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

Pathotypic diversity of Hyaloperonospora brassicae collected from Brassica oleracea

Downy mildew caused by Hyaloperonospora brassicae is an economically destructive disease of brassica crops in many growing regions throughout the world. Specialised pathogenicity of downy mildews from different Brassica species and closely related ornamental or wild relatives has been described from host range studies. Pathotypic variation amongst Hyaloperonospora brassicae isolates from Brassica oleracea has also been described; however, a standard set of B. oleracea lines that could enable reproducible classification of H. brassicae pathotypes was poorly developed. For this purpose, we examined the use of eight genetically refined host lines derived from our previous collaborative work on downy mildew resistance as a differential set to characterise pathotypes in the European population of H. brassicae. Interaction phenotypes for each combination of isolate and host line were assessed following drop inoculation of cotyledons and a spectrum of seven phenotypes was observed based on the level of sporulation on cotyledons and visible host responses. Two host lines were resistant or moderately resistant to the entire collection of isolates, and another was universally susceptible. Five lines showed differential responses to the H. brassicae isolates. A minimum of six pathotypes and five major effect resistance genes are proposed to explain all of the observed interaction phenotypes. The B. oleracea lines from this study can be useful for monitoring pathotype frequencies in H. brassicae populations in the same or other vegetable growing regions, and to assess the potential durability of disease control from different combinations of the predicted downy mildew resistance genes

Negative outcomes evoke cyclic irrational decisions in Rock, Paper, Scissors

Rock, Paper, Scissors (RPS) represents a unique gaming space in which the predictions of human rational decision-making can be compared with actual performance. Playing a computerized opponent adopting a mixed-strategy equilibrium, participants revealed a non-significant tendency to over-select Rock. Further violations of rational decision-making were observed using an inter-trial analysis where participants were more likely to switch their item selection at trial n + 1 following a loss or draw at trial n, revealing the strategic vulnerability of individuals following the experience of negative rather than positive outcome. Unique switch strategies related to each of these trial n outcomes were also identified: after losing participants were more likely to ‘downgrade’ their item (e.g., Rock followed by Scissors) but after drawing participants were more likely to ‘upgrade’ their item (e.g., Rock followed by Paper). Further repetition analysis revealed that participants were more likely to continue their specific cyclic item change strategy into trial n + 2. The data reveal the strategic vulnerability of individuals following the experience of negative rather than positive outcome, the tensions between behavioural and cognitive influences on decision making, and underline the dangers of increased behavioural predictability in other recursive, non-cooperative environments such as economics and politics

Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 × 10(-61) ), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers

Patient and health service delay in the diagnosis of pulmonary tuberculosis in Ethiopia

BACKGROUND: Delay in the diagnosis of tuberculosis may worsen the disease, increase the risk of death and enhance tuberculosis transmission in the community. This study aims to determine the length of delay between the onset of symptoms and patients first visit to health care (patient delay), and the length of delay between health care visit and the diagnosis of tuberculosis (health service delay). METHODS: A cross sectional survey that included all the public health centres was conducted in Addis Ababa from August 1 to December 31 1998. Patients were interviewed on the same day of diagnosis using structured questionnaire. RESULTS: 700 pulmonary TB patients were studied. The median patient delay was 60 days and mean 78.2 days. There was no significant difference in socio-demographic factors in those who delayed and came earlier among smear positives. However, there was a significant difference in distance from home to health institute and knowledge about TB treatment among the smear negatives. The health service delay was low (median 6 days; mean 9.5 days) delay was significantly lower in smear positives compared to smear negatives. Longer health service delay (delay more than 15 days) was associated with far distance. CONCLUSIONS: The time before diagnosis in TB patients was long and appears to be associated with patient inadequate knowledge of TB treatment and distance to the health centre. Further decentralization of TB services, the use of some components of active case finding, and raising public awareness of the disease to increase service utilization are recommended

The effectiveness of a multidisciplinary intervention strategy for the treatment of symptomatic joint hypermobility in childhood:A randomised, single Centre parallel group trial (The Bendy Study)

Introduction: Joint hypermobility is common in childhood and can be associated with musculoskeletal pain and dysfunction. Current management is delivered by a multidisciplinary team, but evidence of effectiveness is limited. This clinical trial aimed to determine whether a structured multidisciplinary, multisite intervention resulted in improved clinical outcomes compared with standard care. Method: A prospective randomised, single centre parallel group trial comparing an 8-week individualised multidisciplinary intervention programme (bespoke physiotherapy and occupational therapy in the clinical, home and school environment) with current standard management (advice, information and therapy referral if deemed necessary). The primary endpoint of the study was between group difference in child reported pain from baseline to 12 months as assessed using the Wong Baker faces pain scale. Secondary endpoints were parent reported pain (100 mm visual analogue scale), parent reported function (child health assessment questionnaire), child reported quality of life (child health utility 9-dimensional assessment), coordination (movement assessment battery for children version 2) and grip strength (handheld dynamometer). Results: 119 children aged 5 to 16 years, with symptomatic hypermobility were randomised to receive an individualised multidisciplinary intervention (I) (n = 59) or standard management (S) (n = 60). Of these, 105 completed follow up at 12 months. No additional significant benefit could be shown from the intervention compared to standard management. However, there was a statistically significant improvement in child and parent reported pain, coordination and grip strength in both groups. The response was independent of the degree of hypermobility. Conclusion: This is the first randomised controlled trial to compare a structured multidisciplinary, multisite intervention with standard care in symptomatic childhood hypermobility. For the majority, the provision of education and positive interventions aimed at promoting healthy exercise and self-management was associated with significant benefit without the need for more complex interventions. Trial registration: The trial was registered prospectively with the national database at the Clinical Research Network (UKCRN Portfolio 9366). The trial was registered retrospectively with ISRCTN (ISRCTN86573140)

