Chronic Stress Alters Striosome-Circuit Dynamics, Leading to Aberrant Decision-Making.

Effective evaluation of costs and benefits is a core survival capacity that in humans is considered as optimal, "rational" decision-making. This capacity is vulnerable in neuropsychiatric disorders and in the aftermath of chronic stress, in which aberrant choices and high-risk behaviors occur. We report that chronic stress exposure in rodents produces abnormal evaluation of costs and benefits resembling non-optimal decision-making in which choices of high-cost/high-reward options are sharply increased. Concomitantly, alterations in the task-related spike activity of medial prefrontal neurons correspond with increased activity of their striosome-predominant striatal projection neuron targets and with decreased and delayed striatal fast-firing interneuron activity. These effects of chronic stress on prefronto-striatal circuit dynamics could be blocked or be mimicked by selective optogenetic manipulation of these circuits. We suggest that altered excitation-inhibition dynamics of striosome-based circuit function could be an underlying mechanism by which chronic stress contributes to disorders characterized by aberrant decision-making under conflict. VIDEO ABSTRACT.

Exploring Experiences of Traumatic Microaggressions Toward Surgeons and Surgical Residents.

INTRODUCTION: Studies have suggested that experiences of gender and racial discrimination are widespread among surgeons and surgical residents. This study examines the relationship between experienced microaggressions and traumatic stress. METHODS: A one-time, deidentified survey was distributed over email to academic surgical societies. The survey consisted of 35 items including questions on prevalence of microaggressions, perceived job impacts as well as a shortened version of the Trauma Symptoms of Discrimination Scale. Chi-square tests and an independence test for trends were utilized to determine significance. RESULTS: We collected data from 130 participants with majority (81%) having experienced microaggressions in the workplace. On measures of worry (P < 0.001), avoidance (P = 0.012), anxiety (P = 0.004), and trouble relaxing (P = 0.002), racial/ethnic minority surgeons and trainees demonstrated significantly higher scores. With perceived job impacts, significant agreement was seen with occurrences of working harder to prove competence (P = 0.005), gaining patient confidence (P < 0.001), reduced career satisfaction (P = 0.011), work-related negative talk (P = 0.018), and burnout at work due to microaggressions (P = 0.019). Among participants who underwent behavioral modifications, female surgeons were more likely to change their nonverbal communication styles (P < 0.001) and spend more time with patients (P < 0.001). CONCLUSIONS: Experiences of microaggressions are associated with increased anxiety-related trauma symptoms in racial/ethnic minority surgeons and surgical trainees. Additionally, these experiences of microaggression can influence job satisfaction, burnout, career perceptions and workplace behaviors. As the field of surgery becomes more diverse, this study contributes to growing awareness of the role of implicit discrimination in the attrition and retention of racial/ethnic minority surgeons and female surgeons.

Biochemical and structural basis for the pharmacological inhibition of nuclear hormone receptor PPARγ by inverse agonists.

Recent studies have reported that the peroxisome proliferator-activated receptor gamma (PPARγ) pathway is activated in approximately 40% of patients with muscle-invasive bladder cancer. This led us to investigate pharmacological repression of PPARγ as a possible intervention strategy. Here, we characterize PPARγ antagonists and inverse agonists and find that the former behave as silent ligands, whereas inverse agonists (T0070907 and SR10221) repress downstream PPARγ target genes leading to growth inhibition in bladder cancer cell lines. To understand the mechanism, we determined the ternary crystal structure of PPARγ bound to T0070907 and the corepressor (co-R) peptide NCOR1. The structure shows that the AF-2 helix 12 (H12) rearranges to bind inside the ligand-binding domain, where it forms stabilizing interactions with the compound. This dramatic movement in H12 unveils a large interface for co-R binding. In contrast, the crystal structure of PPARγ bound to a SR10221 analog shows more subtle structural differences, where the compound binds and pushes H12 away from the ligand-binding domain to allow co-R binding. Interestingly, we found that both classes of compound promote recruitment of co-R proteins in biochemical assays but with distinct conformational changes in H12. We validate our structural models using both site-directed mutagenesis and chemical probes. Our findings offer new mechanistic insights into pharmacological modulation of PPARγ signaling.

