Case-control association testing by graphical modeling for the Genetic Analysis Workshop 17 mini-exome sequence data

We generalize recent work on graphical models for linkage disequilibrium to estimate the conditional independence structure between all variables for individuals in the Genetic Analysis Workshop 17 unrelated individuals data set. Using a stepwise approach for computational efficiency and an extension of our previously described methods, we estimate a model that describes the relationships between the disease trait, all quantitative variables, all covariates, ethnic origin, and the loci most strongly associated with these variables. We performed our analysis for the first 50 replicate data sets. We found that our approach was able to describe the relationships between the outcomes and covariates and that it could correctly detect associations of disease with several loci and with a reasonable false-positive detection rate

Forced Fox-P3 expression can improve the safety and antigen-specific function of engineered regulatory T cells

Regulatory T cells (Treg) are potent inhibitors of autoreactive T cells. The intracellular transcription factor FoxP3 controls the expression levels of a diverse set of genes and plays a critical role in programming functional Tregs. Although, antigen-specific Tregs are more potent than polyclonal Tregs in treating ongoing autoimmunity, phenotype plasticity associated with loss of FoxP3 expression in Tregs can lead to the conversion into antigen-specific effector T cells which might exacerbate autoimmune pathology. In this study, we designed a retroviral vector driving the expression of FoxP3 and a human HLA-DR-restricted TCR from the same promoter. Transduction of purified human Tregs revealed that all TCR-positive cells had elevated levels of FoxP3 expression, increased CD25 and CTLA4 expression and potent suppressive function. Elevated FoxP3 expression did not impair the in vitro expansion of engineered Tregs. Adoptive transfer into HLA-DR transgenic mice revealed that FoxP3+TCR engineered Tregs showed long-term persistence with stable FoxP3 and TCR expression. In contrast, adoptive transfer of Tregs engineered with TCR only resulted in the accumulation of TCR-positive, FoxP3-negative T cells which displayed antigen-specific effector function when stimulated with the TCR-recognised peptides. Our data indicate that forced expression of FoxP3 can prevent accumulation of antigen-specific effector T cells without impairing the engraftment and persistence of engineered Tregs

Theoretical Models of Sunspot Structure and Dynamics

Recent progress in theoretical modeling of a sunspot is reviewed. The observed properties of umbral dots are well reproduced by realistic simulations of magnetoconvection in a vertical, monolithic magnetic field. To understand the penumbra, it is useful to distinguish between the inner penumbra, dominated by bright filaments containing slender dark cores, and the outer penumbra, made up of dark and bright filaments of comparable width with corresponding magnetic fields differing in inclination by some 30 degrees and strong Evershed flows in the dark filaments along nearly horizontal or downward-plunging magnetic fields. The role of magnetic flux pumping in submerging magnetic flux in the outer penumbra is examined through numerical experiments, and different geometric models of the penumbral magnetic field are discussed in the light of high-resolution observations. Recent, realistic numerical MHD simulations of an entire sunspot have succeeded in reproducing the salient features of the convective pattern in the umbra and the inner penumbra. The siphon-flow mechanism still provides the best explanation of the Evershed flow, particularly in the outer penumbra where it often consists of cool, supersonic downflows.Comment: To appear in "Magnetic Coupling between the Interior and the Atmosphere of the Sun", eds. S.S. Hasan and R.J. Rutten, Astrophysics and Space Science Proceedings, Springer-Verlag, Heidelberg, Berlin, 200

The Hagedorn spectrum and large NcN_c QCD in 2+1 and 3+1 dimensions

We show that a Hagedorn spectrum (i.e., spectrum where the number of hadrons grows exponentially with the mass) emerges automatically in large $N_c$ QCD in 2+1 and 3+1 dimensions. The approach is based on the study of Euclidean space correlation functions for composite operators constructed from quark and gluon fields and exploits the fact that the short time behavior of the correlators is known in QCD. The demonstration relies on one critical assumption: that perturbation theory accurately describes the trace of the logarithm of a matrix of point-to-point correlation functions in the regime where the perturbative corrections to the asymptotically free value are small.Comment: 18 pages, 5 figure

