SETD2 mutations do not contribute to clonal fitness in response to chemotherapy in childhood B cell acute lymphoblastic leukemia.

Mutations in genes encoding epigenetic regulators are commonly observed at relapse in B cell acute lymphoblastic leukemia (B-ALL). Loss-of-function mutations in SETD2, an H3K36 methyltransferase, have been observed in B-ALL and other cancers. Previous studies on mutated SETD2 in solid tumors and acute myelogenous leukemia support a role in promoting resistance to DNA damaging agents. We did not observe chemoresistance, an impaired DNA damage response, nor increased mutation frequency in response to thiopurines using CRISPR-mediated knockout in wild-type B-ALL cell lines. Likewise, restoration of SETD2 in cell lines with hemizygous mutations did not increase sensitivity. SETD2 mutations affected the chromatin landscape and transcriptional output that was unique to each cell line. Collectively our data does not support a role for SETD2 mutations in driving clonal evolution and relapse in B-ALL, which is consistent with the lack of enrichment of SETD2 mutations at relapse in most studies.

Self-Rated Versus Clinician-Rated Assessment of Posttraumatic Stress Disorder: An Evaluation of Discrepancies Between the PTSD Checklist for DSM-5 and the Clinician-Administered PTSD Scale for DSM-5.

Posttraumatic stress disorder (PTSD) is commonly assessed with self-rated or clinician-rated measures. Although scores from these assessment modalities are strongly associated, they are often discrepant for individual symptoms, total symptom severity, and diagnostic status. To date, no known studies have empirically identified the sources of these discrepancies. In the present study, we had three aims: (a) replicate previously identified discrepancies; (b) examine contribution of possible objective predictors of discrepancies, including negative response bias, random responding, conscientiousness, neuroticism, and verbal IQ; and (c) identify subjective sources of discrepancies through analysis of participant feedback. Trauma-exposed undergraduates (N = 60) were administered the PTSD Checklist for DSM-5 (PCL-5), the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), and other questionnaires. Interviewers identified discrepancies between corresponding PCL-5/CAPS-5 scores and asked participants to describe their attributions for discrepancies. Discrepancies, both dimensional and dichotomous, occurred at the item, cluster, and total score level. Objective predictors were weakly associated with discrepancies. The most commonly reported reasons for discrepancies were time-frame reminders, comprehension of symptoms, trauma-related attribution errors, increased awareness, and general errors. These findings help explain discordance between the PCL-5 and CAPS-5, and inform use and interpretation of these two widely used PTSD measures in clinical and research applications.

Four profiles of symptom change in residential Cognitive Processing Therapy.

A significant portion of veterans do not respond to evidence-based treatments for PTSD. Therefore, researchers have sought to predict who will respond well to trauma-focused treatment. The present study examined pre- and posttreatment symptom profiles, session-by-session change, as well as demographic and additional diagnostic information to better understand PTSD treatment response. Participants included 332 veterans undergoing residential Cognitive Processing Therapy. Latent profile analyses were computed, and four meaningful profiles emerged: Fast Responders, Steady Responders, Partial Responders, and Minimal Responders. Each profile demonstrated symptom reduction at approximately the same rate in the first half of treatment. Two specific profiles, Steady Responders and Minimal Responders, showed key clinically important differences. Both profiles demonstrated severe pretreatment PTSD symptom severity; however, in the second half of treatment, Steady Responders saw the steepest decrease in symptoms of any of the profiles while Minimal Responders saw less symptom reduction compared to all other profiles. Via a thorough examination, membership in Steady Responders compared to Minimal Responders was not associated with demographic or health variables. Results suggest that pretreatment symptom severity does not necessarily determine a client's posttreatment symptom severity. Pretreatment symptom severity did not determine outcome, though some veterans (Minimal Responders) did not experience the same symptom change and treatment effectiveness. Further identifying the factors that lead to the separation of these groups will add important information for determining treatment selection and potential obstacles to effectiveness.

Evaluating the Factor Structure of the Posttraumatic Cognitions Inventory.

The Posttraumatic Cognitions Inventory (PTCI) is one of the most widely used measure of posttraumatic cognitions. The original factor analysis of the PTCI provided evidence for a three-factor model of negative cognitions about self, world, and self-blame. However, subsequent research has failed to replicate this factor structure without removing multiple items. Given these inconsistent findings, we examined the PTCI factor structure in a sample of trauma-exposed undergraduates (n = 868). First, we conducted a series of four confirmatory factor analyses (CFAs) based on previously published models of the PTCI and a modified model based on previously removed items, all which indicated poor fit. Next, we conducted a CFA of the recently published three-factor PTCI-9, which approached adequate fit. We then replicated the CFA of the PTCI-9 in a second independent sample (n = 971), finding a similar pattern of near adequate fit. These findings highlight the need to revise the PTCI. In addition, results indicate the promising nature of the PTCI-9 as an alternative measure of posttraumatic cognitions.

Posttraumatic Stress Disorder and Suicidal Ideation: The Moderating Effect of Posttraumatic Cognitions.

