CYberinfrastructure for COmparative effectiveness REsearch (CYCORE): improving data from cancer clinical trials

Improved approaches and methodologies are needed to conduct comparative effectiveness research (CER) in oncology. While cancer therapies continue to emerge at a rapid pace, the review, synthesis, and dissemination of evidence-based interventions across clinical trials lag in comparison. Rigorous and systematic testing of competing therapies has been clouded by age-old problems: poor patient adherence, inability to objectively measure the environmental influences on health, lack of knowledge about patients’ lifestyle behaviors that may affect cancer’s progression and recurrence, and limited ability to compile and interpret the wide range of variables that must be considered in the cancer treatment. This lack of data integration limits the potential for patients and clinicians to engage in fully informed decision-making regarding cancer prevention, treatment, and survivorship care, and the translation of research results into mainstream medical care. Particularly important, as noted in a 2009 report on CER to the President and Congress, the limited focus on health behavior-change interventions was a major hindrance in this research landscape (DHHS 2009). This paper describes an initiative to improve CER for cancer by addressing several of these limitations. The Cyberinfrastructure for Comparative Effectiveness Research (CYCORE) project, informed by the National Science Foundation’s 2007 report “Cyberinfrastructure Vision for 21st Century Discovery” has, as its central aim, the creation of a prototype for a user-friendly, open-source cyberinfrastructure (CI) that supports acquisition, storage, visualization, analysis, and sharing of data important for cancer-related CER. Although still under development, the process of gathering requirements for CYCORE has revealed new ways in which CI design can significantly improve the collection and analysis of a wide variety of data types, and has resulted in new and important partnerships among cancer researchers engaged in advancing health-related CI

A pilot study comparing the metabolic profiles of elite-level athletes from different sporting disciplines

Background: The outstanding performance of an elite athlete might be associated with changes in their blood metabolic profile. The aims of this study were to compare the blood metabolic profiles between moderate- and high-power and endurance elite athletes and to identify the potential metabolic pathways underlying these differences. Methods: Metabolic profiling of serum samples from 191 elite athletes from different sports disciplines (121 high- and 70 moderate-endurance athletes, including 44 high- and 144 moderate-power athletes), who participated in national or international sports events and tested negative for doping abuse at anti-doping laboratories, was performed using non-targeted metabolomics-based mass spectroscopy combined with ultrahigh-performance liquid chromatography. Multivariate analysis was conducted using orthogonal partial least squares discriminant analysis. Differences in metabolic levels between high- and moderate-power and endurance sports were assessed by univariate linear models. Results: Out of 743 analyzed metabolites, gamma-glutamyl amino acids were significantly reduced in both high-power and high-endurance athletes compared to moderate counterparts, indicating active glutathione cycle. High-endurance athletes exhibited significant increases in the levels of several sex hormone steroids involved in testosterone and progesterone synthesis, but decreases in diacylglycerols and ecosanoids. High-power athletes had increased levels of phospholipids and xanthine metabolites compared to moderate-power counterparts. Conclusions: This pilot data provides evidence that high-power and high-endurance athletes exhibit a distinct metabolic profile that reflects steroid biosynthesis, fatty acid metabolism, oxidative stress, and energy-related metabolites. Replication studies are warranted to confirm differences in the metabolic profiles associated with athletes’ elite performance in independent data sets, aiming ultimately for deeper understanding of the underlying biochemical processes that could be utilized as biomarkers with potential therapeutic implications

Perturbations of nuclear C*-algebras

Kadison and Kastler introduced a natural metric on the collection of all C*-subalgebras of the bounded operators on a separable Hilbert space. They conjectured that sufficiently close algebras are unitarily conjugate. We establish this conjecture when one algebra is separable and nuclear. We also consider one-sided versions of these notions, and we obtain embeddings from certain near inclusions involving separable nuclear C*-algebras. At the end of the paper we demonstrate how our methods lead to improved characterisations of some of the types of algebras that are of current interest in the classification programme.Comment: 45 page

Increased HIV Incidence in Men Who Have Sex with Men Despite High Levels of ART-Induced Viral Suppression: Analysis of an Extensively Documented Epidemic

