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Background Although aspects of brain morphology have been associated with chronic posttraumatic stress disorder (PTSD), limited work has investigated multimodal patterns in brain morphology that are linked to acute posttraumatic stress severity. In the present study, we utilized multimodal magnetic resonance imaging to investigate if structural covariance networks (SCNs) assessed acutely following trauma were linked to acute posttraumatic stress severity. Methods Structural magnetic resonance imaging data were collected around 1 month after civilian trauma exposure in 78 participants. Multimodal magnetic resonance imaging data fusion was completed to identify combinations of SCNs, termed structural covariance profiles (SCPs), related to acute posttraumatic stress severity collected at 1 month. Analyses assessed the relationship between participant SCP loadings, acute posttraumatic stress severity, the change in posttraumatic stress severity from 1 to 12 months, and depressive symptoms. Results We identified an SCP that reflected greater gray matter properties of the anterior temporal lobe, fusiform face area, and visual cortex (i.e., the ventral visual stream) that varied curvilinearly with acute posttraumatic stress severity and the change in PTSD symptom severity from 1 to 12 months. The SCP was not associated with depressive symptoms. Conclusions We identified combinations of multimodal SCNs that are related to variability in PTSD symptoms in the early aftermath of trauma. The identified SCNs may reflect patterns of neuroanatomical organization that provide unique insight into acute posttraumatic stress. Furthermore, these multimodal SCNs may be potential candidates for neural markers of susceptibility to both acute posttraumatic stress and the future development of PTSD.

Objective The impact of disrupted sleep on the effectiveness of prolonged exposure (PE) therapy for posttraumatic stress disorder (PTSD) is not well understood. Researchers have suggested that comorbid sleep disorders contribute to nonresponse by impairing therapeutic mechanisms such as emotional processing of trauma memories and extinction in cued fear conditioning. Several studies indicate daytime sleepiness, insomnia, and nightmares are correlated with PTSD symptom severity. However, a recent randomized controlled trial found that these sleep disorder symptoms did not affect PTSD symptom change over the course of massed PE (i.e., daily sessions across 2 weeks). Method The current study used an ecologically valid clinical sample to examine whether daytime sleepiness, insomnia, and nightmares interfere with the slope of symptom change in massed PE. Results Results indicate that all 3 sleep disorder symptoms correlate with PTSD symptom severity on the first day of treatment but were not associated with symptom change. Conclusions These findings are consistent with the expectation that the daily structure of massed PE may enhance treatment engagement in patients who are typically drowsy or not well-rested, thus facilitating fear extinction. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Significance\ud \ud Communicating in ways that motivate engagement in social distancing remains a critical global public health priority during the COVID-19 pandemic. This study tested motivational qualities of messages about social distancing (those that promoted choice and agency vs. those that were forceful and shaming) in 25,718 people in 89 countries. The autonomy-supportive message decreased feelings of defying social distancing recommendations relative to the controlling message, and the controlling message increased controlled motivation, a less effective form of motivation, relative to no message. Message type did not impact intentions to socially distance, but people’s existing motivations were related to intentions. Findings were generalizable across a geographically diverse sample and may inform public health communication strategies in this and future global health emergencies.\ud \ud \ud \ud Abstract\ud \ud Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges.

Background Many reports have documented the relationship between previous traumatic experiences, including childhood trauma, and the development of later life psychopathology, including posttraumatic stress disorder (PTSD). Identification of individuals at greatest risk for the development of PTSD could lead to preventative interventions. The present study examined the developmental course of PTSD after trauma exposure, using histories of previous traumatic experiences and the severity of the reaction to the trauma as predictors. Methods Participants (N = 713) were recruited from Emergency Departments in Miami and Atlanta immediately following a traumatic experience. Histories of previous traumatic experiences and the immediate reaction to the new trauma were examined at baseline. Follow-up assessments of PTSD severity were conducted at 1, 3, and 6 months. Results Histories of child abuse and pre-existing trauma symptoms predicted the immediate response to stress (R2 = .21, p 0.86). Conclusions The current findings suggest that previous traumatic experiences lead to a greater immediate reaction to trauma and combine to predict the development of PTSD, the maintenance of which is not moderated by these earlier experiences. The identification of people likely to develop PTSD may be aided by the assessment of prior experiences and immediate reactions.