Health disparities affecting persons living with HIV and using substances in China.

Health disparities affecting persons living with HIV (PLWH) as well as those affecting individuals who use substances have been documented in China. However, health status and outcomes within the intersectional population of those who both live with HIV and use substances is not well understood. One hundred and sixty-nine PLWH receiving care in China completed surveys assessing HIV-clinical factors, substance use, and HIV-related physical health symptoms. We tested associations between substance use and health symptoms using multivariate logistic and ordinal regressions. Using one substance over the past week was associated with greater maximal severity of physical symptoms (p < .01); using two or more substances in the past week was associated with both increased total physical symptom severity (p < .05) and a dosage response in increased maximal severity (p < .01). Findings highlight the need for providers to address substance use for comprehensive care of PLWH to improve overall wellbeing.

Depression and anxiety among HIV-positive men who have sex with men and men who have sex with women in China.

China is experiencing an emerging HIV epidemic among men who have sex with men (MSM). Minority stress theory posits that marginalized populations experience additional stress, which influences experiences of psychological distress and health outcomes. This study aimed to understand psychological distress of MSM relative to men who have sex with women (MSW) in an urban Chinese setting. Cross-sectional survey data were collected from 162 HIV-positive Chinese men receiving HIV treatment at Beijing's Ditan Hospital. Multiple linear regression with imputation was used to identify correlates of psychological distress. Relative to MSW, MSM were younger, more educated, and less likely to be in a relationship or have children. While both groups reported clinically elevated levels of depression and anxiety, sexual behavior was not associated with either outcome. Higher endorsement of depression symptomology was associated with worse reported physical health (ß = -1.37, p < .05) and greater endorsement of maladaptive coping (ß = 2.39, p < .05), whereas higher endorsement of anxiety symptomology was associated with greater endorsement of adaptive coping (ß = 0.78, p < .05), diminished physical health (ß = -0.86, p < .05), and a high school or greater level of education (ß = 4.13, p < .05). These findings suggest that interventions targeting coping strategies may address psychological distress among HIV-positive Chinese men.

Tobacco use and HIV symptom severity in Chinese people living with HIV.

Exposure to nicotine among people living with HIV (PLWH) may impact physical health as indicated by experienced symptoms. Yet, the empirical evidence documenting the relations between tobacco use and symptom experiences among PLWH remains limited. This study aims to assess the relationships between tobacco use and HIV symptoms through a cross-sectional survey conducted in Beijing and Shanghai. The WHO ASSIST screening test was used for frequency of tobacco use. Sixty-four items from the revised signs and symptoms checklist for persons with HIV disease (SSC-HIVrev) were used. "Total number of symptoms" was created by summing all the binary coded and "Maximal symptom severity" was created by taking the maximal severity level across all symptoms for each participant. After controlling for confounding variables, tobacco use was not associated with the total number of symptom, yet was associated with the maximal symptom severity. This study documents the link between tobacco use and experienced symptoms among PLWH by demonstrating that higher frequency of tobacco use is associated with greater odds of reporting more severe symptoms. Smoking cessation strategies should be integrated into symptom management interventions for PLWH to optimize their effectiveness.

Reducing distress and promoting resilience: a preliminary trial of a CBT skills intervention among recently HIV-diagnosed MSM in China.

People living with HIV/AIDS (PLWHA) in China experience significant psychological distress, due to high rates of stigma and low availability of mental health resources. Recently diagnosed Chinese PLWHA who are men who have sex with men (MSM) are particularly vulnerable to distress, facing both HIV and sexual orientation stigma. Reducing distress and enhancing psychological resilience is critical in promoting wellbeing. However, no research to date has examined evidence-based interventions to reduce psychological symptoms and improve resilience in this population. Based on qualitative research on their mental health needs, we developed a culturally tailored, brief 3-session CBT skills-based intervention for integration into primary care [Yang, J. P., Simoni, J., Cheryan, S., Shiu, C., Chen, W., Zhao, H., & Lu, H. (2018). The development of a brief distress reduction intervention for individuals recently diagnosed with HIV in China. Cognitive Behavioral Practice, 25(2), 319-334. doi: 10.1016/j.cbpra.2017.08.002 ]. The intervention includes cognitive restructuring to address depressive thought patterns, behavioral activation to decrease isolation, and paced breathing to reduce anxiety. We conducted a pilot Type 1 hybrid effectiveness-implementation trial assessing pre-post mental health outcomes as well as feasibility, acceptability, and appropriateness information. Ten recently diagnosed MSM completed the research protocol of three individual weekly sessions. Paired-samples t tests demonstrated significant reduction in HIV-related distress, depression, problems with adjustment, as well as improvements in resilience, and perceived social support. Participants and community advisory board members found the intervention highly acceptable, appropriate, and feasible. Preliminary data from the first known study examining a psychological intervention with evidence-based components for recently diagnosed Chinese MSM suggests that this brief intervention may be useful for reducing distress and promoting resilience.

