Interpersonal problems in social anxiety disorder across different relational contexts.

People with social anxiety disorder (SAD) frequently report interpersonal problems across various domains; however, it is unclear whether these problems are observable by others or represent negatively biased self-report. We assessed the interpersonal problems of people with and without SAD using self-report, friend, and romantic partner report. We hypothesized that SAD diagnosis would predict self-reported problems across multiple interpersonal domains, but restricted domains of informant report. Additionally, we hypothesized that diagnosis would predict discrepancy between self and informant report either in the form of a bias toward reporting more problems or in the form of lack of concordance between self and informant reporters. Using structural equation and multilevel models, we found evidence for differences between people with and without SAD in terms of domains of impairment observed by self and informants as well as differences in correspondence across relationship types. Results highlight the utility of multi-informant assessment of SAD.

Symptoms of social anxiety disorder and major depressive disorder: A network perspective.

BACKGROUND: We used network analyses to examine symptoms that may play a role in the co-occurrence of social anxiety disorder (SAD) and major depressive disorder (MDD). Whereas latent variable models examine relations among latent constructs, network analyses have the advantage of characterizing direct relations among the symptoms themselves. METHOD: We conducted network modeling on symptoms of social anxiety and depression in a clinical sample of 130 women who met criteria for SAD, MDD, both disorders, or had no lifetime history of mental illness. RESULTS: In the resulting network, the core symptoms of social fear and depressed mood appeared at opposite ends of the network and were weakly related; so-called "bridges" between these symptoms appeared to occur via intervening variables. In particular, the worthless variable appeared to play a central role in the network. LIMITATIONS: Because our data were cross-sectional, we are unable to draw conclusions about the direction of these effects or whether these variables are related to each other prospectively. CONCLUSIONS: Continued testing of these pathways using longitudinal data will help facilitate the development of more effective clinical interventions for these disorders.

Social anxiety and eating disorder comorbidity and underlying vulnerabilities: Using network analysis to conceptualize comorbidity.

OBJECTIVE: Eating disorders (EDs) and social anxiety disorder (SAD) are highly co-occurring. This comorbidity is extremely relevant, given that individuals with comorbid ED-SAD are less likely to seek and/or benefit from ED treatment. METHOD: We used network analysis to conceptualize ED-SAD comorbidity in a sample of 2,215 participants with a primary diagnosis of ED, SAD, or no known diagnosis. We used novel network analyses methods to select symptoms for our models, identify potential illness pathways (i.e., bridge symptoms) between disorders and underlying vulnerabilities (e.g., perfectionism, social appearance anxiety), and to compare across sample types (e.g., clinical vs. nonclinical). We also tested several novel network analyses methods aimed at the following methodological concerns: (a) topological concerns (i.e., which items should be included in NA models), (b) how to use empirical indices to quantify bridge symptoms and (c) what differences in networks across samples mean. RESULTS: We found that difficulty with drinking beverages and eating in public were bridge symptoms between ED and SAD. We also found that feeling nervous about one's appearance was a bridge symptom. CONCLUSIONS: We identified public eating and drinking as bridge symptoms between EDs and SAD. Future research is needed to test if interventions focused on public eating and drinking might decrease symptoms of both EDs and SAD. Researchers can use this study (code provided) as an exemplar for how to use network analysis, as well as to use network analysis to conceptualize ED comorbidity and compare network structure and density across samples.

Correction to: Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM.

In the original publication of this article [1], published on 8 February 2018, it was noticed that the acknowledgement of the source of the drug ADI-PEG20 was missing.

Metabolomic profiling identifies distinct phenotypes for ASS1 positive and negative GBM.

