Promoting skill use in skill enhanced cognitive behavioral therapy: A case example.

Cognitive behavioral therapy (CBT) appears to achieve its effects at least in part by fostering the development of CBT skills. In an effort to leverage CBT skill development, our group developed and tested a skill-enhanced version of CBT (CBT-SE) in a recent trial. In this paper, we describe our work with a client who participated in a 12-week course of CBT-SE as part of that trial. Although homework is a critical aspect of CBT, the greater emphasis on skill development in CBT-SE means that homework is even more central. This client's course of treatment illustrates the potential benefits of a strong focus on skill development and the use of specific homework assignments to foster mastery and ongoing use of CBT skills. The client developed CBT skills at a rapid pace early in treatment and exhibited enduring symptom reductions. The experience of this client reinforces the value of a focus on CBT skills and highlights strategies for fostering skill development. Given the evidence in support of the therapeutic value of CBT skills and the well-established benefits of homework assignment, we encourage use of skill enhancing procedures, including in-session procedures and assignments that help clients develop and maintain ongoing skill use.

The Friends and Family for Mental Health Program: a pilot study of a cognitive behavioral therapy skills intervention for rural adults.

INTRODUCTION: Limited access to psychological treatment is a pressing problem in the US, especially in more rural areas. One potentially underutilized resource is informal care from friends and family members. Although those in rural areas rely on informal care more than those in urban areas, there is little to guide interested caregivers in how they can be most effective. METHODS: In this study, we conducted a pilot test of the Friends and Family for Mental Health Program, a mental health skills program we developed to enhance informal care and reduce psychological symptoms among informal caregivers. To provide an initial test of the potential benefits of this program, we evaluated the impact of the program on informal care skills, hope, psychological symptoms, and mental health skills. RESULTS: Informal care skills and hope improved. Participants also reported reduced anxiety. We considered intervention feedback to inform intervention development. DISCUSSION: Overall, findings provided preliminary support for the program and provide directions for future refinements. CONCLUSION: Though further research is needed, initial evidence suggests mental health skills programs directed at informal caregivers are both desired and beneficial in rural areas.

Vindicating pollyanna? An experimental test of cognitive restructuring and positive thinking interventions.

OBJECTIVE: Despite its considerable potential, psychotherapy research has made limited use of small-scale experimental study designs to test intervention components. This study employs such a design to test the immediate effects on emotional experience of two approaches to changing negative thoughts, cognitive restructuring and fostering positive thinking. Cognitive restructuring draws on the strategies core to cognitive behavioral therapies. Fostering positive thinking has also received attention, though less so as a psychological intervention. METHOD: We tested the benefits of these strategies over a brief interval by randomizing 230 participants to complete a worksheet introducing one of the two strategies. Participants reported their skills prior to exposure to these worksheets and affect was assessed immediately prior to and following use of worksheets. RESULTS: Participants' negative affect reduced following both strategies. Conditions did not differ significantly in affect change. Analysis of potential moderators showed that, among those with higher levels of cognitive behavioral therapy skills, the positive thinking condition produced greater gains in positive affect than the cognitive restructuring condition. CONCLUSIONS: These results indicate that both forms of brief interventions promote reductions in negative affect. Positive thinking interventions, which are not focused on the accuracy of one's thinking, appear to be particularly effective in promoting positive affect.

Accommodation of helium in PuO2±x and the role of americium.

The high alpha-activity of plutonium dioxide (PuO2) results in significant ingrowth of radiogenic helium (He) in the aged material. To safely store/dispose PuO2 or use in applications such as space exploration, the impact of He accumulation needs to be understood. In this work, defect energies obtained using a density functional theory (DFT) + U + D3 scheme are used in a point defect model constructed for PuO2 to predict the method of He incorporation within the PuO2 lattice. The simulations predict that the preferred incorporation site for He in PuO2 is a plutonium vacancy, however, the point defect model indicates that helium will be accommodated as an interstitial irrespective of He concentration and across a wide stoichiometric range. By considering the charge imbalance that arises due to incorporation of Am3+ ions it is shown that He accommodation in oxygen vacancy sites will dominate in PuO2-x as the material ages.

CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated fibrotic disorder that has been linked to CD4+ cytotoxic T lymphocytes (CD4+CTLs). The effector phenotype of CD4+CTLs and the relevance of both CD8+ cytotoxic T lymphocytes (CD8+CTLs) and apoptotic cell death remain undefined in IgG4-RD. OBJECTIVE: We sought to define CD4+CTL heterogeneity, characterize the CD8+CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG4-RD. METHODS: Blood analyses were undertaken using flow cytometry, cell sorting, transcriptomic analyses at the population and single-cell levels, and next-generation sequencing for the TCR repertoire. Tissues were interrogated using multicolor immunofluorescence. Results were correlated with clinical data. RESULTS: We establish that among circulating CD4+CTLs in IgG4-RD, CD27loCD28loCD57hi cells are the dominant effector subset, exhibit marked clonal expansion, and differentially express genes relevant to cytotoxicity, activation, and enhanced metabolism. We also observed prominent infiltration of granzyme A-expressing CD8+CTLs in disease tissues and clonal expansion in the blood of effector/memory CD8+ T cells with an activated and cytotoxic phenotype. Tissue studies revealed an abundance of cells undergoing apoptotic cell death disproportionately involving nonimmune, nonendothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR. CONCLUSIONS: CD4+CTLs and CD8+CTLs may induce apoptotic cell death in tissues of patients with IgG4-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin.

Framing an intervention as focused on one's strength: Does framing enhance therapeutic benefit?

INTRODUCTION: A capitalization approach to enhancing client skills in cognitive behavioral interventions is focused on enhancing skills that represent relative strengths. This approach may bolster outcomes because the targeted skills are those that clients can most effectively use to recover from negative moods. Alternatively, the benefits might be due to client attitudes about these skills, such as their confidence that they can use these skills effectively. METHODS: In an unselected sample of 616 undergraduates, we randomized to one of two brief interventions (a cognitive or mindfulness intervention) and one of two framing conditions (framing the intervention as focusing on a relative strength or a weakness), resulting in four conditions. Participants were then asked to use the skill targeted in their intervention to recover from a sad mood induction. RESULTS: Framing conditions did not differ on expectations of benefit from sustained use of an intervention but did differ on mood recovery. Participants told that the intervention focused on a strength recovered more quickly following the mood induction. There was no difference between the skill interventions. DISCUSSION: Our finding suggests intervention framing positively contributes to the effects of strengths focused treatments, though perhaps not by enhancing treatment expectations.

The therapeutic alliance and dropout in cognitive behavioral therapy of depression.

Identifying predictors of dropout is an important step in improving treatment outcomes. The alliance is the most frequently studied psychotherapy process variable, but its relation to dropout in cognitive behavioral therapy (CBT) of depression is not well understood.We evaluated the alliance at session one as reported by clients and therapists as predictors of dropout among 126 clients with major depressive disorder participating in CBT for depression.Over a similar time period, those who dropped out experienced less symptom change than those who did not. Client, but not therapist reported alliance was related to reduced risk for dropout. This relation remained significant even when clients' pre-treatment predictions of the alliance were included as a covariate. Concurrent use of medication did not moderate the alliance-dropout relation.Our findings are consistent with alliance being an important contributor to risk of dropout in CBT for depression. Future research should investigate intervention strategies that might promote the alliance as a means of reducing dropout.

The defect chemistry of non-stoichiometric PuO2±x.

An increased knowledge of the chemistry of PuO2 is imperative for the design of procedures to store, dispose, or make use of PuO2. In this work, point defect concentrations in PuO2 are determined by combining density functional theory (DFT) defect energies and empirical potential calculations of vibrational entropies. The obtained defect concentrations are expressed as a function of temperature and oxygen partial pressure and used to calculate non-stoichiometry in PuO2±x. The results show that the defect chemistry of PuO2 is dominated by oxygen vacancies and interstitials. Hypo-stoichiometric PuO2-x is accommodated by both the uncharged oxygen vacancy and positively charged oxygen vacancy at small values of x, with increasingly dominant with increasing x. The negatively charged oxygen interstitial (O2-i) is found to accommodate hyper-stoichiometry (PuO2+x), but reluctance to form hyper-stoichiometric PuO2+x is observed, with oxygen interstitials present only in very low concentrations irrespective of conditions. The small degree of hyper-stoichiometry found is favoured by low temperatures.

In vivo genome editing restores haemostasis in a mouse model of haemophilia.

Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells. The development of zinc finger nucleases (ZFNs) has permitted efficient genome editing in transformed and primary cells that were previously thought to be intractable to such genetic manipulation. In vitro, ZFNs have been shown to promote efficient genome editing via homology-directed repair by inducing a site-specific double-strand break (DSB) at a target locus, but it is unclear whether ZFNs can induce DSBs and stimulate genome editing at a clinically meaningful level in vivo. Here we show that ZFNs are able to induce DSBs efficiently when delivered directly to mouse liver and that, when co-delivered with an appropriately designed gene-targeting vector, they can stimulate gene replacement through both homology-directed and homology-independent targeted gene insertion at the ZFN-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of haemophilia B, and remained persistent after induced liver regeneration. Thus, ZFN-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease.

Exposure to Trauma and Mental Health Service Engagement Among Adults Who Were Children of the Northern Ireland Troubles of 1968 to 1998.

Northern Ireland is an appropriate region to examine the impact of traumatic experiences, owing to the many years of civil violence that have characterized its recent history, known colloquially as the "Troubles." Given the prominence of traumatic experiences among the aging population of Northern Ireland (NI), an evidence base is required to inform the planning and provision of effective mental health and other services. We analyzed the follow-up interviews (n = 225) of individuals from the Northern Ireland Study of Health and Stress (NISHS), aged 45 years and older, who experienced one or more conflict-related traumatic events. This study demonstrated that in NI traumatic events, such as being involved in an explosion, seeing someone killed or seriously injured, and living in a region of terror were most likely to be related to the Troubles. However, event types that we had not previously known to be related to conflict (such as the sudden death of a loved one), were also often related to the Troubles. Two-thirds of participants (67.1%) reported exposure to a Troubles-related event, and 57.8% reported being a civilian in a region of terror. The vast majority (85.9%) of participants who experienced a Troubles-related trauma never sought help, despite 59.1% meeting the criteria for a lifetime mental disorder. The reasons for not seeking help and sources of help are outlined. Policy makers must address Troubles-related mental health effects, in terms of how they carry forward into aging, and consider ways of improving engagement with services and treatments.

The role of religious advisors in mental health care in the World Mental Health surveys.

OBJECTIVES: To examine the role of religious advisors in mental health care (MHC) according to disorder severity, socio-demographics, religious involvement and country income groups. METHODS: Face to face household surveys in ten high income (HI), six upper-middle income (UMI) and five low/lower-middle (LLMI) income countries totalling 101,258 adults interviewed with the WMH CIDI plus questions on use of care for mental health problems and religiosity. RESULTS: 1.1% of participants turned to religious providers for MHC in the past year. Among those using services, 12.3% used religious services; as much as 30% in some LLMI countries, around 20% in some UMI; in the HI income countries USA, Germany, Italy and Japan are between 15 and 10% whenever the remaining countries are much lower. In LLMI 20.9% used religious advisors for the most severe mental disorders compared to 12.3 in UMI and 9.5% in HI. For severe cases most of religious providers use occurred together with formal care except in Nigeria, Iraq and Ukraine where, respectively, 41.6, 25.7 and 17.7% of such services are outside any formal care. Frequency of attendance at religious services was a strong predictor of religious provider usage OR 6.5 for those who attended over once a week (p < 0.0001); as seeking comfort "often" through religion in case of difficulties OR was 3.6 (p = 0.004) while gender and individual income did not predict use of religious advisors nor did the type of religious affiliation; in contrast young people use them more as well as divorced and widowed OR 1.4 (p = 0.02). Some country differences persisted after controlling for all these factors. CONCLUSIONS: Religious advisors play an important role in mental health care and require appropriate training and collaboration with formal mental healthcare systems. Religious attitudes are strong predictors of religious advisors usage.

The Economic Burden of PTSD in Northern Ireland.

The objective of this study was to estimate the economic costs of posttraumatic stress disorder (PTSD) among the Northern Ireland (NI) adult population. The authors present a prevalence-based, bottom-up study based primarily on data from 1,986 participants in the Northern Ireland Study of Health and Stress (NISHS). Both direct costs of treatment and indirect costs of productivity losses were included. Units of service and medication resource use were obtained from the NISHS and combined with their relevant unit costs from the Personal Social Services Research Unit and Prescription Costs Analysis data for NI. Indirect costs included the costs of incapacity days due to PTSD and presenteeism costs, with gender-specific wage rates used as the relevant unit costs. The total direct and indirect cost of PTSD in NI (2008) was £172,756,062. This figure is likely to be conservative due to the exclusion of a number of cost categories. Nevertheless, comparison of estimates of the burden of PTSD with the estimated cost of treating all adults with PTSD with the recommended treatments shows the potential for substantial economic gains to be made through extension and investment in effective evidence-based treatments.