A structural equation model of patient-healthcare provider relationships and HIV-infected patient outcomes in Chinese populations.

Obtaining maximum antiretroviral therapy (ART) adherence is critical for maintaining a high CD4 count and strong immune function in PLWHA. Key factors for achieving optimum adherence include good medication self-efficacy, decreased medication-taking difficulties, and positive patient-healthcare provider (HCP) relationships. Limited studies have analyzed the correlation of these factors and ART adherence in Chinese population. In this paper, structural equation modeling was performed to assess the proposed model of relations between patient-HCP relationships and adherence. Audio Computer-Assisted Self-Interview (ACASI) software was used to collect data on ART adherence and patient variables among 227 PLWHA in Shanghai and Taipei. Participants completed a one-time 60-minute ACASI survey that consisted of standardized measures to assess demographics, recent CD4 counts, self-efficacy, patient-HCP relationship, adherence, and medication-taking difficulties. The data shown the relationship between patient-HCP relationships and adherence was significantly consistent with mediation by medication self-efficacy. However, patient-HCP interaction did not directly influence medication-taking difficulties, and medication-taking difficulties did not significantly affect CD4 counts. Furthermore, patient-HCP interactions did not directly impact CD4 counts; rather, the relation was consistent with mediation (by either better medication self-efficacy or better adherence) or by improved adherence alone. Future interventions should be designed to enhance self-management and provide better patient-HCP communication. This improved communication will enhance medication self-efficacy and decrease medication-taking difficulties. This in turn will improve medication adherence and immune function among PLWHA.

Quality of life in HIV-infected Chinese women and their family caregivers: an intervention study.

China is experiencing a rapid increase in the number of HIV-infected women. In this study, we describe the development and preliminary evaluation of an intervention tailored for Chinese HIV-infected women and caregivers to improve their self- and family management, with goals of enhancing their physical quality of life (QOL) and decreasing their depressive symptomatology. Forty-one HIV-infected women and their caregivers were recruited from two premier Chinese hospitals from July 2014 through March 2016. Participants were randomized to either the control or intervention arm for the Self- and Family Management Intervention (SAFMI). Each study dyad in the intervention arm received three counseling sessions with a nurse interventionist. At baseline, immediate post-intervention (month 1) and follow-up (month 3), the participants were assessed by a self-reported survey. Generalized Hierarchical Linear Modeling was used to evaluate the efficacy of the intervention. Chinese HIV-infected women in the intervention arm had significantly higher probability of higher physical QOL at month 1 and lower probability of clinically meaningful depressive symptomatology at month 3 compared with women in the control arm. In contrast, the effects of the intervention were less salient for caregivers. This study represents one of the first in China to include family caregivers in HIV management. Feasibility and acceptability were high, in that family members were willing to join the study, learn about HIV, and practice new skills to support the HIV-infected women in their lives. A larger trial is needed to fully evaluate this intervention which shows promising preliminary effects in promoting physical QOL and decreasing depressive symptomatology among Chinese HIV-infected women.

The Development of a Brief Distress Reduction Intervention for Individuals Recently Diagnosed With HIV in China.