Background: There is interest in expanding ART to prevent HIV transmission, but in the group with the highest levels of ART use, men-who-have-sex-with-men (MSM), numbers of new infections diagnosed each year have not decreased as ART coverage has increased for reasons which remain unclear. Methods: We analysed data on the HIV-epidemic in MSM in the UK from a range of sources using an individual-based simulation model. Model runs using parameter sets found to result in good model fit were used to infer changes in HIV-incidence and risk behaviour. Results: HIV-incidence has increased (estimated mean incidence 0.30/100 person-years 1990–1997, 0.45/100 py 1998–2010), associated with a modest (26%) rise in condomless sex. We also explored counter-factual scenarios: had ART not been introduced, but the rise in condomless sex had still occurred, then incidence 2006–2010 was 68% higher; a policy of ART initiation in all diagnosed with HIV from 2001 resulted in 32% lower incidence; had levels of HIV testing been higher (68% tested/year instead of 25%) incidence was 25% lower; a combination of higher testing and ART at diagnosis resulted in 62% lower incidence; cessation of all condom use in 2000 resulted in a 424% increase in incidence. In 2010, we estimate that undiagnosed men, the majority in primary infection, accounted for 82% of new infections. Conclusion: A rise in HIV-incidence has occurred in MSM in the UK despite an only modest increase in levels of condomless sex and high coverage of ART. ART has almost certainly exerted a limiting effect on incidence. Much higher rates of HIV testing combined with initiation of ART at diagnosis would be likely to lead to substantial reductions in HIV incidence. Increased condom use should be promoted to avoid the erosion of the benefits of ART and to prevent other serious sexually transmitted infections

The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin

Tetherin (CD317/BST2) is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles. Several mammalian viruses have evolved countermeasures that inactivate tetherin, with the prototype being the HIV-1 Vpu protein. Here we show that the human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is sensitive to tetherin restriction and its activity is counteracted by the KSHV encoded RING-CH E3 ubiquitin ligase K5. Tetherin expression in KSHV-infected cells inhibits viral particle release, as does depletion of K5 protein using RNA interference. K5 induces a species-specific downregulation of human tetherin from the cell surface followed by its endosomal degradation. We show that K5 targets a single lysine (K18) in the cytoplasmic tail of tetherin for ubiquitination, leading to relocalization of tetherin to CD63-positive endosomal compartments. Tetherin degradation is dependent on ESCRT-mediated endosomal sorting, but does not require a tyrosine-based sorting signal in the tetherin cytoplasmic tail. Importantly, we also show that the ability of K5 to substitute for Vpu in HIV-1 release is entirely dependent on K18 and the RING-CH domain of K5. By contrast, while Vpu induces ubiquitination of tetherin cytoplasmic tail lysine residues, mutation of these positions has no effect on its antagonism of tetherin function, and residual tetherin is associated with the trans-Golgi network (TGN) in Vpu-expressing cells. Taken together our results demonstrate that K5 is a mechanistically distinct viral countermeasure to tetherin-mediated restriction, and that herpesvirus particle release is sensitive to this mode of antiviral inhibition

Access and utilisation of maternity care for disabled women who experience domestic abuse:a systematic review

BACKGROUND: Although disabled women are significantly more likely to experience domestic abuse during pregnancy than non-disabled women, very little is known about how maternity care access and utilisation is affected by the co-existence of disability and domestic abuse. This systematic review of the literature explored how domestic abuse impacts upon disabled women’s access to maternity services. METHODS: Eleven articles were identified through a search of six electronic databases and data were analysed to identify: the factors that facilitate or compromise access to care; the consequences of inadequate care for pregnant women’s health and wellbeing; and the effectiveness of existing strategies for improvement. RESULTS: Findings indicate that a mental health diagnosis, poor relationships with health professionals and environmental barriers can compromise women’s utilisation of maternity services. Domestic abuse can both compromise, and catalyse, access to services and social support is a positive factor when accessing care. Delayed and inadequate care has adverse effects on women’s physical and psychological health, however further research is required to fully explore the nature and extent of these consequences. Only one study identified strategies currently being used to improve access to services for disabled women experiencing abuse. CONCLUSIONS: Based upon the barriers and facilitators identified within the review, we suggest that future strategies for improvement should focus on: understanding women’s reasons for accessing care; fostering positive relationships; being women-centred; promoting environmental accessibility; and improving the strength of the evidence base

Comparison of digital and conventional impression techniques: evaluation of patients’ perception, treatment comfort, effectiveness and clinical outcomes

Background: The purpose of this study was to compare two impression techniques from the perspective of patient preferences and treatment comfort.Methods: Twenty-four (12 male, 12 female) subjects who had no previous experience with either conventional or digital impression participated in this study. Conventional impressions of maxillary and mandibular dental arches were taken with a polyether impression material (Impregum, 3 M ESPE), and bite registrations were made with polysiloxane bite registration material (Futar D, Kettenbach). Two weeks later, digital impressions and bite scans were performed using an intra-oral scanner (CEREC Omnicam, Sirona). Immediately after the impressions were made, the subjects' attitudes, preferences and perceptions towards impression techniques were evaluated using a standardized questionnaire. The perceived source of stress was evaluated using the State-Trait Anxiety Scale. Processing steps of the impression techniques (tray selection, working time etc.) were recorded in seconds. Statistical analyses were performed with the Wilcoxon Rank test, and p < 0.05 was considered significant.Results: There were significant differences among the groups (p < 0.05) in terms of total working time and processing steps. Patients stated that digital impressions were more comfortable than conventional techniques.Conclusions: Digital impressions resulted in a more time-efficient technique than conventional impressions. Patients preferred the digital impression technique rather than conventional techniques

