostheses seem to be a strong co-factor for extensive bone level changes compared to fixed reconstructions. However, these results have to be considered for evaluation of the included special cohort under private dental office conditions.

Power Games in Strategy Formation Processes – A Performative Interpretation

The article approaches an understanding of power within strategy formation processes established by verbal and bodily communication. On this note, we examined concepts of power constituted by hierarchy and developed a conceptual framework for a performative interpretation of power. In line with Austin’s (1962) and Butler’s (1990, 1993, 1997) concept of performativity as well as strategy-as-practice research (Balogun et al., 2007; Jarzabkowski & Spee, 2009) we ask: How is persuasion achieved by strategic actors during strategy formation processes? To explore verbal and bodily communication empirically we developed an experimental setting in a small high-tech company located in Germany in December, 2012. The Results indicate that (1) during critical incidents – when perspectives clash – actors use arguments to gain persuasion. (2) The data illustrates that independently of their hierarchical position within the company, strategic actors show an equal distribution of argumentative techniques.

Development of a 3D Game Engine

This paper presents the development history and specification of a 3D game engine titled "Spark Engine". The term "engine" is used to describe a complex graphics software suite that streamlines application development and provides efficient rendering functionality. A game engine specifically provides tools to simplify game development. Spark Engine is fully shader driven and is built on top of Microsoft's XNA Framework. It is a reusable and flexible platform that can be used to build any type of graphics application ranging from gaming to simulation. The engine was released as open source software under the New BSD License with an interest in furthering its development.

Sequential Pre-Marital Investment Games: Implications for Unemployment

Agents on the same side of a two-sided matching market (such as the marriage or labor market) compete with each other by making self-enhancing investments to improve their worth in the eyes of potential partners. Because these expenditures generally occur prior to matching, this activity has come to be known in recent literature (Peters, 2007) as pre-marital investment. This paper builds on that literature by considering the case of sequential pre-marital investment, analyzing a matching game in which one side of the market invests first, followed by the other. Interpreting the first group of agents as workers and the other group as firms, the paper provides a new perspective on the incentive structure that is inherent in labor markets. It also demonstrates that a positive rate of unemployment can exist even in the absence of matching frictions. Policy implications follow, as the prevailing set of equilibria can be altered by restricting entry into the workforce, providing unemployment insurance, or subsidizing pre-marital investment.

Assessing fun in serious games: Formative evaluation of games from two diabetes prevention interventions

Purpose. To determine the usability of two video games to prevent type 2 diabetes and obesity among youth through analysis of data collected during alpha-testing. ^ Subjects. Ten children aged 9 to 12 were selected for three 2-hour alpha testing sessions.^ Methods. "Escape from Diab" and "Nanoswarm" were designed to change dietary and physical inactivity behaviors, based on a theoretical framework of mediating variables obtained from social cognitive theory, self-determination theory, elaboration likelihood model, and behavioral inoculation theory. Thirteen mini-games developed by the software company were divided into 3 groups based on completion date. Children tested 4-5 mini-games in each of three sessions. Observed game play was followed by a scripted interview. Results from observation forms and interview transcripts were tabulated and coded to determine usability. Suggestions for game modifications were delivered to the software design firm, and a follow-up table reports rationale for inclusion or exclusion of such modifications.^ Results. Participants were 50% frequent video game players and 20% non game-players. Most (60%) were female. The mean grade (indicating likeability as a subset of usability) across all games given by children was significantly greater than a neutral grade of 80% (89%, p < 0.01), indicating a positive likeability score. The games on average also received positive ratings for fun, helpfulness of instructions and length compared to neutral values (midpoint on likert scales) (all p < 0.01). Observation notes indicated that participants paid attention to the instructions, did not appear to have much difficulty with the games, and were "not frustrated", "not bored", "very engaged", "not fidgety" and "very calm" (all p < 0.01). The primary issues noted in observations and interviews were unclear instructions and unclear purpose of some games. Player suggestions primarily involved ways to make on screen cues more visible or noticeable, instructions more clear, and games more elaborate or difficult.^ Conclusions. The present study highlights the importance of alpha testing video game components for usability prior to completion to enhance usability and likeability. Results indicate that creating clear instructions, making peripheral screen cues more eye-catching or noticeable, and vigorously stating the purpose of the game to improve understandability are important elements. However, future interventions will each present unique materials and user-interfaces and should therefore also be thoroughly alpha-tested. ^

Rb-Sr and K-Ar data for Upper Vendian clayey rocks of the Russian Platform

Geochemical behavior of Rb-Sr and K-Ar systems in Upper Vendian clayey rocks of the Russian Platform is under consideredation. The use of additional data on grain size fractions of sedimentary rocks recovered from boreholes drilled in the Gavrilov Yam area made it possible to confirm the previous conclusion on two stages of epigenetic matter transformation (approximately 600 and 400 Ma ago). Distortions are related to transformation of sediments due to interaction in the water-rock system. Interaction degree was more intense in the upper part of the sedimentary section relative to its lower strata. These conclusions are substantiated by materials from boreholes that characterize different types of Vendian sections and different tectonic zones.