In China, where there are few mental health resources, the majority of HIV-related efforts have focused on medical treatment and transmission prevention rather than psychosocial support. Yet people living with HIV/AIDS (PLWHA) report high levels of psychological distress, especially upon first receiving their HIV diagnosis. We conducted mixed methods research of a qualitative study with (N = 31) individual interviews and 3 focus groups (n = 6 in each group) of HIV-affected participants, and a quantitative survey (N = 200) with individuals living with HIV in Shanghai and Beijing, China. Our qualitative data revealed themes of forms of distress experienced and types of psychosocial support that our participants wished they could have accessed upon diagnosis as well as suggestions for intervention structure that would be most feasible and acceptable. Our quantitative surveys provided further evidence of the high degree of psychosocial distress among recently diagnosed PLWHA. Our findings informed the development of the Psychology Toolbox intervention, a brief CBT skills-based intervention comprising cognitive restructuring, behavioral activation, and paced breathing, designed to be integrated into primary care for recently diagnosed PLWHA. This study describes the intervention development process and contents of each session. Future research should evaluate the intervention for efficacy as well as examine best strategies for eventual implementation and dissemination.

Substance use, anxiety, and self-management efficacy in HIV-positive individuals: A mediation analysis.

CONTEXT: In China, the social stigma of both substance use and HIV remains major barriers. HIV+ individuals have been demonstrated to have higher psychosocial distress in the literature. To ensure quality of life among HIV+ Chinese individuals, self-efficacy in HIV-related management including substance use and anxiety is the key to suppress viral load and maintain healthy lives. OBJECTIVES: We examine the mediation relationship among substance use, anxiety, and self-management efficacy. METHOD: A cross-sectional study design was used. 137 HIV+ individuals were recruited from two premier Chinese hospitals: Beijing's Ditan Hospital and Shanghai's Public Health Clinic Center (SPHCC). RESULTS: HIV+ substance users had significantly lower HIV-management efficacy and higher anxiety scores. About a third of the relations between substance use and anxiety was mediated by HIV-management self-efficacy. Those who used substances in the previous week had higher anxiety levels suggesting the presence of a recent effect. Their higher levels of anxiety could be largely explained by their lower HIV-management efficacy. CONCLUSION: It is useful for healthcare providers to assess substance use behaviors in HIV+ individuals as well as provide support in managing anxiety in this population. Meanwhile, enhancing self-management efficacy to ensure healthy lifestyles may support achieving optimal lives with HIV.

Structures of three distinct activator-TFIID complexes.

Sequence-specific DNA-binding activators, key regulators of gene expression, stimulate transcription in part by targeting the core promoter recognition TFIID complex and aiding in its recruitment to promoter DNA. Although it has been established that activators can interact with multiple components of TFIID, it is unknown whether common or distinct surfaces within TFIID are targeted by activators and what changes if any in the structure of TFIID may occur upon binding activators. As a first step toward structurally dissecting activator/TFIID interactions, we determined the three-dimensional structures of TFIID bound to three distinct activators (i.e., the tumor suppressor p53 protein, glutamine-rich Sp1 and the oncoprotein c-Jun) and compared their structures as determined by electron microscopy and single-particle reconstruction. By a combination of EM and biochemical mapping analysis, our results uncover distinct contact regions within TFIID bound by each activator. Unlike the coactivator CRSP/Mediator complex that undergoes drastic and global structural changes upon activator binding, instead, a rather confined set of local conserved structural changes were observed when each activator binds holo-TFIID. These results suggest that activator contact may induce unique structural features of TFIID, thus providing nanoscale information on activator-dependent TFIID assembly and transcription initiation.

Unable to be a Human Being in Front of Other People: A Qualitative Study of Self-Isolation Among People Living with HIV/AIDS in China.

In China, acute stigma accompanying an HIV diagnosis can lead to self-isolation. In a cultural setting where family relationships are highly valued and contribute critically to well-being, such self-isolation can thwart HIV self-management and engagement in medical care, and so heighten risk for health disparities. To understand this phenomenon, we conducted individual in-depth interviews with 34 persons living with HIV/AIDS (PLwHA) in Shanghai and Beijing. Inductive content analysis revealed a range of forms of self-isolation motivation, beliefs, and behaviors influenced by: 1) internalized stigma and desire to avoid discrimination; 2) HIV-related factors such as HIV knowledge and disease progression; and 3) familial factors such as a sense of responsibility and family members' reactions. Based on a proposed framework centering on dialectical family influences (whereby PLwHA are pushed away from, yet pulled toward the family fold), implications for provision of multidisciplinary care in medical settings are considered, including culturally appropriate strategies to decrease health disparities.