Background Posttraumatic stress disorder (PTSD) is linked to a specific event, providing the opportunity to intervene in the immediate aftermath of trauma to prevent the development of this disorder. A previous trial demonstrated that trauma survivors who received three sessions of modified prolonged exposure therapy demonstrated decreased PTSD and depression prospectively compared to assessment only. The present study investigated the optimal dosing of this early intervention to test one versus three sessions of exposure therapy in the immediate aftermath of trauma. Methods Participants (n = 95) recruited from a Level 1 Trauma Center were randomly assigned in a 1.5:1.5:1 ratio in a parallel-group design to the three conditions: one-session exposure therapy, three-session exposure therapy, and assessment only. Follow-up assessments were conducted by study assessors blind to study condition. Results Mixed-effects model results found no significant differences in PTSD or depression symptoms between the control condition and those who received one or three exposure therapy sessions across 1-12-month follow-up assessment. Results indicate that the intervention did not interfere with natural recovery. Receiver operating characteristic curve analyses on the screening measure used for study inclusion (Predicting PTSD Questionnaire; PPQ) in the larger sample from which the treatment sample was drawn (n = 481) found that the PPQ was a poor predictor of likely PTSD at all follow-up time points (Area under the curve's = 0.55-0.62). Conclusions This likely impacted study results as many participants demonstrated natural recovery. Recommendations for future early intervention research are reviewed, including strategies to identify more accurately those at risk for PTSD and oversampling more severe trauma types.

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological Psychiatry Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods. publishersversion published

Biomarkers that predict symptom trajectories after trauma can facilitate early detection or intervention for posttraumatic stress disorder (PTSD) and may also advance our understanding of its biology. Here, we aimed to identify trajectory-based biomarkers using blood transcriptomes collected in the immediate aftermath of trauma exposure. Participants were recruited from an Emergency Department in the immediate aftermath of trauma exposure and assessed for PTSD symptoms at baseline, 1, 3, 6, and 12 months. Three empirical symptom trajectories (chronic-PTSD, remitting, and resilient) were identified in 377 individuals based on longitudinal symptoms across four data points (1, 3, 6, and 12 months), using latent growth mixture modeling. Blood transcriptomes were examined for association with longitudinal symptom trajectories, followed by expression quantitative trait locus analysis. GRIN3B and AMOTL1 blood mRNA levels were associated with chronic vs. resilient post-trauma symptom trajectories at a transcriptome-wide significant level (N = 153, FDR-corrected p value = 0.0063 and 0.0253, respectively). We identified four genetic variants that regulate mRNA blood expression levels of GRIN3B. Among these, GRIN3B rs10401454 was associated with PTSD in an independent dataset (N = 3521, p = 0.04). Examination of the BrainCloud and GTEx databases revealed that rs10401454 was associated with brain mRNA expression levels of GRIN3B. While further replication and validation studies are needed, our data suggest that GRIN3B, a glutamate ionotropic receptor NMDA type subunit-3B, may be involved in the manifestation of PTSD. In addition, the blood mRNA level of GRIN3B may be a promising early biomarker for the PTSD manifestation and development.

The Supplemental Nutrition Assistance Program (SNAP), the only universal US means-tested safety net program, has a low benefit-reduction rate. Thus, many SNAP recipients are working. We apply recent methods to study whether there is evidence of moral hazard among SNAP recipients. We see if individuals respond to incentives in SNAP eligibility by bunching near kink points in the budget set. While this responsiveness has been shown for various taxes and tax credits, little work has examined responsiveness of safety net program participants to kinks in their eligibility formulae. We use novel administrative data on eligibility determination and find little evidence of responsiveness around these kinks.

The clinical construct of "anxiety neurosis" was broad and poorly defined, so that the delineation of specific anxiety disorders in the DSM-III was an important advance. However, anxiety and related disorders are not only frequently comorbid, but each is also quite heterogeneous; thus diagnostic manuals provide only a first step towards formulating a management plan, and the development of additional decision support tools for the treatment of anxiety conditions is needed. This paper aims to describe systematically important domains that are relevant to the personalization of management of anxiety and related disorders in adults. For each domain, we summarize the available research evidence and review the relevant assessment instruments, paying special attention to their suitability for use in routine clinical practice. We emphasize areas where the available evidence allows the clinician to personalize the management of anxiety conditions, and we point out key unmet needs. Overall, the evidence suggests that we are becoming able to move from simply recommending that anxiety and related disorders be treated with selective serotonin reuptake inhibitors, cognitive-behavioral therapy, or their combination, to a more complex approach which emphasizes that the clinician has a broadening array of management modalities available, and that the treatment of anxiety and related disorders can already be personalized in a number of important respects.