Element contents, sulfur and oxygen isotopes, and molecular biomarkers of phosphatic crust samples from the Chimbote Platform of the shelf off Peru

Authigenic phosphatic laminites enclosed in phosphorite crusts from the shelf off Peru (10°01' S and 10°24' S) consist of carbonate fluorapatite layers, which contain abundant sulfide minerals including pyrite (FeS2) and sphalerite (ZnS). Low d34Spyrite values (average -28.8 per mill) agree with bacterial sulfate reduction and subsequent pyrite formation. Stable sulfur isotopic compositions of sulfate bound in carbonate fluorapatite are lower than that of sulfate from ambient sea water, suggesting bacterial reoxidation of sulfide by sulfide-oxidizing bacteria. The release of phosphorus and subsequent formation of the autochthonous phosphatic laminites are apparently caused by the activity of sulfate-reducing bacteria and associated sulfide-oxidizing bacteria. Following an extraction-phosphorite dissolution-extraction procedure, molecular fossils of sulfate-reducing bacteria (mono-O-alkyl glycerol ethers, di-O-alkyl glycerol ethers, as well as the short-chain branched fatty acids i/ai-C15:0, i/ai-C17:0 and 10MeC16:0) are found to be among the most abundant compounds. The fact that these molecular fossils of sulfate-reducing bacteria are distinctly more abundant after dissolution of the phosphatic laminite reveals that the lipids are tightly bound to the mineral lattice of carbonate fluorapatite. Moreover, compared with the autochthonous laminite, molecular fossils of sulfate-reducing bacteria are: (1) significantly less abundant and (2) not as tightly bound to the mineral lattice in the other, allochthonous facies of the Peruvian crusts consisting of phosphatic coated grains. These observations confirm the importance of sulfate-reducing bacteria in the formation of the phosphatic laminite. Model calculations highlight that organic matter degradation by sulfate-reducing bacteria has the potential to liberate sufficient phosphorus for phosphogenesis.

El fratricidio en las Crónicas del Canciller Ayala y en El Victorial de Díaz de Games

Se analiza la lucha fratricida entre Pedro I y Enrique II de Castilla a la luz del "Cuento de los Reyes" inserto en El Victorial, de Gutierre Díaz de Games, y de las Crónicas de Pero López de Ayala. En el transcurso de una guerra civil, inscripta en un conflicto aún mayor, la Guerra de los Cien Años, dos reyes luchan por la misma corona. Ya que Pedro I tiene un origen claramente legítimo, los cronistas, favorables al usurpador Enrique, deben crear para éste una legitimidad, basada en este caso en la denuncia del profundo daño que causa al reino la notoria inconducta del rey legítimo. Una vez perpetrado el doble crimen que significa el asesinato de Pedro a manos de Enrique ?a la vez fratricidio y regicidio? se ejerce la violencia en su función fundacional, instaurando a la vez un nuevo reinado y una nueva dinastía. Por otra parte, lo que sucede en la cúspide de la sociedad se repite en otros niveles, ya que en la guerra civil también se cometerían fratricidios, porque el enemigo no es el Otro, sino un Igual.

Las representaciones de la alteridad en El Victorial de Gutierre Díaz de Games

Fil: Chicote, Gloria Beatriz. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación; Argentina.

Las representaciones de la alteridad en El Victorial de Gutierre Díaz de Games

Fil: Chicote, Gloria Beatriz. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación; Argentina.

Las representaciones de la alteridad en El Victorial de Gutierre Díaz de Games

Fil: Chicote, Gloria Beatriz. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación; Argentina.

El fratricidio en las Crónicas del Canciller Ayala y en El Victorial de Díaz de Games

Se analiza la lucha fratricida entre Pedro I y Enrique II de Castilla a la luz del "Cuento de los Reyes" inserto en El Victorial, de Gutierre Díaz de Games, y de las Crónicas de Pero López de Ayala. En el transcurso de una guerra civil, inscripta en un conflicto aún mayor, la Guerra de los Cien Años, dos reyes luchan por la misma corona. Ya que Pedro I tiene un origen claramente legítimo, los cronistas, favorables al usurpador Enrique, deben crear para éste una legitimidad, basada en este caso en la denuncia del profundo daño que causa al reino la notoria inconducta del rey legítimo. Una vez perpetrado el doble crimen que significa el asesinato de Pedro a manos de Enrique ?a la vez fratricidio y regicidio? se ejerce la violencia en su función fundacional, instaurando a la vez un nuevo reinado y una nueva dinastía. Por otra parte, lo que sucede en la cúspide de la sociedad se repite en otros niveles, ya que en la guerra civil también se cometerían fratricidios, porque el enemigo no es el Otro, sino un Igual.