BACKGROUND: Tumour cells have a high demand for arginine. However, a subset of glioblastomas has a defect in the arginine biosynthetic pathway due to epigenetic silencing of the rate limiting enzyme argininosuccinate synthetase (ASS1). These tumours are auxotrophic for arginine and susceptible to the arginine degrading enzyme, pegylated arginine deiminase (ADI-PEG20). Moreover, ASS1 deficient GBM have a worse prognosis compared to ASS1 positive tumours. Since altered tumour metabolism is one of the hallmarks of cancer we were interested to determine if these two subtypes exhibited different metabolic profiles that could allow for their non-invasive detection as well as unveil additional novel therapeutic opportunities. METHODS: We looked for basal metabolic differences using one and two-dimensional gas chromatography-time-of-flight mass spectrometry (1D/2D GC-TOFMS) followed by targeted analysis of 29 amino acids using liquid chromatography-time-of-flight mass spectrometry (LC-TOFMS). We also looked for differences upon arginine deprivation in a single ASS1 negative and positive cell line (SNB19 and U87 respectively). The acquired data was evaluated by chemometric based bioinformatic methods. RESULTS: Orthogonal partial least squares-discriminant analysis (OPLS-DA) of both the 1D and 2D GC-TOFMS data revealed significant systematic difference in metabolites between the two subgroups with ASS1 positive cells generally exhibiting an overall elevation of identified metabolites, including those involved in the arginine biosynthetic pathway. Pathway and network analysis of the metabolite profile show that ASS1 negative cells have altered arginine and citrulline metabolism as well as altered amino acid metabolism. As expected, we observed significant metabolite perturbations in ASS negative cells in response to ADI-PEG20 treatment. CONCLUSIONS: This study has highlighted significant differences in the metabolome of ASS1 negative and positive GBM which warrants further study to determine their diagnostic and therapeutic potential for the treatment of this devastating disease.

The structure of vulnerabilities for social anxiety disorder.

Social anxiety disorder symptoms are generally proposed to be related to broad temperamental vulnerabilities (e.g., a low level of approach and high level of avoidance temperament), specific psychological vulnerabilities (e.g., fears of negative and positive evaluation), and additional disorders (e.g., major depressive disorder). However, existing tests of such a model have either not considered depressive symptoms or relied on samples of undergraduates. We examined these and related questions via a latent variable model in a large dataset (N=2253) that combined participants across a variety of studies. The model had adequate fit in the whole sample, and good fit in a subsample in which more participants completed the depression measure. The model indicated that low level of approach and high level of avoidance temperament contributed to fears of evaluation and social anxiety symptoms, and that fears of evaluation additionally contributed independently to social anxiety symptoms. The relationship between social anxiety and depressive symptoms was entirely accounted for by these vulnerabilities: Depressive symptoms were only predicted by avoidance temperament.

Unreliability as a threat to understanding psychopathology: The cautionary tale of attentional bias.

The use of unreliable measures constitutes a threat to our understanding of psychopathology, because advancement of science using both behavioral and biologically oriented measures can only be certain if such measurements are reliable. Two pillars of the National Institute of Mental Health's portfolio-the Research Domain Criteria (RDoC) initiative for psychopathology and the target engagement initiative in clinical trials-cannot succeed without measures that possess the high reliability necessary for tests involving mediation and selection based on individual differences. We focus on the historical lack of reliability of attentional bias measures as an illustration of how reliability can pose a threat to our understanding. Our own data replicate previous findings of poor reliability for traditionally used scores, which suggests a serious problem with the ability to test theories regarding attentional bias. This lack of reliability may also suggest problems with the assumption (in both theory and the formula for the scores) that attentional bias is consistent and stable across time. In contrast, measures accounting for attention as a dynamic process in time show good reliability in our data. The field is sorely in need of research reporting findings and reliability for attentional bias scores using multiple methods, including those focusing on dynamic processes over time. We urge researchers to test and report reliability of all measures, considering findings of low reliability not just as a nuisance but as an opportunity to modify and improve upon the underlying theory. Full assessment of reliability of measures will maximize the possibility that RDoC (and psychological science more generally) will succeed. (PsycINFO Database Record

A network analysis of developmental change in ADHD symptom structure from preschool to adulthood.