Virtual reality exposure therapy (VRE) for posttraumatic stress disorder (PTSD) is an innovative and increasingly popular approach to delivering trauma-focused exposure therapy to a range of populations exposed to trauma. VRE is best viewed as another medium for prolonged exposure (PE), which is the most extensively researched treatment for PTSD and is one of the universally recommended psychotherapies in clinical practice guidelines. The unique application of VRE is imaginal exposure to the trauma memory conducted with the eyes open within a VR environment to help activate and sustain the memory sufficiently. Since its proof of concept over two decades ago, the availability and acceptability of VR technologies in the context of mental health treatment has greatly increased. This article describes the theory, evidence, and procedures of VRE. Clinicians interested in VRE are encouraged to pursue appropriate training and consultation. [ Psychiatr Ann. 2019;49(8):343–347.]

Objective: Critical care nurses work in a challenging intensive care (ICU) environment that results in work-related psychological distress. Our objective was to pilot an in-person or virtual mindfulness-based cognitive therapy (MBCT) program enhanced resilience and a similarly designed attention control group. Methods: We randomized ICU nurses with symptoms of burnout syndrome and decreased resilience to an MBCT program or a similarly formatted book club control. Our primary outcome was change in resilience as measured by the Connor-Davidson Resilience Scale (CD-RISC). Results: One-hundred one nurses completed study-related procedures. Overall, 70% had baseline symptoms of anxiety and 26% had symptoms of depression. For the in-person cohorts, there was no statistical difference between intervention and control groups regarding the total number of sessions attended (3.85 days ± 1.4 versus 3.75 days ± 0.15; p = 0.64). Using the Client/Patient Satisfaction Questionnaire-8 (CSQ-8), satisfaction scores were higher in the intervention group for weeks two through four of the program: p = 0.03, 0.0003, 0.007 respectively. There was no difference in the change in CD-RISC scores between the two groups (mean difference: treatment = 5.0, control = 7.0; p = 0.30). The online intervention cohort had greater improvements in the change of their median emotional exhaustion burnout scores when compared to the in-person intervention cohorts (-5 [-8 to -1.5] vs. 2 [-5 to 8], p = 0.049). Conclusions: We developed a feasible and acceptable in-person and online MBCT-ICU intervention that did not increase resilience scores in ICU nurses when compared to an attention control group. These results could help guide the proper design of larger trials to determine the efficacy of other resilience interventions.

Background Anhedonic symptoms of posttraumatic stress disorder (PTSD) reflect deficits in reward processing that have significant functional consequences. Although recent evidence suggests that disrupted integrity of fronto-limbic circuitry is related to PTSD development, including anhedonic PTSD symptoms (posttrauma anhedonia [PTA]), little is known about potential structural biomarkers of long-term PTA as well as structural changes in fronto-limbic pathways associated with recovery from PTA over time. Methods We investigated associations between white matter microstructure, gray matter volume, and PTA in 75 recently traumatized individuals, with a subset of participants (n = 35) completing follow-up assessment 12 months after trauma exposure. Deterministic tractography and voxel-based morphometry were used to assess changes in white and gray matter structure associated with changes in PTA. Results Reduced fractional anisotropy (FA) of the uncinate fasciculus at around the time of trauma predicted greater PTA at 12-months posttrauma. Further, increased FA of the fornix over time was associated with lower PTA between 1 and 12-months posttrauma. Increased gray matter volume of the ventromedial prefrontal cortex and precuneus over time was also associated with reduced PTA. Conclusions The microstructure of the uncinate fasciculus, an amygdala-prefrontal white matter connection, may represent a biomarker of vulnerability for later PTA. Conversely, development and recovery from PTA appear to be facilitated by white and gray matter structural changes in a major hippocampal pathway, the fornix. The present findings shed new light on neuroanatomical substrates of recovery from PTA and characterize white matter biomarkers of risk for posttraumatic dysfunction.