Cellular localization and characterization of cytosolic binding partners for Gla domain-containing proteins PRRG4 and PRRG2.

The genes encoding a family of proteins termed proline-rich γ-carboxyglutamic acid (PRRG) proteins were identified and characterized more than a decade ago, but their functions remain unknown. These novel membrane proteins have an extracellular γ-carboxyglutamic acid (Gla) protein domain and cytosolic WW binding motifs. We screened WW domain arrays for cytosolic binding partners for PRRG4 and identified novel protein-protein interactions for the protein. We also uncovered a new WW binding motif in PRRG4 that is essential for these newly found protein-protein interactions. Several of the PRRG-interacting proteins we identified are essential for a variety of physiologic processes. Our findings indicate possible novel and previously unidentified functions for PRRG proteins.

CD8(+) T-cell responses to adeno-associated virus capsid in humans.

Hepatic adeno-associated virus (AAV)-serotype 2 mediated gene transfer results in transgene product expression that is sustained in experimental animals but not in human subjects. We hypothesize that this is caused by rejection of transduced hepatocytes by AAV capsid-specific memory CD8(+) T cells reactivated by AAV vectors. Here we show that healthy subjects carry AAV capsid-specific CD8(+) T cells and that AAV-mediated gene transfer results in their expansion. No such expansion occurs in mice after AAV-mediated gene transfer. In addition, we show that AAV-2 induced human T cells proliferate upon exposure to alternate AAV serotypes, indicating that other serotypes are unlikely to evade capsid-specific immune responses.

Traumatic events and their relative PTSD burden in Northern Ireland: a consideration of the impact of the 'Troubles'.

PURPOSE: Over a 30-year period in its recent history, daily life in Northern Ireland (NI) was characterised by civil violence, colloquially termed as the 'Troubles'. The current report examines exposure to 29 traumatic event types and the associated conditional prevalence of post-traumatic stress disorder (PTSD) among the Northern Ireland population, with a focus on the impact of traumatic events that were characteristic of the NI 'Troubles'. METHOD: Results presented are based on analysis of data from the Northern Ireland Study of Health and Stress (NISHS). The NISHS is a representative epidemiological study of mental health among the NI adult population (N = 4,340) and part of the World Mental Health Survey Initiative. RESULTS: Perpetration of violence, physical assault by a spouse or partner and private events were the event types associated with the highest conditional prevalence of PTSD. Despite this elevated risk, collectively these events accounted for just 16.8% of the overall public burden of PTSD, given their low prevalence among the general population. Events that were characteristic of civil conflict, including unexpected death of a loved one, witnessing death or a dead body or someone seriously injured and being mugged or threatened with a weapon accounted for the highest proportion of the overall public health burden of PTSD (18.6, 9.4 and 7.8%, respectively). These findings are a feature of the higher prevalence of these events among the general population coupled with their moderate to above average risk of PTSD. CONCLUSIONS: Despite the formal end to conflict in NI in 1999, a substantial proportion of the adult population continue to suffer the adverse mental health effects of chronic trauma exposure. Given rates of recovery of PTSD in the absence of evidence-based treatments, it is likely that the legacy of mental ill health associated with conflict, if not adequately addressed, will endure for many years.

Symptom contributors to quality of life in schizophrenia: Exploratory factor and network analyses.

Individuals with schizophrenia and other associated disorders experience significant disturbance to their quality of life (QoL) due to a multitude of co-occurring symptoms. Popular evidence-based practices (EBPs) devote significant effort to reduce positive symptomatology in order to prevent relapse, while emerging research posits that other symptoms (cognitive deficits, negative and affective symptoms) are more indicative of QoL disturbance. This study sought to examine the impact of symptom constructs on QoL and attempt to infer directionality of influence via network analysis. A total of 102 recovery phase adult outpatients with schizophrenia spectrum disorders were assessed on positive, negative, and affective symptomatology, in addition to QoL and cognitive abilities. Exploratory factor analysis and network analysis were performed to identify associations and infer directed influence between symptom constructs, and a directed acyclic graph was constructed to observe associations between symptom domains and QoL. Factor analysis results indicated that individual measures align with their respective symptom constructs. Strong factor correlations were found between QoL and the negative and affective symptom constructs, with weaker associations found between positive symptoms and cognition. Visualization of the network structure illustrated QoL as the central cluster of the network, and examination of the weighted edges found the strongest connectivity between QoL, negative symptomatology, and affective symptoms. More severe negative and affective symptoms were most directly linked with poorer QoL and may prove to be integral in attaining positive outcomes in schizophrenia treatment. Incorporation of psychosocial treatments in addition to pharmacotherapy may prove effective in targeting negative and affective symptoms.