Although individuals with posttraumatic stress disorder (PTSD) are at an increased risk for suicidal ideation (SI), it is unclear what factors might influence this association. Investigators have hypothesized that posttraumatic cognitions (PTCs), such as self-blame (SB) or negative cognitions about the self (NCAS) or world (NCAW), would play a role, but this has not been investigated empirically. Accordingly, we evaluated a model in which the association between PTSD symptoms and SI was moderated by PTCs in a sample of trauma-exposed undergraduate students (N = 410). To identify the specific source of this hypothesized moderation effect, we ran the moderation model separately for PTSD total severity, PTSD total severity without the cognition-related items, and each of four DSM PTSD symptom clusters in combination with each of three types of PTCs (i.e., NCAS, NCAW, SB), accounting for quadratic effects. The results revealed that NCAW moderated the positive association between all six of the PTSD variables and SI, f2 s < .01 to .04. Analyses of simple slopes generally revealed strong positive associations between PTSD symptoms with SI at high levels of NCAW, no associations at moderate levels, and negative associations at low levels. We also found one statistically significant quadratic effect when examining avoidance and NCAW. In contrast, neither NCAS nor SB emerged as a significant moderator in any of our regression models. These findings highlight the importance of addressing PTCs-particularly NCAW-in trauma survivors.

An item response theory analysis of the PTSD checklist for DSM-5: Implications for DSM-5 and ICD-11.

The PTSD Checklist (PCL) is a widely used, extensively validated questionnaire for posttraumatic stress disorder (PTSD). The PCL was revised for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5; Friedman, 2013), and the updated version, the PCL-5, has continued the strong psychometric performance of the original version. To further explore the PCL-5's psychometric properties, we used item response theory (IRT) to examine item difficulty and discrimination parameters in separate samples of trauma-exposed undergraduates (N = 1213) and community members (N = 367). Considering item difficulty, nightmares, flashbacks, and reckless or self-destructive behavior emerged among the most difficult items across samples and internal avoidance emerged as the least difficult items across samples. In terms of item discrimination, inability to experience positive emotions, detachment from others, diminished interest, and negative emotions emerged as highly discriminating items in both samples, and traumatic amnesia and reckless or self-destructive behavior emerged as the least discriminating items in both samples. These results have implications for the divergent conceptualizations of PTSD in DSM-5 versus International Classification of Diseases, 11th Edition (ICD-11; WHO, 2018). Future research should employ IRT in a clinical population.

Network models of posttraumatic stress symptoms across trauma types.

Evidence suggests that posttraumatic stress (PTS) disorder (PTSD) symptom presentations may vary as a function of index trauma type. Network analysis was employed in the present study to examine differences in PTS symptom centrality (i.e., the relative influence of a symptom on the network), and PTS symptom associations across three trauma types: motor vehicle accident (MVA), sexual assault (SA), and sudden accidental/violent death of a loved one (SAD). The final sample comprised 554 female undergraduates who had experienced a MVA (n = 226), SA (n = 222), or SAD (n = 106) per Diagnostic Statistical Manual-Fifth Edition (DSM-5) criteria. Within the pooled network, anhedonia and dysphoria emerged as the most central symptoms, while trauma-related amnesia was the least central. The SA network was largely consistent with the DSM-5 conceptualization of PTSD. In contrast, the SAD network was the least consistent with the DSM-5 conceptualization of PTSD, and centrality estimates for the SAD network were inconsistent with the MVA and SA networks. Findings of the current study suggest a need to consider index trauma type as an important factor in the ontology of PTSD. Findings also add to the ongoing discussions about the suitability of SAD as a PTSD-relevant trauma type and about the importance of trauma-related amnesia as a PTSD symptom.

Dimensions of Growth? Examining the Distinctiveness of the Five Factors of the Posttraumatic Growth Inventory.

Posttraumatic growth, defined as positive transformation following trauma, is commonly measured using the Posttraumatic Growth Inventory (PTGI; Tedeschi & Calhoun, 1996) and is postulated to comprise five distinct domains: Changes in Relationships, Life Possibilities, Personal Strength, Spirituality, and Appreciation of Life. However, research has indicated that the model fit is not good and the factors are highly intercorrelated. Further, no studies have formally examined the heterogeneity of correlations of the five factors with external constructs. In an effort to examine the construct validity of the five-factor model of the PTGI, the present study aimed to examine the degree to which the theorized five factors demonstrate meaningful differential associations with relevant external correlates. Participants were 400 undergraduate students who reported having experienced a stressful event and completed the Life Events Checklist for DSM-5, PTGI, Posttraumatic Stress Disorder Checklist for DSM-5, Grit Scale-12, Connor-Davidson Resilience Scale-10, and Work and Social Adjustment Scale. We found few instances of significant differentiation, and effect sizes for pairwise comparisons were generally small, Cohen's qs = 0.01-0.35. Although factor analytic evidence suggests there are five distinct underlying constructs, our results indicated that these factors do not significantly differ in their associations with external correlates. Implications for use of the PTGI and future research directions are discussed.

Construct validation of the hybrid model of posttraumatic stress disorder: Distinctiveness of the new symptom clusters.

Despite the factor analytic support for the seven-factor hybrid model (Armour et al., 2015) of posttraumatic stress disorder (PTSD), little research has examined the degree to which newly established symptom clusters (i.e., negative affect, anhedonia, dysphoric arousal, anxious arousal, externalizing behavior) functionally and meaningfully differ in their associations with other clinical phenomena. The aim of the current study was to examine the degree to which newly established PTSD symptom clusters differentially relate to co-occurring psychopathology and related clinical phenomena through Wald testing using latent variable modeling. Participants were 535 trauma-exposed undergraduates who completed the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5; Weathers et al., 2013) and Personality Assessment Inventory (PAI; Morey, 1991). As expected and in line with results from previous studies, significant heterogeneity emerged for dysphoric arousal, anxious arousal, and externalizing behavior. However, there was less evidence for the distinctiveness of negative affect and anhedonia. Results indicate that only some of the newly established symptom clusters significantly differ in their associations with related clinical phenomena and that the hybrid model might not provide a meaningful framework for understanding which PTSD symptoms relate to associated features. Limitations include a non-clinical sample and reliance on retrospective self-report assessment measures.