The factors that attract and concern medical students about a career in neurosurgery have never been clearly characterized or delineated in a large nationwide cohort of medical students intending to pursue a career in neurosurgery. The objective of the present study was to characterize the factors that influence medical student interest in neurosurgery and assess the effects of a formal neurosurgery training course on participants' perceptions of a career in neurosurgery.Before the Medical Student Neurosurgery Training Camp for subinternship preparation, registered students were surveyed about their interest level in neurosurgery, factors that attracted or concerned them about a career in neurosurgery, attendance at a national neurosurgery conference or course, formal clinical neurosurgery exposure in medical school, and whether they had a resident or attending mentor in neurosurgery. At the end of the course, all the participants completed the surveyed again. P0.05 was considered significant on Pearson's χOf the training camp attendees,95% completed both pre- and postcourse surveys, including 41 first-year, 19 second-year, 30 third-year, and 5 fourth-year medical school students. The most common factors that concerned students about a career in neurosurgery were work-life balance (76%) and competitiveness (56%). All factors of concern were decreased in the postcourse survey, except for competitiveness. A small cohort (8.4%) of students had no concerns about a career in neurosurgery; this cohort had doubled to 17% after the course (P0.05). The students that indicated no concern had a greater postcourse interest level in neurosurgery (95.8 ± 8.7 vs. 86.7 ± 20.5; P0.05). Student reasons for an interest in neurosurgery included intellectually stimulating work (94%), interest in neurosciences (93%), effect on patients (84%), innovation and new technology (80%), research opportunities (77%), and prestige (24%). All reasons increased after the course, with the exception of prestige, which decreased to 22%.A training camp for students pursuing a neurosurgery subinternship was effective in providing transparency and positively influencing the factors that attract and concern students about a career in neurosurgery. Characterization of medical student perceptions of neurosurgery from a large, nationwide cohort of students pursuing a subinternship has provided novel data and could help identify factors protecting against burnout later in life.

Annually, approximately 30 million patients are discharged from the emergency department (ED) after a traumatic event1. These patients are at substantial psychiatric risk, with approximately 10-20% developing one or more disorders, including anxiety, depression or post-traumatic stress disorder (PTSD)2-4. At present, no accurate method exists to predict the development of PTSD symptoms upon ED admission after trauma5. Accurate risk identification at the point of treatment by ED services is necessary to inform the targeted deployment of existing treatment6-9 to mitigate subsequent psychopathology in high-risk populations10,11. This work reports the development and validation of an algorithm for prediction of post-traumatic stress course over 12 months using two independently collected prospective cohorts of trauma survivors from two level 1 emergency trauma centers, which uses routinely collectible data from electronic medical records, along with brief clinical assessments of the patient's immediate stress reaction. Results demonstrate externally validated accuracy to discriminate PTSD risk with high precision. While the predictive algorithm yields useful reproducible results on two independent prospective cohorts of ED patients, future research should extend the generalizability to the broad, clinically heterogeneous ED population under conditions of routine medical care.

Traditionally, evidence-based treatment for PTSD is delivered in an outpatient format with dropout rates ranging from 30 to 62%. Modifications of existing protocols for delivery in intensive outpatient format offer promise for retention and excellent therapeutic outcomes. This article will review the existing literature on evidence-based psychotherapy for PTSD delivered within an intensive outpatient format. Studies indicate that the intensive outpatient format substantially increases retention rates and demonstrates treatment outcomes at least equivalent to those demonstrated in traditional outpatient settings. Findings are limited by the dearth of randomized clinical trials to date. Current research highlights the utility of implementing evidence-based PTSD treatment in massed intensive format, which evidences improved treatment retention and comparable outcomes with traditional outpatient formats.

While emotion dysregulation is associated with many psychological disorders, including posttraumatic stress disorder (PTSD), it remains uncertain whether pre-existing emotion dysregulation increases individual risk for prospectively developing PTSD in the aftermath of trauma exposure. Thus, the objective of the current study was to determine whether emotion dysregulation could prospectively predict the development of chronic PTSD symptoms following a traumatic event above and beyond other known associated factors, including depressive symptoms, baseline PTSD symptoms, total traumas experienced, and exposure to interpersonal trauma. Participants (N = 135) were recruited from the emergency department (ED) at Grady Memorial Hospital in Atlanta and follow-up assessments were conducted at 1-, 3-, 6-, and 12-months following trauma exposure. Latent Growth Mixture Modeling was used to identify PTSD symptom trajectories based on symptoms assessed at 1, 3, 6, and 12 months; three trajectories emerged: “chronic”, “recovery”, and “resilient”. For the present study, probability of chronic PTSD symptoms was used as the outcome variable of interest. Linear regression modeling showed that emotion dysregulation was significantly associated with probability of developing chronic PTSD symptoms (p = 0.001) and accounted for an additional 7% of unique predictive variance when controlling for trauma exposure, baseline PTSD, and depressive symptoms. Our findings suggest that emotion dysregulation can be used as both a predictor of chronic PTSD and as a treatment target. Thus, identifying individuals with high levels of emotion dysregulation at the time of trauma and implementing treatments designed to improve emotion regulation could aid in decreasing the development of chronic PTSD among these at-risk individuals.