A Mixed-Methods Study Supporting a Model of Chinese Parental HIV Disclosure.

Parents who are HIV-positive confront difficult decisions regarding whether, when, and how to disclose their HIV status to their children. In China, a setting of acute HIV stigma where family harmony is culturally valued, limited research has been conducted on parental disclosure. We aimed to develop a model of parental disclosure that accounts for the cultural context in China based on a mixed-methods study. In our individual, in-depth interviews (N = 24) as well as survey data (N = 84) collected from parents living with HIV in Shanghai and Beijing, we found the primary barriers to disclosure were stigma, fear of exposing the mode by which they acquired HIV, psychologically burdening the child, rejection by the child, and negative social consequences for the family. Parents concurrently cited many motivations for disclosure, such as disease progression, ensuring safety of the child, gaining assistance, and fulfilling their parental responsibility. Most parents had not actively disclosed their HIV status (68 %); many parents reported some form of partial disclosure (e.g., sharing they have a blood disease but not labeling it HIV), unplanned disclosure, or unintentional disclosure to their children by other people. Findings informed the development of a Chinese Parental HIV Disclosure Model, with primary components accounting for distal cultural factors, decision-making (balancing approach and avoid motivations), the disclosure event, and outcomes resulting from the disclosure. This model highlights the cultural context of the Chinese parental disclosure process, and may be useful in guiding future observational research and intervention work.

Recognition of depression, anxiety, and alcohol abuse in a Chinese rural sample: a cross-sectional study.

BACKGROUND: Under-utilization of mental health services is a global health issue. Recognition of mental disorders, as the first step to seeking help from professional sources, has been well studied in developed countries, yet little is known about the situation in rural areas of developing countries like China. The purpose of the study is to understand the recognition of depression, anxiety, and alcohol abuse and its predictive factors in a Chinese rural sample METHODS: Face-to-face interviews were conducted on a representative rural adult sample in a cross-sectional study in China (N = 2052). Respondents were presented with three vignettes depicting depression, anxiety and alcohol abuse and asked to label the disorder and its cause to assess their recognition of the three mental disorders. They also completed the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder Scale (GAD-7), and the Alcohol Use Disorders Identification Test (AUDIT) to assess their current mental health status. RESULTS: The alcohol abuse vignette was more frequently attributed as a mental problem than the depression vignette and anxiety vignette. The correct labeling rate was 16.1 % in the depression vignette, 15.5 % in the anxiety vignette, and 58.2 % in the alcohol vignette. Higher education is the common and also strongest factor positively predicting the recognition of all three vignettes. Beyond that, being female is an independent predictor of correct recognition of alcohol abuse, while recognition of depression and anxiety were positively predicted by younger age. CONCLUSIONS: Lower recognition of depression and anxiety as compared to alcohol abuse confirms the importance and need to increase the public's awareness and knowledge about common mental disorders. Recognition of common mental disorders could be improved through general public campaign and education, while paying attention to the unique predictive factors for each specific disorder and implement targeted intervention.

Introduction to using structured evocative activities in Functional Analytic Psychotherapy.

Functional Analytic Psychotherapy (FAP) focuses on what happens in session between clients and therapists in order to create more intense and curative therapeutic relationships. FAP may be used as a standalone treatment or as an adjunct to other therapies in order to maximize therapeutic gains through strengthened alliance and differential reinforcement. When it fits within a client's case conceptualization, FAP clinicians often choose to use structured, evocative activities to progress the therapy at a faster pace. This article provides a rationale for using structured evocative activities in FAP with concrete examples to facilitate clinicians' implementation of the exercises.

"Please Don't Make Me Ask for Help": Implicit Social Support and Mental Health in Chinese Individuals Living with HIV.

China faces a growing HIV epidemic; psychosocial needs of HIV-positive individuals remain largely unaddressed. Research is needed to consider the gap between need for mental healthcare and lack of sufficiently trained professionals, in a culturally acceptable manner. This study assessed explicit and implicit forms of social support and mental health symptoms in 120 HIV-positive Chinese. Explicit social support refers to interactions involving active disclosure and discussion of problems and request for assistance, whereas implicit social support refers to the emotional comfort one obtains from social networks without disclosing problems. We hypothesized and found using multiple linear regression, that after controlling for demographics, only implicit, but not explicit social support positively predicted mental health. Future research is warranted on the effects of utilizing implicit social support to bolster mental health, which has the potential to circumvent the issues of both high stigma and low professional resources in this population.