Eurythmy Therapy in clinical studies: a systematic literature review

<p>Abstract</p> <p>Background</p> <p>We aimed to overview the current literature on eurythmy therapy (EYT) which is an integral part of Anthroposophic Medicine. EYT can be described as a movement therapy in which speech movements are transposed into exercises which address the patient's capability to soul expression and strengthen his salutogenetic resources.</p> <p>Methods</p> <p>We searched several databases such as Cochrane, EMBASE, NCCAM, NLM, DIMDI, CAMbase, and Medline for case-control studies, cohort studies and randomised controlled trials on the treatment effects of EYT in a clinical setting. In a second search we included journal databases from Karger, Kluwer, Springer, Thieme, and Merkurstab archive.</p> <p>Results</p> <p>We found 8 citations which met the inclusion criterion: 4 publications referring to a prospective cohort study without control group (the AMOS study), and 4 articles referring to 2 explorative pre-post studies without control group, 1 prospective, non-randomized comparative study, and 1 descriptive study with a control group. The methodological quality of studies ranged in from poor to good, and in sample size from 5 to 898 patients. In most studies, EYT was used as an add-on, not as a mono-therapy. The studies described positive treatment effects with clinically relevant effect sizes in most cases.</p> <p>Conclusion</p> <p>Indications, study designs and the usage of additional treatments within the identified studies were quite heterogeneous. Despite of this, EYT can be regarded as a potentially relevant add-on in a therapeutic concept, although its specific relevance remains to be clarified. Well performed controlled studies on this unique treatment are highly recommended.</p

Bridging the data gaps in the epidemiology of hepatitis C virus infection in Malaysia using multi-parameter evidence synthesis

BACKGROUND: Collecting adequate information on key epidemiological indicators is a prerequisite to informing a public health response to reduce the impact of hepatitis C virus (HCV) infection in Malaysia. Our goal was to overcome the acute data shortage typical of low/middle income countries using statistical modelling to estimate the national HCV prevalence and the distribution over transmission pathways as of the end of 2009. METHODS: Multi-parameter evidence synthesis methods were applied to combine all available relevant data sources - both direct and indirect - that inform the epidemiological parameters of interest. RESULTS: An estimated 454,000 (95% credible interval [CrI]: 392,000 to 535,000) HCV antibody-positive individuals were living in Malaysia in 2009; this represents 2.5% (95% CrI: 2.2-3.0%) of the population aged 15-64 years. Among males of Malay ethnicity, for 77% (95% CrI: 69-85%) the route of probable transmission was active or a previous history of injecting drugs. The corresponding proportions were smaller for male Chinese and Indian/other ethnic groups (40% and 71%, respectively). The estimated prevalence in females of all ethnicities was 1% (95% CrI: 0.6 to 1.4%); 92% (95% CrI: 88 to 95%) of infections were attributable to non-drug injecting routes of transmission. CONCLUSIONS: The prevalent number of persons living with HCV infection in Malaysia is estimated to be very high. Low/middle income countries often lack a comprehensive evidence base; however, evidence synthesis methods can assist in filling the data gaps required for the development of effective policy to address the future public health and economic burden due to HCV. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0564-6) contains supplementary material, which is available to authorized users

Moving from evidence-based medicine to evidence-based health.

While evidence-based medicine (EBM) has advanced medical practice, the health care system has been inconsistent in translating EBM into improvements in health. Disparities in health and health care play out through patients' limited ability to incorporate the advances of EBM into their daily lives. Assisting patients to self-manage their chronic conditions and paying attention to unhealthy community factors could be added to EBM to create a broader paradigm of evidence-based health. A perspective of evidence-based health may encourage physicians to consider their role in upstream efforts to combat socially patterned chronic disease