Results of a randomized, double-blind phase II clinical trial of NY-ESO-1 vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in participants with high-risk resected melanoma.

BACKGROUND: To compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence. METHODS: Participants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity. RESULTS: The ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4+ and CD8+ responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)+/Human Leukocyte Antigen (HLA) class I+ double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants. CONCLUSIONS: The vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse

Risk-adjusted CUSUM control charts for shared frailty survival models with application to hip replacement outcomes: a study using the NJR dataset

Background:  Continuous monitoring of surgical outcomes after joint replacement is needed to detect which brands’ components have a higher than expected failure rate and are therefore no longer recommended to be used in surgical practice. We developed a monitoring method based on cumulative sum (CUSUM) chart specifically for this application.  Methods:  Our method entails the use of the competing risks model with the Weibull and the Gompertz hazard functions adjusted for observed covariates to approximate the baseline time-to-revision and time-to-death distributions, respectively. The correlated shared frailty terms for competing risks, corresponding to the operating unit, are also included in the model. A bootstrap-based boundary adjustment is then required for risk-adjusted CUSUM charts to guarantee a given probability of the false alarm rates. We propose a method to evaluate the CUSUM scores and the adjusted boundary for a survival model with the shared frailty terms. We also introduce a unit performance quality score based on the posterior frailty distribution. This method is illustrated using the 2003-2012 hip replacement data from the UK National Joint Registry (NJR). Results:  We found that the best model included the shared frailty for revision but not for death. This means that the competing risks of revision and death are independent in NJR data. Our method was superior to the standard NJR methodology. For one of the two monitored components, it produced alarms four years before the increased failure rate came to the attention of the UK regulatory authorities. The hazard ratios of revision across the units varied from 0.38 to 2.28. Conclusions:  An earlier detection of failure signal by our method in comparison to the standard method used by the NJR may be explained by proper risk-adjustment and the ability to accommodate time-dependent hazards. The continuous monitoring of hip replacement outcomes should include risk adjustment at both the individual and unit level

The evolution of rotating stars

First, we review the main physical effects to be considered in the building of evolutionary models of rotating stars on the Upper Main-Sequence (MS). The internal rotation law evolves as a result of contraction and expansion, meridional circulation, diffusion processes and mass loss. In turn, differential rotation and mixing exert a feedback on circulation and diffusion, so that a consistent treatment is necessary. We review recent results on the evolution of internal rotation and the surface rotational velocities for stars on the Upper MS, for red giants, supergiants and W-R stars. A fast rotation is enhancing the mass loss by stellar winds and reciprocally high mass loss is removing a lot of angular momentum. The problem of the ``break-up'' or $\Omega$-limit is critically examined in connection with the origin of Be and LBV stars. The effects of rotation on the tracks in the HR diagram, the lifetimes, the isochrones, the blue to red supergiant ratios, the formation of W-R stars, the chemical abundances in massive stars as well as in red giants and AGB stars, are reviewed in relation to recent observations for stars in the Galaxy and Magellanic Clouds. The effects of rotation on the final stages and on the chemical yields are examined, as well as the constraints placed by the periods of pulsars. On the whole, this review points out that stellar evolution is not only a function of mass M and metallicity Z, but of angular velocity $\Omega$ as well.Comment: 78 pages, 7 figures, review for Annual Review of Astronomy and Astrophysics, vol. 38 (2000

The Open AUC Project

Progress in analytical ultracentrifugation (AUC) has been hindered by obstructions to hardware innovation and by software incompatibility. In this paper, we announce and outline the Open AUC Project. The goals of the Open AUC Project are to stimulate AUC innovation by improving instrumentation, detectors, acquisition and analysis software, and collaborative tools. These improvements are needed for the next generation of AUC-based research. The Open AUC Project combines on-going work from several different groups. A new base instrument is described, one that is designed from the ground up to be an analytical ultracentrifuge. This machine offers an open architecture, hardware standards, and application programming interfaces for detector developers. All software will use the GNU Public License to assure that intellectual property is available in open source format. The Open AUC strategy facilitates collaborations, encourages sharing, and eliminates the chronic impediments that have plagued AUC innovation for the last 20 years. This ultracentrifuge will be equipped with multiple and interchangeable optical tracks so that state-of-the-art electronics and improved detectors will be available for a variety of optical systems. The instrument will be complemented by a new rotor, enhanced data acquisition and analysis software, as well as collaboration software. Described here are the instrument, the modular software components, and a standardized database that will encourage and ease integration of data analysis and interpretation software

