Predictors of response to cognitive-behavioral therapy for body dysmorphic disorder

Body dysmorphic disorder (BDD) is a common and distressing or impairing preoccupation with a perceived defect in physical appearance. Individuals with BDD engage in time-consuming rituals to check, hide, or "fix" their appearance or alleviate distress. BDD is associated with substantial psychosocial impairment and high rates of depression, hospitalization, and suicidality. Cognitive-behavioral therapy (CBT) is the treatment of choice for BDD, but not everyone benefits. We examined predictors of CBT-related improvement, an important topic that has received very limited investigation. Treatment was delivered in weekly individual sessions over 18-22 weeks. Results indicated that greater motivation/readiness to change (University of Rhode Island Change Assessment Questionnaire), greater treatment expectancy (Treatment Credibility/Expectancy Questionnaire), and better baseline BDD-related insight (Brown Assessment of Beliefs Scale) significantly predicted better CBT response at posttreatment. Baseline BDD symptom severity and depression did not predict outcome, suggesting that even patients with more severe BDD and depressive symptoms can benefit from CBT for BDD. Efforts should be aimed at enhancing readiness to change and confidence in the treatment at treatment onset as well as addressing the poor insight that often characterizes BDD.R34 MH070490 - NIMH NIH HHSAccepted manuscrip

Molecular determinants of drug-specific sensitivity for epidermal growth factor receptor (EGFR) exon 19 and 20 mutants in non-small cell lung cancer.

We hypothesized that aberrations activating epidermal growth factor receptor (EGFR) via dimerization would be more sensitive to anti-dimerization agents (e.g., cetuximab). EGFR exon 19 abnormalities (L747_A750del; deletes amino acids LREA) respond to reversible EGFR kinase inhibitors (TKIs). Exon 20 in-frame insertions and/or duplications (codons 767 to 774) and T790M mutations are clinically resistant to reversible/some irreversible TKIs. Their impact on protein function/therapeutic actionability are not fully elucidated.In our study, the index patient with non-small cell lung cancer (NSCLC) harbored EGFR D770_P772del_insKG (exon 20). A twenty patient trial (NSCLC cohort) (cetuximab-based regimen) included two participants with EGFR TKI-resistant mutations ((i) exon 20 D770>GY; and (ii) exon 19 LREA plus exon 20 T790M mutations). Structural modeling predicted that EGFR exon 20 anomalies (D770_P772del_insKG and D770>GY), but not T790M mutations, stabilize the active dimer configuration by increasing the interaction between the kinase domains, hence sensitizing to an agent preventing dimerization. Consistent with predictions, the two patients harboring D770_P772del_insKG and D770>GY, respectively, responded to an EGFR antibody (cetuximab)-based regimen; the T790M-bearing patient showed no response to cetuximab combined with erlotinib. In silico modeling merits investigation of its ability to optimize therapeutic selection based on structural/functional implications of different aberrations within the same gene

Aberrant error processing in relation to symptom severity in obsessive–compulsive disorder: A multimodal neuroimaging study

Background: Obsessive–compulsive disorder (OCD) is characterized by maladaptive repetitive behaviors that persist despite feedback. Using multimodal neuroimaging, we tested the hypothesis that this behavioral rigidity reflects impaired use of behavioral outcomes (here, errors) to adaptively adjust responses. We measured both neural responses to errors and adjustments in the subsequent trial to determine whether abnormalities correlate with symptom severity. Since error processing depends on communication between the anterior and the posterior cingulate cortex, we also examined the integrity of the cingulum bundle with diffusion tensor imaging. Methods: Participants performed the same antisaccade task during functional MRI and electroencephalography sessions. We measured error-related activation of the anterior cingulate cortex (ACC) and the error-related negativity (ERN). We also examined post-error adjustments, indexed by changes in activation of the default network in trials surrounding errors. Results: OCD patients showed intact error-related ACC activation and ERN, but abnormal adjustments in the post- vs. pre-error trial. Relative to controls, who responded to errors by deactivating the default network, OCD patients showed increased default network activation including in the rostral ACC (rACC). Greater rACC activation in the post-error trial correlated with more severe compulsions. Patients also showed increased fractional anisotropy (FA) in the white matter underlying rACC. Conclusions: Impaired use of behavioral outcomes to adaptively adjust neural responses may contribute to symptoms in OCD. The rACC locus of abnormal adjustment and relations with symptoms suggests difficulty suppressing emotional responses to aversive, unexpected events (e.g., errors). Increased structural connectivity of this paralimbic default network region may contribute to this impairment

Non–Destructive Imaging of Phytosulfokine Trafficking Using a Fiber–Optic Fluorescence Microscope

Plants secrete peptide ligands and use receptor signaling to respond to stress and control development. Understanding the signaling mechanisms and associated molecular trafficking is key to improving plant health and productivity for food, fiber and energy applications. However, one of the challenges to elucidating communication pathways in plants is to study the trafficking of molecules and signals iteratively and non-destructively. This study focuses on using fiber-optic fluorescence microscopy to image live plants iteratively and non-destructively after delivering both labeled and unlabeled phytosulfokine (PSK) into the plant. PSK is a sulfated peptide hormone involved in the regulation of plant cell division and growth via specific receptors, PSKRs. It also plays a role in regulating how plants are able to tolerate stress conditions. The microscope provides two-color (FITC/TRITC) optics and provides high-resolution (3–5 µm) epifluorescence micrographs via a 1-m coherent imaging fiber and a GRIN objective lens. To obtain high-quality images, the fiber was mounted either to a conventional upright microscope body equipped with a leaf compressor, or to a leaf clip with 5-axis positioning (X–Y–Z plus pitch and yaw) mounted on an extensible arm. PSK and TAMRA-labelled PSK were delivered into the roots of various Arabidopsis thaliana genotypes (wt; receptor-deficient: pskr1/pskr2; and tagged receptor overproducing: PSKR1‑GFP), and their movement in roots and leaves was tracked with the fiber-optic fluorescence microscope. Peptide trafficking was successfully observed in live plants non- destructively, confirming that PSK is mobile in both wt and receptor-deficient plants. Preliminary results suggest that the level of receptor PSKR1 may change in response to PSK, and that levels of PSKR1, PSKR2 or both may impact the trafficking of PSK. Understanding how PSK is trafficked in plants will offer insights into how we can improve plants health and productivity

Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study

Background: Neuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation. Methods: We measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response. Results: We replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant. Conclusions: DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation

Neuroimaging Correlates of Suicidality in Decision-Making Circuits in Posttraumatic Stress Disorder

In depression, brain and behavioral correlates of decision-making differ between individuals with and without suicidal thoughts and behaviors. Though promising, it remains unknown if these potential biomarkers of suicidality will generalize to other high-risk clinical populations. To preliminarily assess whether brain structure or function tracked suicidality in individuals with posttraumatic stress disorder (PTSD), we measured resting-state functional connectivity and cortical thickness in two functional networks involved in decision-making, a ventral fronto-striatal reward network and a lateral frontal cognitive control network. Neuroimaging data and self-reported suicidality ratings, and suicide-related hospitalization data were obtained from 50 outpatients with PTSD and also from 15 healthy controls, and all were subjected to seed-based resting-state functional connectivity and cortical thickness analyses using a priori seeds from reward and cognitive control networks. First, general linear models (GLM) were used to evaluate whether ROI-to-ROI functional connectivity was predictive of self-reported suicidality after false discovery rate (FDR)-correction for multiple comparisons and covariance of age and depression symptoms. Next, regional cortical thickness statistics were included as predictors of ROI-to-ROI functional connectivity in follow-up GLMs evaluating structure-function relationships. Functional connectivity between reward regions was positively correlated with suicidality (p-FDR ≤ 0.05). Functional connectivity of the lateral pars orbitalis to anterior cingulate/paracingulate control regions also tracked suicidality (p-FDR ≤ 0.05). Furthermore, cortical thickness in anterior cingulate/paracingulate was associated with functional correlates of suicidality in the control network (p-FDR < 0.05). These results provide a preliminary demonstration that biomarkers of suicidality in decision-making networks observed in depression may generalize to PTSD and highlight the promise of these circuits as transdiagnostic biomarkers of suicidality

Sex Differences in Substance Use and Misuse: A Toxicology Investigators\u27 Consortium (ToxIC) Registry Analysis

Background: Variations between male and female populations are previously reported in classes of harmfully used/misused drugs, severity of substance use disorder and risk of relapse. The aim of this study was to provide a review of bedside medical toxicologist managed, sex-specific poisonings in adults that present with harmful drug use/misuse. Methods: ToxIC Registry cases \u3e /=19 and \u3c /=65 years old, with harmful drug use or misuse during the timeframe June 2010-December 2016, were studied. Demographics, primary agents of toxic exposure, administration route and complications were analyzed. Descriptive methods were used in the analysis. Results: The database included 51,440 cases. Of these, 3426 cases were analyzed in which the primary reason for the encounter was harmful substance use/misuse. Females were found to harmfully use/misuse pharmaceutical drugs (N=806, 65.6%) more than nonpharmaceutical drugs (N=423, 34.4%). Males more frequently used nonpharmaceutical drugs (N=1189, 54.1%) than pharmaceutical drugs (1008, 45.9%). Analgesics were used by females (N= 215, 18.2%) and males (N=137, 6.6%). Sedative hypnotics were used by females (N=165, 14%) and males (N=160, 7.8%). Psychoactive agents were used by males (N=325, 15.8%) and females (N=67, 5.7%). Sympathomimetics were used by males (N=381, 18.5%) and females (N=151, 12.8%). The majority of both male and female participants, 1712 (57.9%), utilized an oral route of administration. However, 312 (16.5%) of males utilized inhalation vs 73 (6.8%) of females inhaled their substance. Conclusion: There were sex-specific differences among patients evaluated for harmful substance use/misuse by toxicologists. Considering these differences in regards to management and preventive approaches may be indicated

Understanding ownership of patient care: A dual-site qualitative study of faculty and residents from medicine and psychiatry

Introduction: With changes in duty hours and supervision requirements, educators have raised concerns about erosion of patient care ownership by resident physicians. However, the definition of ownership is unclear. This qualitative study investigated definitions of ownership in medicine and psychiatry faculty and residents. Methods: The authors distributed an anonymous online survey regarding definitions of ownership to faculty and residents at the psychiatry and internal medicine residency programs at the University of Washington and the Harvard Longwood psychiatry residency and conducted a qualitative analysis of free-text responses to identify emergent themes. Results: 225 faculty (48.6%) and 131 residents (43.8%) across the three programs responded. Responses yielded themes in five domains: Physician Actions, Physician Attitudes, Physician Identity, Physician Qualities, and Quality of Patient Care. All groups identified themes of advocacy, communication and care coordination, decision-making, follow through, knowledge, leadership, attitudes of going ‘above and beyond’ and ‘the buck stops here’, responsibility, serving as primary provider, demonstrating initiative, and providing the best care as central to ownership. Residents and faculty had differing perspectives on ‘shift work’ and transitions of care and on resident decision-making as elements of ownership. Discussion This study expanded and enriched the definition of patient care ownership. There were more similarities than differences across groups, a reassuring finding for those concerned about a decreasing understanding of ownership in trainees. Findings regarding shared values, shift work, and the decision-making role can inform educators in setting clear expectations and fostering ownership despite changing educational and care models