Although there is substantial support for the validity of the diagnosis of ADHD, there is considerable disagreement about how to best capture developmental changes in the expression of ADHD symptomatology. The current paper examines the associations among the 18 individual ADHD symptoms using a novel network analysis approach, from preschool to adulthood. The 1,420 participants were grouped into four age brackets: Preschool (age 3-6, n = 109), childhood (age 6-12, n = 548), adolescence (age 13-17, n = 357), and young adulthood (age 18-36, n = 406). All participants completed a multi-stage, multi-informant diagnostic process, and self and informant symptom ratings were obtained. Network analysis indicated ADHD symptom structure became more differentiated over development. Two symptoms Often easily distracted and Difficulty sustaining attention appeared as central, or core, symptoms across all age groups. Thus, a small number of core symptoms may warrant extra weighting in future diagnostic systems.

Short-term affective recovery from hip fracture prospectively predicts depression and physical functioning.

OBJECTIVE: The goals of the current study were to determine the average affective experiences in the weeks and months after a hip fracture and assess how these experiences relate to physical and mental health functioning over time. METHOD: Positive and negative affect were assessed over time in a sample of older adults recruited after surgery for hip fracture (n = 500) and a comparison sample of older adults without hip fracture (n = 102) for 1 year longitudinally. RESULTS: For most of the individuals with a hip fracture, positive affect tended to increase over time and negative affect tended to decrease over time, suggesting that most people had at least some recovery of affect. In addition, individuals who showed a slower decrease in negative affect had higher levels of depression 1 year later, and individuals who showed a sharper increase in positive affect had superior physical function 1 year later. CONCLUSION: The current study provides evidence that both positive and negative affect in the first 12 weeks of recovery from hip fracture are potential targets for intervention to maximize psychological and physical recovery in the ensuing year.

Psychological sequelae of surgery in a prospective cohort of patients from three intraoperative awareness prevention trials.

BACKGROUND: Elective surgery can have long-term psychological sequelae, especially for patients who experience intraoperative awareness. However, risk factors, other than awareness, for symptoms of posttraumatic stress disorder (PTSD) after surgery are poorly defined, and practical screening methods have not been applied to a broad population of surgical patients. METHODS: The Psychological Sequelae of Surgery study was a prospective cohort study of patients previously enrolled in the United States and Canada in 3 trials for the prevention of intraoperative awareness. The 68 patients who experienced definite or possible awareness were matched with 418 patients who denied awareness based on age, sex, surgery type, and awareness risk. Participants completed the PTSD Checklist-Specific (PCL-S) and/or a modified Mini-International Neuropsychiatric Interview telephone assessment to identify symptoms of PTSD and symptom complexes consistent with a PTSD diagnosis. We then used structural equation modeling to produce a composite PTSD score and examined potential risk factors. RESULTS: One hundred forty patients were unreachable; of those contacted, 303 (88%) participated a median of 2 years postoperatively. Forty-four of the 219 patients (20.1%) who completed the PCL-S exceeded the civilian screening cutoff score for PTSD symptoms resulting from their surgery (15 of 35 [43%] with awareness and 29 of 184 [16%] without). Nineteen patients (8.7%; 5 of 35 [14%] with awareness and 14 of 184 [7.6%] without) both exceeded the cutoff and endorsed a breadth of symptoms consistent with the Diagnostic and Statistical Manual Fourth Edition diagnosis of PTSD attributable to their surgery. Factors independently associated with PTSD symptoms were poor social support, previous PTSD symptoms, previous mental health treatment, dissociation related to surgery, perceiving that one's life was threatened during surgery, and intraoperative awareness (all P ≤ 0.017). Perioperative dissociation was identified as a potential mediator for perioperative PTSD symptoms. CONCLUSIONS: Events in the perioperative period can precipitate psychological symptoms consistent with subsyndromal and syndromal PTSD. We not only confirmed the high rate of postoperative PTSD in awareness patients but also identified a significant rate in matched nonawareness controls. Screening surgical patients, especially those with potentially mediating risk factors such as intraoperative awareness or perioperative dissociation, for postoperative PTSD symptoms with the PCL-S is practical and could promote early referral, evaluation, and treatment.

Self and friend's differing views of social anxiety disorder's effects on friendships.