Factor analyses of a social support scale using two methods.

PURPOSE: Evaluation and comparison of the factor structure of the Medical Outcomes Study Social Support Survey (MOS-SSS) using both confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) with two samples of people living with HIV/AIDS in China. METHODS: Secondary analyses were conducted with data from two comparable samples of 320 people living with HIV/AIDS from the same hospital using the same inclusion criteria. The first sample of 120 was collected in 2006, and the second sample of 200 was collected in 2012. For each sample, CFA was first performed on the original four-factor structure to check model fit, followed by EFA to explore other factor structures and a subsequent CFA for model fit statistics to be compared to the original four-factor CFA. RESULTS: In both samples, CFA on the originally hypothesized four-factor structure yielded an acceptable model fit. The EFA yielded a two-factor solution in both samples, with different items included in each factor for the two samples. Comparison of CFA on the a priori four-factor structure and the new two-factor structure in both samples indicated that both factor structures were of acceptable model fit, with the four-factor model performing slightly better than the two-factor model. CONCLUSION: Factor structure of the MOS-SSS is method-dependent, with CFA supporting a four-factor structure, while EFA yielded a two-factor structure in two separate samples. We need to be careful in selecting the analytic method when applying the MOS-SSS to various samples and choose the factor structure that best fits the theoretical model.

Optimization of scarless human stem cell genome editing.

Efficient strategies for precise genome editing in human-induced pluripotent cells (hiPSCs) will enable sophisticated genome engineering for research and clinical purposes. The development of programmable sequence-specific nucleases such as Transcription Activator-Like Effectors Nucleases (TALENs) and Cas9-gRNA allows genetic modifications to be made more efficiently at targeted sites of interest. However, many opportunities remain to optimize these tools and to enlarge their spheres of application. We present several improvements: First, we developed functional re-coded TALEs (reTALEs), which not only enable simple one-pot TALE synthesis but also allow TALE-based applications to be performed using lentiviral vectors. We then compared genome-editing efficiencies in hiPSCs mediated by 15 pairs of reTALENs and Cas9-gRNA targeting CCR5 and optimized ssODN design in conjunction with both methods for introducing specific mutations. We found Cas9-gRNA achieved 7-8× higher non-homologous end joining efficiencies (3%) than reTALENs (0.4%) and moderately superior homology-directed repair efficiencies (1.0 versus 0.6%) when combined with ssODN donors in hiPSCs. Using the optimal design, we demonstrated a streamlined process to generated seamlessly genome corrected hiPSCs within 3 weeks.

A public resource facilitating clinical use of genomes.

Rapid advances in DNA sequencing promise to enable new diagnostics and individualized therapies. Achieving personalized medicine, however, will require extensive research on highly reidentifiable, integrated datasets of genomic and health information. To assist with this, participants in the Personal Genome Project choose to forgo privacy via our institutional review board- approved "open consent" process. The contribution of public data and samples facilitates both scientific discovery and standardization of methods. We present our findings after enrollment of more than 1,800 participants, including whole-genome sequencing of 10 pilot participant genomes (the PGP-10). We introduce the Genome-Environment-Trait Evidence (GET-Evidence) system. This tool automatically processes genomes and prioritizes both published and novel variants for interpretation. In the process of reviewing the presumed healthy PGP-10 genomes, we find numerous literature references implying serious disease. Although it is sometimes impossible to rule out a late-onset effect, stringent evidence requirements can address the high rate of incidental findings. To that end we develop a peer production system for recording and organizing variant evaluations according to standard evidence guidelines, creating a public forum for reaching consensus on interpretation of clinically relevant variants. Genome analysis becomes a two-step process: using a prioritized list to record variant evaluations, then automatically sorting reviewed variants using these annotations. Genome data, health and trait information, participant samples, and variant interpretations are all shared in the public domain-we invite others to review our results using our participant samples and contribute to our interpretations. We offer our public resource and methods to further personalized medical research.