Examining hope as a transdiagnostic mechanism of change across anxiety disorders and CBT treatment protocols.

Hope is a trait that represents the capacity to identify strategies or pathways to achieve goals and the motivation or agency to effectively pursue those pathways. Hope has been demonstrated to be a robust source of resilience to anxiety and stress and there is limited evidence that, as has been suggested for decades, hope may function as a core process or transdiagnostic mechanism of change in psychotherapy. The current study examined the role of hope in predicting recovery in a clinical trial in which 223 individuals with 1 of 4 anxiety disorders were randomized to transdiagnostic cognitive behavior therapy (CBT), disorder-specific CBT, or a waitlist controlled condition. Effect size results indicated moderate to large intraindividual increases in hope, that changes in hope were consistent across the five CBT treatment protocols, that changes in hope were significantly greater in CBT relative to waitlist, and that changes in hope began early in treatment. Results of growth curve analyses indicated that CBT was a robust predictor of trajectories of change in hope compared to waitlist, and that changes in hope predicted changes in both self-reported and clinician-rated anxiety. Finally, a statistically significant indirect effect was found indicating that the effects of treatment on changes in anxiety were mediated by treatment effects on hope. Together, these results suggest that hope may be a promising transdiagnostic mechanism of change that is relevant across anxiety disorders and treatment protocols.R01 MH090053 - NIMH NIH HHSAccepted manuscrip

Global behavior of solutions to the static spherically symmetric EYM equations

The set of all possible spherically symmetric magnetic static Einstein-Yang-Mills field equations for an arbitrary compact semi-simple gauge group $G$ was classified in two previous papers. Local analytic solutions near the center and a black hole horizon as well as those that are analytic and bounded near infinity were shown to exist. Some globally bounded solutions are also known to exist because they can be obtained by embedding solutions for the $G=SU(2)$ case which is well understood. Here we derive some asymptotic properties of an arbitrary global solution, namely one that exists locally near a radial value $r_{0}$, has positive mass $m(r)$ at $r_{0}$ and develops no horizon for all $r>r_{0}$. The set of asymptotic values of the Yang-Mills potential (in a suitable well defined gauge) is shown to be finite in the so-called regular case, but may form a more complicated real variety for models obtained from irregular rotation group actions.Comment: 43 page

Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: a Phase I Multiple Myeloma Research Consortium study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92443/1/bjh9173.pd

Dissection of a Complex Disease Susceptibility Region Using a Bayesian Stochastic Search Approach to Fine Mapping.

Identification of candidate causal variants in regions associated with risk of common diseases is complicated by linkage disequilibrium (LD) and multiple association signals. Nonetheless, accurate maps of these variants are needed, both to fully exploit detailed cell specific chromatin annotation data to highlight disease causal mechanisms and cells, and for design of the functional studies that will ultimately be required to confirm causal mechanisms. We adapted a Bayesian evolutionary stochastic search algorithm to the fine mapping problem, and demonstrated its improved performance over conventional stepwise and regularised regression through simulation studies. We then applied it to fine map the established multiple sclerosis (MS) and type 1 diabetes (T1D) associations in the IL-2RA (CD25) gene region. For T1D, both stepwise and stochastic search approaches identified four T1D association signals, with the major effect tagged by the single nucleotide polymorphism, rs12722496. In contrast, for MS, the stochastic search found two distinct competing models: a single candidate causal variant, tagged by rs2104286 and reported previously using stepwise analysis; and a more complex model with two association signals, one of which was tagged by the major T1D associated rs12722496 and the other by rs56382813. There is low to moderate LD between rs2104286 and both rs12722496 and rs56382813 (r2 ≃ 0:3) and our two SNP model could not be recovered through a forward stepwise search after conditioning on rs2104286. Both signals in the two variant model for MS affect CD25 expression on distinct subpopulations of CD4+ T cells, which are key cells in the autoimmune process. The results support a shared causal variant for T1D and MS. Our study illustrates the benefit of using a purposely designed model search strategy for fine mapping and the advantage of combining disease and protein expression data.We acknowledge use of DNA from The UK Blood Services collection of Common Controls (UKBS-CC collection), which is funded by the Wellcome Trust grant 076113/C/04/Z and by the USA National Institute for Health Research program grant to the National Health Service Blood and Transplant (RP-PG-0310-1002). We acknowledge the use of DNA from the British 1958 Birth Cohort collection, which is funded by the UK Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. This research utilized resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Human Genome Research Institute, the National Institute of Child Health and Human Development and the JDRF and is supported by the USA National Institutes of Health grant U01-DK062418. The JDRF/Wellcome Trust Diabetes and Inflammation Laboratory is funded by the JDRF (9-2011-253), the Wellcome Trust (091157) and the National Institute for Health Research Cambridge Biomedical Centre. The research leading to these results has received funding from the European Union's 7th Framework Programme (FP7/2007-2013) under grant agreement no.241447 (NAIMIT). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). CW is supported by the Wellcome Trust (089989). We acknowledge the National Institute for Health Research Cambridge Biomedical Research Centre for funding.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pgen.100527