Social anxiety disorder is known to be associated with self-report of global friendship quality. However, information about specific friendships, as well as information beyond self-report, is lacking. Such information is crucial, because known biases in information processing related to social anxiety disorder render global self-ratings particularly difficult to interpret. We examined these issues focusing on diagnosed participants (n = 77) compared with community control participants (n = 63). We examined self-report regarding global (i.e., overall) friendship quality and a specific friendship's quality; in addition, we examined friend-report of that friendship's quality. Results suggested that social anxiety disorder has a negative impact on self-perception of friendship quality for a specific friendship, but that this effect is less evident as reported by the friends. Specifically, social anxiety disorder was associated with a tendency to report worse friendship quality in comparison to friend-report, particularly in participants who were younger or had less long-lasting friendships. However, friend-report did show clear differences based on diagnostic group, with friends reporting participants with social anxiety disorder to be less dominant in the friendship and less well-adjusted. Overall, the findings are consistent with results of other studies indicating that social anxiety disorder has a strong association with self-ratings of impairment, but that these ratings appear out of proportion with the report of observers (in this case, friends).

Psychometric properties of the gaze anxiety rating scale: convergent, discriminant, and factorial validity.

Fear and avoidance of gaze are two features thought to be associated with problematic social anxiety. Avoidance of eye contact has been linked with such undesirable traits as deceptiveness, insincerity, and lower self-esteem. The Gaze Anxiety Rating Scale (GARS) is a self-report measure designed to assess gaze anxiety and avoidance, but its psychometric properties have only been assessed in one preliminary study. We further investigated psychometric properties of the GARS by assessing convergent and factorial validity. We obtained a two-factor solution: gaze anxiety and avoidance across situations (1) in general (GARS-General) and (2) related to dominance communication (GARS-Dominance). The GARS-General factor related more strongly to social anxiety than the GARS-Dominance, and convergent validity of the factors was supported by expected relationships with personality and social anxiety variables. Our results indicate that the GARS subscales are psychometrically valid measures of gaze aversion, supporting their use in future study of the relationship between social anxiety and eye contact behavior.

Validation of the ambivalent and purposeful engagement--trait measure.

The Ambivalent and Purposeful Engagement-Trait Measure (APE-TM) was developed to assess two ways that people may react to stressful social interactions: ambivalent engagement (AE: counterproductive attempts to avoid thoughts and feelings) and purposeful engagement (PE: effortfully approaching and working through thoughts and feelings). We carried out three studies in undergraduate and clinical populations to (i) test the robustness of previous psychometric findings and (ii) determine whether AE and PE are specific to social anxiety. Across three studies, our results indicate that the APE-TM is a psychometrically valid measure of ambivalent and purposeful engagement. However, PE appeared less specific to social anxiety and may represent a more general tendency toward adaptive coping. In contrast, AE was specific to social anxiety in both undergraduate samples and clinical samples of individuals with a variety of anxiety disorders and depression.

Reactivity to exclusion prospectively predicts social anxiety symptoms in young adults.

Peer victimization leads to negative outcomes such as increased anxiety and depression. The prospective relationship between peer victimization and social anxiety in children and adolescents is well established, and adults with social anxiety disorder (SAD) are more likely than individuals with other anxiety disorders to report a history of teasing. However, a crucial bridge between these findings (peer victimization in young adults) is missing. We manipulated perceptions of peer exclusion in a young adult sample (N=108) using the Cyberball Ostracism Task. Reactivity to exclusion prospectively predicted social anxiety symptoms at a 2-month follow-up, whereas self-reported teasing during high school and current relational victimization did not. This research suggests that reactions to peer victimization may be a worthwhile target for clinical interventions in young adults. Targeting how young adults react to stressful social interactions such as exclusion may help prevent the development of SAD. Future research should test if reactivity to exclusion plays a role in the relationship between other disorders (e.g., depression) and peer victimization.

Interpersonal constraint conferred by generalized social anxiety disorder is evident on a behavioral economics task.