Cis-regulatory evolution of the recently expanded Ly49 gene family.

Comparative genomics has revealed the rapid expansion of multiple gene families involved in immunity. Members within each gene family often evolved distinct roles in immunity. However, less is known about the evolution of their epigenome and cis-regulation. Here we systematically profile the epigenome of the recently expanded murine Ly49 gene family that mainly encode either inhibitory or activating surface receptors on natural killer cells. We identify a set of cis-regulatory elements (CREs) for activating Ly49 genes. In addition, we show that in mice, inhibitory and activating Ly49 genes are regulated by two separate sets of proximal CREs, likely resulting from lineage-specific losses of CRE activity. Furthermore, we find that some Ly49 genes are cross-regulated by the CREs of other Ly49 genes, suggesting that the Ly49 family has begun to evolve a concerted cis-regulatory mechanism. Collectively, we demonstrate the different modes of cis-regulatory evolution for a rapidly expanding gene family.

From Rhetoric to Action: Justice, Equity, Diversity, and Inclusion in Coordinated Specialty Care for Early Psychosis.

Attention to inclusivity and equity in health research and clinical practice has grown in recent years; however, coordinated specialty care (CSC) for early psychosis lags in efforts to improve equity despite evidence of ongoing disparities and inequities in CSC care. This Open Forum argues that marginalization and disparities in early psychosis research and clinical care are interrelated, and the authors provide suggestions for paths forward. Commitment to equity and justice demands recentering the perspectives of those most affected by early psychosis services and investing in the integration of historically excluded perspectives across all aspects of practice, policy, and research.

Tissue determinants of the human T cell receptor repertoire.

98% of T cells reside in tissues, yet nearly all human T cell analyses are performed from peripheral blood. We single-cell sequenced 5.7 million T cells from ten donors' autologous blood and tonsils and sought to answer key questions about T cell receptor biology previously unanswerable by smaller-scale experiments. We identified distinct clonal expansions and distributions in blood compared to tonsils, with surprisingly low (1-7%) clonal sharing. These few shared clones exhibited divergent phenotypes across bodily sites. Analysis of antigen-specific CD8 T cells revealed location as a main determinant of frequency, phenotype, and immunodominance. Finally, diversity estimates from the tissue recalibrates current repertoire diversity estimates, and we provide a refined estimate of whole-body repertoire. Given the tissue-restricted nature of T cell phenotypes, functions, differentiation, and clonality revealed by this dataset, we conclude that tissue analyses are crucial for accurate repertoire analysis and monitoring changes after perturbing therapies.

Pharmacological modulation of humoral immunity in a nonhuman primate model of AAV gene transfer for hemophilia B.

Liver gene transfer for hemophilia B has shown very promising results in recent clinical studies. A potential complication of gene-based treatments for hemophilia and other inherited disorders, however, is the development of neutralizing antibodies (NAb) against the therapeutic transgene. The risk of developing NAb to the coagulation factor IX (F.IX) transgene product following adeno-associated virus (AAV)-mediated hepatic gene transfer for hemophilia is small but not absent, as formation of inhibitory antibodies to F.IX is observed in experimental animals following liver gene transfer. Thus, strategies to modulate antitransgene NAb responses are needed. Here, we used the anti-B cell monoclonal antibody rituximab (rtx) in combination with cyclosporine A (CsA) to eradicate anti-human F.IX NAb in rhesus macaques previously injected intravenously with AAV8 vectors expressing human F.IX. A short course of immunosuppression (IS) resulted in eradication of anti-F.IX NAb with restoration of plasma F.IX transgene product detection. In one animal, following IS anti-AAV6 antibodies also dropped below detection, allowing for successful AAV vector readministration and resulting in high levels (60% or normal) of F.IX transgene product in plasma. Though the number of animals is small, this study supports for the safety and efficacy of B cell-targeting therapies to eradicate NAb developed following AAV-mediated gene transfer.