Many reports have documented the relationship between post-traumatic stress disorder (PTSD) and substance use. Substance use is commonly comorbid with PTSD and is a risk factor for trauma exposure. The aim of this study was to prospectively examine how recent substance use, abuse, or dependence influenced the development of PTSD in the context of a prior trauma history, including child abuse, and the severity of initial trauma reactions. Participants (N = 81) were recruited and assessed at the emergency department of a large urban hospital in Miami and serum levels of common drugs of abuse were measured. Although substance use appeared to be a risk factor for trauma exposure, neither self-reported nor blood toxicology influenced the development of PTSD. Positive toxicology screens were more likely to be associated with a diagnosis of substance abuse or dependence, χ2 (1) = 4.11, p = .04. Participants with a history of physical abuse were more likely to have a positive toxicology screen, χ2 (1) = 4.03, p = .05. The majority of our trauma-exposed subjects (66%) were found to be positive for one or more illicit substances at presentation at the ED. The current findings provide support for the “high risk” hypothesis in which substance use is associated with increased trauma exposure.

PURPOSE Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL). METHODS Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee–assessed noninferiority of progression-free survival (PFS). RESULTS Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients. CONCLUSION In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.

Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European (n = 70,870) and African (n = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: β = 2.83, standard error (SE) = 0.06, p < 1E-20; DBP: β = 1.32, SE = 0.04, p < 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study – United Kingdom Biobank – PTSD symptoms were negatively associated with SBP levels (β = −1.46, SE = 0.44, p = 9.8E-4) and positively associated with DBP levels (β = 0.70, SE = 0.26, p = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (β = 2.81, SE = 1.13, p = 0.01); no significant association was observed for DBP (β = 0.43, SE = 0.78, p = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.

Although several reports have documented heightened systemic inflammation in posttraumatic stress disorder (PTSD), few studies have assessed whether inflammatory markers serve as prospective biomarkers for PTSD risk. The present study aimed to characterize whether peripheral immune factors measured in blood samples collected in an emergency department immediately after trauma exposure would predict later chronic development of PTSD.Participants (N=505) were recruited from a hospital emergency department and underwent a 1.5-hour assessment. Blood samples were drawn, on average, about 3 hours after trauma exposure. Follow-up assessments were conducted 1, 3, 6, and 12 months after trauma exposure. Latent growth mixture modeling was used to identify classes of PTSD symptom trajectories.Three distinct classes of PTSD symptom trajectories were identified: chronic (N=28), resilient (N=160), and recovery (N=85). Multivariate analyses of covariance revealed a significant multivariate main effect of PTSD symptom trajectory class membership on proinflammatory cytokines. Univariate analyses showed a significant main effect of trajectory class membership on plasma concentrations of proinflammatory tumor necrosis factor α (TNFα) and interferon-γ (IFNγ). Concentrations of proinflammatory TNFα and IFNγ were significantly lower in individuals in the chronic PTSD class compared with those in the recovery and resilient classes. There were no significant differences in interleukin (IL) 1β and IL-6 concentrations by PTSD symptom trajectory class. Anti-inflammatory and other cytokines, as well as chemokines and growth factor concentrations, were not associated with development of chronic PTSD.Overall, the study findings suggest that assessing the proinflammatory immune response to trauma exposure immediately after trauma exposure, in the emergency department, may help identify individuals most at risk for developing chronic PTSD in the aftermath of trauma.