Trajectories of change in well-being during cognitive-behavior therapies for anxiety disorders: quantifying the impact and covariation with improvements in anxiety

Despite substantial evidence supporting the efficacy of cognitive behavioral therapy for reducing many forms of mental illness, less is known about whether CBT also promotes mental health or well being. We will discuss results of a recent study (Gallagher et al., 2019) examining changes in well being d uring different CBT treatments for anxiety disorders and how these changes relate to anxiety. In that study, 223 adults (55.6% female, Mage=31.1 yrs) were randomized to one of five CBT protocols for anxiety disorders at an outpatient clinic. Effect sizes w ere calculated to examine the timing and magnitude of changes in well being as a result of CBT. Further, parallel process latent growth curve models were conducted to examine the extent to which trajectories of changes in well being correlated with the tra jectories of change in both clinician rated and self reported anxiety during active treatment. Results indicated that there were moderate to large increases in overall well being and the three components of subjective, psychological, and social well being, mainly during the second half of CBT, and these increases were maintained at a 6 month follow up. Further, trajectories of change in well being across treatment were strongly correlated with trajectories of change in clinician rated and self reported anxi ety. Together, these findings suggest that different CBT protocols for anxiety consistently produce robust and lasting changes in different domains of positive mental health and increases in well being are strongly linked to changes in anxiety during treatment.Published versio

Detection of enterovirus RNA in peripheral blood mononuclear cells correlates with the presence of the predisposing allele of the type 1 diabetes risk gene IFIH1 and with disease stage

Aims/hypothesis Enteroviral infection has been implicated consistently as a key environmental factor correlating with the appearance of autoimmunity and/or the presence of overt type 1 diabetes, in which pancreatic insulin-producing beta cells are destroyed by an autoimmune response. Genetic predisposition through variation in the type 1 diabetes risk gene IFIH1 (interferon induced with helicase C domain 1), which encodes the viral pattern-recognition receptor melanoma differentiation-associated protein 5 (MDA5), supports a potential link between enterovirus infection and type 1 diabetes. Methods We used molecular techniques to detect enterovirus RNA in peripheral blood samples (in separated cellular compartments or plasma) from two cohorts comprising 79 children or 72 adults that include individuals with and without type 1 diabetes who had multiple autoantibodies. We also used immunohistochemistry to detect the enteroviral protein VP1 in the pancreatic islets of post-mortem donors (n=43) with type 1 diabetes. Results We observed enhanced detection sensitivity when sampling the cellular compartment compared with the non-cellular compartment of peripheral blood (OR 21.69; 95% CI 3.64, 229.20; p Conclusions/interpretation Our data indicate that, in peripheral blood, antigen-presenting cells are the predominant source of enterovirus infection, and that infection is correlated with disease stage and genetic predisposition, thereby supporting a role for enterovirus infection prior to disease onset.Peer reviewe

A comparative study of fragment screening methods on the p38α kinase: new methods, new insights

The stress-activated kinase p38α was used to evaluate a fragment-based drug discovery approach using the BioFocus fragment library. Compounds were screened by surface plasmon resonance (SPR) on a Biacore(™) T100 against p38α and two selectivity targets. A sub-set of our library was the focus of detailed follow-up analyses that included hit confirmation, affinity determination on 24 confirmed, selective hits and competition assays of these hits with respect to a known ATP binding site inhibitor. In addition, functional activity against p38α was assessed in a biochemical assay using a mobility shift platform (LC3000, Caliper LifeSciences). A selection of fragments was also evaluated using fluorescence lifetime (FLEXYTE(™)) and microscale thermophoresis (Nanotemper) technologies. A good correlation between the data for the different assays was found. Crystal structures were solved for four of the small molecules complexed to p38α. Interestingly, as determined both by X-ray analysis and SPR competition experiments, three of the complexes involved the fragment at the ATP binding site, while the fourth compound bound in a distal site that may offer potential as a novel drug target site. A first round of optimization around the remotely bound fragment has led to the identification of a series of triazole-containing compounds. This approach could form the basis for developing novel and active p38α inhibitors. More broadly, it illustrates the power of combining a range of biophysical and biochemical techniques to the discovery of fragments that facilitate the development of novel modulators of kinase and other drug targets. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10822-011-9454-9) contains supplementary material, which is available to authorized users