Although social anxiety disorder appears to confer impairment in friendships, evidence beyond self-report is minimal. We used the flexible iterated prisoner's dilemma as a simulated interaction with a friend with 27 individuals with the generalized type of social anxiety disorder and 23 demographically equivalent individuals without the disorder. Participants with generalized social anxiety disorder were less giving on the task. Lower giving was also moderately associated with interpersonal variables (e.g., coldness). A trend was also found for participants with generalized social anxiety disorder to show lower assertiveness on the task. The connection between generalized social anxiety disorder and friendship impairment appears likely to be partially explained by interpersonal constraint that is perceived by others as coldness and manifests in a behavioral economics task.

The longitudinal relationship between fear of positive evaluation and fear of negative evaluation.

Available research suggests that fear of negative evaluation and fear of positive evaluation are related but distinct constructs that each contribute to social anxiety, implying a need to focus on these fears in treatment. Yet, this research is almost entirely based on cross-sectional data. We examined the longitudinal relationship between fears of positive and negative evaluation over three time points in a sample of undergraduate students. We tested competing models consistent with two basic positions regarding these fears: (1) that fear of positive evaluation only appears to affect social anxiety because it arises from the same, single underlying trait as fear of negative evaluation, and (2) fears of positive and negative evaluation are correlated, but clearly distinct, constructs. The best-fitting model was an autoregressive latent-trajectory model in which each type of fear had a separate trait-like component. The correlation between these trait-like components appeared to fully account for the relationships between these constructs over time. This investigation adds to the evidence in support of the second position described above: fear of positive evaluation is best interpreted as a separate construct from fear of negative evaluation.

ATM and p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance.

In this report, we investigated the role and regulation of forkhead box M1 (FOXM1) in breast cancer and epirubicin resistance. We generated epirubicin-resistant MCF-7 breast carcinoma (MCF-7-EPI(R)) cells and found FOXM1 protein levels to be higher in MCF-7-EPI(R) than in MCF-7 cells and that FOXM1 expression is downregulated by epirubicin in MCF-7 but not in MCF-7-EPI(R) cells. We also established that there is a loss of p53 function in MCF-7-EPI(R) cells and that epirubicin represses FOXM1 expression at transcription and gene promoter levels through activation of p53 and repression of E2F activity in MCF-7 cells. Using p53(-/-) mouse embryo fibroblasts, we showed that p53 is important for epirubicin sensitivity. Moreover, transient promoter transfection assays showed that epirubicin and its cellular effectors p53 and E2F1 modulate FOXM1 transcription through an E2F-binding site located within the proximal promoter region. Chromatin immunoprecipitation analysis also revealed that epirubicin treatment increases pRB (retinoblastoma protein) and decreases E2F1 recruitment to the FOXM1 promoter region containing the E2F site. We also found ataxia-telangiectasia mutated (ATM) protein and mRNA to be overexpressed in the resistant MCF-7-EPI(R) cells compared with MCF-7 cells and that epirubicin could activate ATM to promote E2F activity and FOXM1 expression. Furthermore, inhibition of ATM in U2OS cells with caffeine or depletion of ATM in MCF-7-EPI(R) with short interfering RNAs can resensitize these resistant cells to epirubicin, resulting in downregulation of E2F1 and FOXM1 expression and cell death. In summary, our data show that ATM and p53 coordinately regulate FOXM1 via E2F to modulate epirubicin response and resistance in breast cancer.

Measuring social anxiety related interpersonal constraint with the flexible iterated prisoner's dilemma.

Data from self-report and observational studies make it clear that problematic social anxiety confers interpersonal constraint that may contribute to the interpersonal dysfunction reported by individuals with social anxiety disorder. Direct observation of interpersonal behavior in established relationships is rare and difficult to obtain for practical reasons. We tested a flexible iterated prisoner's dilemma computer task to examine whether it might capture interpersonal constraint related to social anxiety. Our first study suggested that, at least for men, the task directly captures social anxiety's constraint on responses to friendly giving. Our second study more strongly supported the assertion that the task directly assesses interpersonal constraint. The data support a model in which social anxiety directly confers trait-like tendencies toward interpersonal constraint and indirectly constrains behavior in specific interactions. These studies provide further evidence that constrained responses to positive social behaviors are characteristic of people with problematic social anxiety and may be particularly important to dysfunctions in the close relationships of these individuals.