Asteroseismology and Interferometry

Asteroseismology provides us with a unique opportunity to improve our understanding of stellar structure and evolution. Recent developments, including the first systematic studies of solar-like pulsators, have boosted the impact of this field of research within Astrophysics and have led to a significant increase in the size of the research community. In the present paper we start by reviewing the basic observational and theoretical properties of classical and solar-like pulsators and present results from some of the most recent and outstanding studies of these stars. We centre our review on those classes of pulsators for which interferometric studies are expected to provide a significant input. We discuss current limitations to asteroseismic studies, including difficulties in mode identification and in the accurate determination of global parameters of pulsating stars, and, after a brief review of those aspects of interferometry that are most relevant in this context, anticipate how interferometric observations may contribute to overcome these limitations. Moreover, we present results of recent pilot studies of pulsating stars involving both asteroseismic and interferometric constraints and look into the future, summarizing ongoing efforts concerning the development of future instruments and satellite missions which are expected to have an impact in this field of research.Comment: Version as published in The Astronomy and Astrophysics Review, Volume 14, Issue 3-4, pp. 217-36

Optimization of Immunoglobulin Substitution Therapy by a Stochastic Immune Response Model

Background: The immune system is a complex adaptive system of cells and molecules that are interwoven in a highly organized communication network. Primary immune deficiencies are disorders in which essential parts of the immune system are absent or do not function according to plan. X-linked agammaglobulinemia is a B-lymphocyte maturation disorder in which the production of immunoglobulin is prohibited by a genetic defect. Patients have to be put on life-long immunoglobulin substitution therapy in order to prevent recurrent and persistent opportunistic infections. Methodology: We formulate an immune response model in terms of stochastic differential equations and perform a systematic analysis of empirical therapy protocols that differ in the treatment frequency. The model accounts for the immunoglobulin reduction by natural degradation and by antigenic consumption, as well as for the periodic immunoglobulin replenishment that gives rise to an inhomogeneous distribution of immunoglobulin specificities in the shape space. Results are obtained from computer simulations and from analytical calculations within the framework of the Fokker-Planck formalism, which enables us to derive closed expressions for undetermined model parameters such as the infection clearance rate. Conclusions: We find that the critical value of the clearance rate, below which a chronic infection develops, is strongly dependent on the strength of fluctuations in the administered immunoglobulin dose per treatment and is an increasing function of the treatment frequency. The comparative analysis of therapy protocols with regard to the treatment frequency yields quantitative predictions of therapeutic relevance, where the choice of the optimal treatment frequency reveals a conflict of competing interests: In order to diminish immunomodulatory effects and to make good economic sense, therapeutic immunoglobulin levels should be kept close to physiological levels, implying high treatment frequencies. However, clearing infections without additional medication is more reliably achieved by substitution therapies with low treatment frequencies. Our immune response model predicts that the compromise solution of immunoglobulin substitution therapy has a treatment frequency in the range from one infusion per week to one infusion per two weeks

Angular-momentum coupling through the tachocline

Astronomical observation of stellar rotation suggests that at least the surface layers of the Sun have lost a substantial amount of the angular momentum that they possessed at the beginning of the main-sequence phase of evolution; and solar-wind observations indicate that magnetic coupling is still draining angular momentum from the Sun today. In addition, helioseismological analysis has shown that the specific angular momentum at the top of the almost uniformly rotating radiative interior is approximately (although not exactly) the same as the spherically averaged value at the base of the (differentially rotating) convection zone, suggesting that angular momentum is being transported through the tachocline. The mechanism by which that transport is taking place is not understood. Nor is there a consensus of opinion. I review some of the suggestions that have been put forward, biassing my discussion, no doubt, according to my own opinions.Comment: 19 pages, 7 figures, conference on `Magnetic coupling between the interior and the atmosphere of the Sun' ed. S. S. Hasan and R. J. Rutten, Bangalore, December 200

Effects of Simulated Microgravity on Embryonic Stem Cells

There have been many studies on the biological effects of simulated microgravity (SMG) on differentiated cells or adult stem cells. However, there has been no systematic study on the effects of SMG on embryonic stem (ES) cells. In this study, we investigated various effects (including cell proliferation, cell cycle distribution, cell differentiation, cell adhesion, apoptosis, genomic integrity and DNA damage repair) of SMG on mouse embryonic stem (mES) cells. Mouse ES cells cultured under SMG condition had a significantly reduced total cell number compared with cells cultured under 1 g gravity (1G) condition. However, there was no significant difference in cell cycle distribution between SMG and 1G culture conditions, indicating that cell proliferation was not impaired significantly by SMG and was not a major factor contributing to the total cell number reduction. In contrast, a lower adhesion rate cultured under SMG condition contributed to the lower cell number in SMG. Our results also revealed that SMG alone could not induce DNA damage in mES cells while it could affect the repair of radiation-induced DNA lesions of mES cells. Taken together, mES cells were sensitive to SMG and the major alterations in cellular events were cell number expansion, adhesion rate decrease, increased apoptosis and delayed DNA repair progression, which are distinct from the responses of other types of cells to SMG