The formation of garnet in olivine-bearing metagabbros from the Adirondacks

A regional study of olivine-bearing metagabbros in the Adirondacks has permitted testing of the P(pressure)-T(temperature)-X(composition) dependence of garnet-forming reactions as well as providing additional regional metamorphic pressure data. Six phases, olivine, orthopyroxene, clinopyroxene, garnet, plagioclase and spinel, which can be related by the reactions: orthopyroxene+clinopyroxene+spinel +anorthite=garnet, and forsterite+anorthite=garnet occur together both in coronal and in equant textures indicative of equilibrium. Compositions of the respective minerals are typically Fo 25–72 , En 44–75 , En 30–44 Fs 9–23 Wo 47–49 , Pp 13–42 Alm 39–63 Gr 16–20 , An 29–49 and Sp 16–58 . When they occur in the same rock, equant and coronal garnets are homogeneous and compositionally identical suggesting that chemical equilibrium may have been attained despite coronal textures. Extrapolating reactions in the simple CMAS system to granulite temperatures and making thermodynamic corrections for solid solutions gives equilibration pressures (using the thermometry of Bohlen et al. 1980b) ranging from about 6.5 kb in the Lowlands and southern Adirondacks to 7.0–8.0 kb in the Highlands for the assemblage olivine-plagioclase-garnet. These results are consistent with inferred peak metamorphic conditions in the Adirondacks (Valley and Bohlen 1979; Bohlen and Boettcher 1981). Thus the isobaric retrograde path suggested by Whitney and McLelland (1973) and Whitney (1978) for the formation of coronal garnet in olivine metagabbros may not be required. Application of the same equilibria gives >8.7 kb for South Harris, Scotland and 0.9 kb for the Nain Complex. Disagreement of the latter value with orthopyroxeneolivine-quartz barometry (Bohlen and Boettcher 1981) suggests that the use of iron-rich rocks (olivines ≧Fa 50 ) results in errors in calculated pressures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47335/1/410_2004_Article_BF00371301.pd

Design of erosion/abrasion studies - insights and rational concepts

In vitro and in situ studies modelling the wear of dental hard tissues due to erosion and abrasion are characterised by a high variation in study designs and experimental parameters. Based on a summary of the existing protocols, the present review aimed to describe and discuss the parameters which must be carefully considered in erosion-abrasion research, especially when it is intended to simulate clinical conditions. Experimental characteristics and parameters were retrieved from a total of 42 in vitro and 20 in situ studies. The key experimental characteristics included parameters of erosion (duration and pH) and abrasion (duration, kinds of toothbrush and toothpaste, brushing force, and time point) as well as co-factors (e.g. dental hard tissue). The majority of studies used models with alternating erosion/abrasion treatments intended to simulate clinical conditions, while other studies exaggerated clinical conditions intentionally, often using only a single erosion/abrasion treatment. Both in vitro and in situ models shared a high level of standardisation, but several studies showed a trend to severe erosion (e.g. >5 min/cycle) or extensive brushing (e.g. >100 brushing strokes/cycle) at a high frequency and repetition rate. Thus, studies often tend to produce a higher amount of wear than in the clinical situation, especially as modifying biological factors (e.g. the dilution of the erosive solution by saliva and the protective effect of the pellicle) cannot be simulated adequately. With respect to the existing models, it seems advisable to diminish duration and frequency of erosion and abrasion to more realistic clinical conditions when the everyday situation is to be simulated. Experimental parameters must be chosen with care to ensure that the problem is investigated in an appropriate mode at standardised conditions and with adequate measuring systems to allow prediction of clinical outcomes

Compliance & dexterity, factors to consider in home care and maintenance procedures Adherencia e destreza: factores a considerar en programas preventivos

Mechanical plaque control appears to be the primary means of controlling supragingival dental plaque build-up. Although daily oral hygiene practices and periodic professional care are considered the basis for any program aimed at the prevention and treatment of oral diseases, these procedures are technically demanding, time consuming and can be affected by the compliance and manual dexterity of the patient. Individual skills and acquired behavior patterns determine effectiveness of a preventive program and oral hygiene practice. Successful preventive programs and home care procedures clearly depend on the interaction and commitment between the dental professional and the patient. Identifying the capacity of the individual to comply with the professional recommendations and evaluating the dexterity of the patient to remove supragingival dental plaque will permit the implementation of an adequate preventive program and can help on the selection of adjunctive antimicrobial agents and devices needed to reach an effective oral care routine.<br>El control de la placa dental parece ser el mecanismo primario para controlar el crecimiento de la placa dental supragingival. Aunque la práctica diaria de la higiene bucal y el cuidado profesional periódico, son considerados la base para cualquier programa dirigido a la prevención y tratamiento de las enfermedades de la cavidad bucal, estos procedimientos son técnicamente exigentes, consumen tiempo y pueden ser afectados por la aceptación y la destreza manual del paciente. Las destrezas individuales y los patrones de comportamiento adquiridos, determinan la efectividad de un programa preventivo y la práctica de la higiene bucal. El éxito de los programas preventivos y los procedimientos del cuidado bucal en el hogar dependen claramente de la interacción y compromiso entre el odontólogo y el paciente. La importancia de identificar la capacidad del individuo para cumplir con las recomendaciones y la evaluación de la destreza del paciente para remover la placa dental supragingival, permitirán la implementación de un adecuado programa de prevención que podría ayudar a la selección de un agente antibacteriano coadyuvante y los dispositivos necesarios para alcanzar una rutina de cuidado bucal efectivo