Analysis of rolling group therapy data using conditionally autoregressive priors

Group therapy is a central treatment modality for behavioral health disorders such as alcohol and other drug use (AOD) and depression. Group therapy is often delivered under a rolling (or open) admissions policy, where new clients are continuously enrolled into a group as space permits. Rolling admissions policies result in a complex correlation structure among client outcomes. Despite the ubiquity of rolling admissions in practice, little guidance on the analysis of such data is available. We discuss the limitations of previously proposed approaches in the context of a study that delivered group cognitive behavioral therapy for depression to clients in residential substance abuse treatment. We improve upon previous rolling group analytic approaches by fully modeling the interrelatedness of client depressive symptom scores using a hierarchical Bayesian model that assumes a conditionally autoregressive prior for session-level random effects. We demonstrate improved performance using our method for estimating the variance of model parameters and the enhanced ability to learn about the complex correlation structure among participants in rolling therapy groups. Our approach broadly applies to any group therapy setting where groups have changing client composition. It will lead to more efficient analyses of client-level data and improve the group therapy research community's ability to understand how the dynamics of rolling groups lead to client outcomes.Comment: Published in at http://dx.doi.org/10.1214/10-AOAS434 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Polymer Translocation Dynamics in the Quasi-Static Limit

Monte Carlo (MC) simulations are used to study the dynamics of polymer translocation through a nanopore in the limit where the translocation rate is sufficiently slow that the polymer maintains a state of conformational quasi-equilibrium. The system is modeled as a flexible hard-sphere chain that translocates through a cylindrical hole in a hard flat wall. In some calculations, the nanopore is connected at one end to a spherical cavity. Translocation times are measured directly using MC dynamics simulations. For sufficiently narrow pores, translocation is sufficiently slow that the mean translocation time scales with polymer length N according to \propto (N-N_p)^2, where N_p is the average number of monomers in the nanopore; this scaling is an indication of a quasi-static regime in which polymer-nanopore friction dominates. We use a multiple-histogram method to calculate the variation of the free energy with Q, a coordinate used to quantify the degree of translocation. The free energy functions are used with the Fokker-Planck formalism to calculate translocation time distributions in the quasi-static regime. These calculations also require a friction coefficient, characterized by a quantity N_{eff}, the effective number of monomers whose dynamics are affected by the confinement of the nanopore. This was determined by fixing the mean of the theoretical distribution to that of the distribution obtained from MC dynamics simulations. The theoretical distributions are in excellent quantitative agreement with the distributions obtained directly by the MC dynamics simulations for physically meaningful values of N_{eff}. The free energy functions for narrow-pore systems exhibit oscillations with an amplitude that is sensitive to the nanopore length. Generally, larger oscillation amplitudes correspond to longer translocation times.Comment: 13 pages, 13 figure

Histone Acetylation-Mediated Regulation of the Hippo Pathway

The Hippo pathway is a signaling cascade recently found to play a key role in tumorigenesis therefore understanding the mechanisms that regulate it should open new opportunities for cancer treatment. Available data indicate that this pathway is controlled by signals from cell-cell junctions however the potential role of nuclear regulation has not yet been described. Here we set out to verify this possibility and define putative mechanism(s) by which it might occur. By using a luciferase reporter of the Hippo pathway, we measured the effects of different nuclear targeting drugs and found that chromatin-modifying agents, and to a lesser extent certain DNA damaging drugs, strongly induced activity of the reporter. This effect was not mediated by upstream core components (i.e. Mst, Lats) of the Hippo pathway, but through enhanced levels of the Hippo transducer TAZ. Investigation of the underlying mechanism led to the finding that cancer cell exposure to histone deacetylase inhibitors induced secretion of growth factors and cytokines, which in turn activate Akt and inhibit the GSK3 beta associated protein degradation complex in drug-affected as well as in their neighboring cells. Consequently, expression of EMT genes, cell migration and resistance to therapy were induced. These processes were suppressed by using pyrvinium, a recently described small molecule activator of the GSK 3 beta associated degradation complex. Overall, these findings shed light on a previously unrecognized phenomenon by which certain anti-cancer agents may paradoxically promote tumor progression by facilitating stabilization of the Hippo transducer TAZ and inducing cancer cell migration and resistance to therapy. Pharmacological targeting of the GSK3 beta associated degradation complex may thus represent a unique approach to treat cancer. © 2013 Basu et al

Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.

Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants

Terrane boundary reactivation, barriers to lateral fault propagation and reactivated fabrics - Rifting across the Median Batholith Zone, Great South Basin, New Zealand

Prominent pre‐existing structural heterogeneities within the lithosphere may localise or partition deformation during tectonic events. The NE‐trending Great South Basin, offshore New Zealand, formed perpendicular to a series of underlying crustal terranes, including the dominantly granitic Median Batholith Zone, which along with the boundaries between individual terranes, exert a strong control on rift physiography and kinematics. We find that the crustal‐to‐lithospheric scale southern terrane boundary of the Median Batholith Zone is associated with a crustal‐scale shear zone that was reactivated during Late Cretaceous extension between Zealandia and Australia. This reactivated terrane boundary is oriented at a high‐angle to the faults defining the Great South Basin. We identify a large granitic laccolith along the southern margin of the Median Batholith, expressed as sub‐horizontal packages of reflectivity and acoustically transparent areas on seismic reflection data. The presence of this strong granitic body inhibits the lateral south‐westward propagation of NE‐trending faults, which segment into a series of splays that rotate to align along the margin as they approach. Further, we also identify two E‐W and NE‐SW oriented basement fabrics, likely corresponding to prominent foliations, which are exploited by small‐scale faults across the basin. We show that different mechanisms of structural inheritance are able to operate simultaneously, and somewhat independently, within rift systems at different scales of observation. The presence of structural heterogeneities across all scales need to be incorporated into our understanding of the structural evolution of complex rift systems