Progestin Receptor-Mediated Reduction of Anxiety-Like Behavior in Male Rats

BACKGROUND: It is well known progesterone can have anxiolytic-like effects in animals in a number of different behavioral testing paradigms. Although progesterone is known to influence physiology and behavior by binding to classical intracellular progestin receptors, progesterone's anxiety reducing effects have solely been attributed to its rapid non-genomic effects at the GABA A receptor. This modulation occurs following the bioconversion of progesterone to allopregnanolone. Seemingly paradoxical results from some studies suggested that the function of progesterone to reduce anxiety-like behavior may not be entirely clear; therefore, we hypothesized that progesterone might also act upon progestin receptors to regulate anxiety. METHODOLOGY/PRINCIPAL FINDINGS: To test this, we examined the anxiolytic-like effects of progesterone in male rats using the elevated plus maze, a validated test of anxiety, and the light/dark chamber in the presence or absence of a progestin receptor antagonist, RU 486. Here we present evidence suggesting that the anxiolytic-like effects of progesterone in male rats can be mediated, in part, by progestin receptors, as these effects are blocked by prior treatment with a progestin receptor antagonist. CONCLUSION/SIGNIFICANCE: This indicates that progesterone can act upon progestin receptors to regulate anxiety-like behavior in the male rat brain

Alexithymia in juvenile primary headache sufferers: a pilot study

Starting in the 1990s, there has been accumulating evidence of alexithymic characteristics in adult patients with primary headache. Little research has been conducted, however, on the relationship between alexithymia and primary headache in developmental age. In their research on alexithymia in the formative years, the authors identified one of the most promising prospects for research, as discussed here. The aim of this study was to verify whether there is: (a) a link between tension-type headache and alexithymia in childhood and early adolescence; and (b) a correlation between alexithymia in children/preadolescents and their mothers. This study was based on an experimental group of 32 patients (26 females and 6 males, aged from 8 to 15 years, mean 11.2 ± 2.0) suffering from tension-type headache and 32 control subjects (26 females and 6 males, aged from 8 to 15 years, mean 11.8 ± 1.6). Tension-type headache was diagnosed by applying the International Headache Classification (ICHD-II, 2004). The alexithymic construct was measured using an Italian version of the Alexithymia Questionnaire for Children in the case of the juvenile patients and the Toronto Alexithymia Scale (TAS-20) for their mothers. Higher rates of alexithymia were observed in the children/preadolescents in the experimental group (EG) than in the control group; in the EG there was no significant correlation between the alexithymia rates in the children/preadolescents and in their mothers

Modeling the Population-Level Effects of Male Circumcision as an HIV-Preventive Measure: A Gendered Perspective

BACKGROUND: Evidence from biological, epidemiological, and controlled intervention studies has demonstrated that male circumcision (MC) protects males from HIV infection, and MC is now advocated as a public-health intervention against HIV. MC provides direct protection only to men, but is expected to provide indirect protection to women at risk of acquiring HIV from heterosexual transmission. How such indirect protection interacts with the possibility that MC campaigns will lead to behavior changes, however, is not yet well understood. Our objective here is to investigate the link between individual-level effects of MC campaigns and long-term population-level outcomes resulting from disease dynamics, looking at both genders separately, over a broad range of parameters. METHODS AND FINDINGS: We use simple mathematical models of heterosexual transmission to investigate the potential effects of a circumcision scale-up, combined with possible associated behavioral disinhibition. We examine patterns in expected long-term prevalence using a simple equilibrium model based on transmission factors, and validate our results with ODE-based simulations, focusing on the link between effects on females and those on males.We find that the long-term population-level effects on females and males are not strongly linked: there are many possible ways in which an intervention which reduces prevalence in males might nonetheless increase prevalence in females. CONCLUSIONS: Since an intervention that reduces long-term male prevalence could nonetheless increase long-term female prevalence, MC campaigns should explicitly consider both the short-term and long-term effects of MC interventions on females. Our findings strongly underline the importance of pairing MC programs with education, support programs and HIV testing and counseling, together with other prevention measures