Influence of variable decoupling between vertically separated fault populations on structural inheritance – The Laminaria High, NW Shelf of Australia

When extension events are greatly separated in time, older faults may be buried and stratigraphically separated from newly developing faults at shallower depths. During rifting, the buried structures may reactivate and propagate upwards to be expressed within the shallow system. The degree of linkage between structural levels determines the influence that the deeper structures can exert over the geometry and evolution of the incipient fault system. In this study we use 3D seismic reflection data to examine how a deep fault population across the Laminaria High, NW shelf of Australia influences the development of a younger fault system at shallow depths. These fault populations are non-parallel and decoupled across a mechanically weak interval. The majority of shallow faults are not linked to those at depth. However, the reactivation and upward propagation of some of the deeper faults produce anomalously oriented structures at shallow depths, hard-linked to the deeper structures. One fault in particular shows along-strike variability, with the deep segment reactivated and present at shallow depths in the west. To the east, the shallow and deep fault segments become decoupled across the mechanically weak interval, although some soft-linkage and strain transfer still occurs. We suggest that this switch in the degree of coupling along the fault is due to the geometry of the deeper structure, with the transition corresponding to a prominent relay ramp. We show how the geometry of a deeper fault may affect its propensity to reactivate during subsequent extensional events, ultimately affecting the degree of structural inheritance that is expressed within younger, shallower fault populations

Science Basis for Changing Forest Structure to Modify Wildfire Behavior and Severity

This report describes the kinds, quality, amount, and gaps of scientific knowledge for making informed decisions on fuel treatments used to modify wildfire behavior and effects in dry forests of the interior Western United States (especially forests dominated by ponderosa pine and Douglas-fir). A review of scientific principles and applications relevant to fuel treatment primarily for the dry forests is provided for the following topics: fuels, fire hazard, fire behavior, fire effects, forest structure, treatment effects and longevity, landscape fuel patterns, and scientific tools useful for management and planning

Health-related quality of life measured using the EQ-5D-5L: South Australian population norms

© 2016 The Author(s). Background: Although a five level version of the widely-used EuroQol 5 dimensions (EQ-5D) instrument has been developed, population norms are not yet available for Australia to inform the future valuation of health in economic evaluations. The aim of this study was to estimate HrQOL normative values for the EQ-5D-5L preference-based measure in a large, randomly selected, community sample in South Australia. Methods: The EQ-5D-5L instrument was included in the 2013 South Australian Health Omnibus Survey, an interviewer-administered, face-to-face, cross-sectional survey. Respondents rated their level of impairment across dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and global health rating on a visual analogue scale (EQ-VAS). Utility scores were derived using the newly-developed UK general population-based algorithm and relationships between utility and EQ-VAS scores and socio-demographic factors were also explored using multivariate regression analyses. Results: Ultimately, 2,908 adults participated in the survey (63.4 % participation rate). The mean utility and EQ-VAS scores were 0.91 (95 CI 0.90, 0.91) and 78.55 (95 % CI 77.95, 79.15), respectively. Almost half of respondents reported no problems across all dimensions (42.8 %), whereas only 7.2 % rated their health >90 on the EQ-VAS (100=the best health you can imagine). Younger age, male gender, longer duration of education, higher annual household income, employment and marriage/de facto relationships were all independent, statistically significant predictors of better health status (p<0.01) measured with the EQ-VAS. Only age and employment status were associated with higher utility scores, indicating fundamental differences between these measures of health status. Conclusions: This is the first Australian study to apply the EQ-5D-5L in a large, community sample. Overall, findings are consistent with EQ-5D-5L utility and VAS scores reported for other countries and indicate that the majority of South Australian adults report themselves in full health. When valuing health in Australian economic evaluations, the utility population norms can be used to estimate HrQOL. More generally, the EQ-VAS score may be a better measure of population health given the smaller ceiling effect and broader coverage of HrQOL dimensions. Further research is recommended to update EQ-5D-5L population norms using the Australian general population specific scoring algorithm once this becomes publically available

The role of valuation and bargaining in optimising transboundary watercourse treaty regimes

In the face of water scarcity, growing water demands, population increase, ecosystem degradation, climate change, and so on transboundary watercourse states inevitably have to make difficult decisions on how finite quantities of water are distributed. Such waters, and their associated ecosystem services, offer multiple benefits. Valuation and bargaining can play a key role in the sharing of these ecosystems services and their associated benefits across sovereign borders. Ecosystem services in transboundary watercourses essentially constitute a portfolio of assets. Whilst challenging, their commodification, which creates property rights, supports trading. Such trading offers a means by which to resolve conflicts over competing uses and allows states to optimise their ‘portfolios’. However, despite this potential, adoption of appropriate treaty frameworks that might facilitate a market-based approach to the discovery and allocation of water-related ecosystem services at the transboundary level remains both a challenge, and a topic worthy of further study. Drawing upon concepts in law and economics, this paper therefore seeks to advance the study of how treaty frameworks might be developed in a way that supports such a market-based approach to ecosystem services and transboundary waters