OBJECTIVEPostoperative surgical site infections (SSIs) in neurosurgical patients carry a significant risk of increased morbidity and mortality. With SSIs accounting for approximately 20% of nosocomial infections and costing approximately $1.6 billion USD annually, there is a need for additional prophylaxis to improve current standards of care. Topical vancomycin is increasingly utilized in instrumented spinal and cardiothoracic procedures, where it has been shown to reduce the risk of SSIs. A randomized controlled trial assessing its efficacy in the general neurosurgical population is currently underway. Here, the authors report their initial impressions of topical vancomycin safety among patients enrolled during the 1st year of the trial.METHODSThis prospective, multicenter, patient-blinded, randomized controlled trial will enroll 2632 patients over 5 years. Here, the authors report the incidence of adverse events, the degree of systemic vancomycin absorption in treated patients, and pattern changes of antibiotic-resistant profiles of Staphylococcus aureus flora among patients enrolled during the 1st year.RESULTSThe topical vancomycin treatment group comprised 257 patients (514 total enrolled patients), of whom 2 exhibited weakly positive serum levels of vancomycin (> 3.0 mg/dl). S. aureus was detected preoperatively in the anterior nares of 35 (18.1%) patients and the skin near the surgical site of 9 (4.7%). Colonization in the nares remained for many patients (71.4%) through postoperative day 30. The authors found a significant association between preoperative S. aureus colonization and postoperative colonization. Seven methicillin-resistant isolates were detected among 6 different patients. Two isolates were detected preoperatively, and 5 were de novo postoperative colonization. No adverse responses to treatment have been reported to date.CONCLUSIONSThe authors’ data indicate that the use of topical vancomycin is safe with no significant adverse effects and minimal systemic absorption, and no development of vancomycin-resistant microorganisms.Clinical trial registration no.: NCT02284126 (clinicaltrials.gov)

Anhedonia emerges in some people after psychological trauma, reflected by a loss of interest, diminished affect, and detachment. Structural abnormalities in specific neural pathways at the time of trauma may influence the development of these posttraumatic anhedonia (PTA) symptoms. In this prospective study, we determined whether white matter connectivity at around one month post-trauma predicts PTA and other PTSD symptoms at six months post-trauma. Thirty men and women aged 19–62 were recruited from the emergency department of a Level I trauma center. Participants received diffusion tensor imaging at approximately one month post-trauma and clinical assessments at one and six months post-trauma. Probabilistic tractography was used to examine connectivity of select pathways. A replication sample (N = 57) in an independent, cross-sectional dataset of traumatized women was similarly analyzed. Logistic regression results indicated that, after accounting for early PTSD symptoms (at one month) and other clinical risk factors, the integrity of the uncinate fasciculus (UF) uniquely predicted the presence of PTA at six months post-trauma (Beta = −225.6, p < .05). Together, these factors contributed to 76% of the variance in PTA. Integrity of the UF also predicted re-experiencing PTSD symptoms at six months post-trauma. These results were supported in our replication analyses. Our findings indicate that the integrity of the UF around 1 month post-trauma affects vulnerability for the development of anhedonic PTSD symptoms as well as re-experiencing symptoms. Connectivity of this amygdalaventromedial prefrontal pathway appears to be a salient predictor of anhedonia, above and beyond clinical risk factors.

Background: Food addiction (FA) is a dysregulated eating pattern characterized by difficulties in controlling the intake of certain foods. There is an overlap in physical and mental health correlates of FA and post-traumatic stress disorder (PTSD). The purpose of this study was to examine sex differences in the rates of positive FA status in individuals with threshold/subthreshold PTSD, and to examine sex differences in the physical and mental health correlates of FA. Methods: Post-9/11 veterans/service members seeking PTSD treatment were recruited. Participants were diagnosed with PTSD via the administration of a clinical interview. FA status was determined using Modified Yale Food Addiction Scale-2, binary sex and body mass index were assessed with demographics questions. Results: Nearly half (43%) of the sample were women. There were no sex differences in the rates of FA, with an overall FA prevalence of 18%. There were no sex differences in FA symptom count in the whole sample (M = 1.63) or those with FA status (M = 6.21). Individuals with FA reported higher frequency of disordered eating, higher severity of PTSD, and depression symptoms. Conclusions: FA should be assessed in tandem with PTSD symptoms, as its prevalence in that sample is higher than in the general population, and it appears to affect both sexes at similar rates.

Therapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13]) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade ≥3 AEs (occurring in ≥5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Background Exposure to a traumatic event leads to posttraumatic stress disorder in 10% to 20% of exposed individuals. Predictors of risk are needed to target early interventions to those who are most vulnerable. The objective of the study was to test whether a noninvasive mobile device that measures a physiological biomarker of autonomic nervous system activation could predict future posttraumatic stress disorder symptoms. Methods Skin conductance response was collected during a trauma interview in the emergency department within hours of exposure to trauma in 95 individuals. Trajectories of posttraumatic stress disorder symptoms over 12-month posttrauma were identified using latent growth mixture modeling. Results Skin conductance response was significantly correlated with the probability of being in the chronic posttraumatic stress disorder trajectory following trauma exposure in the emergency department (r = 0.489, p Conclusions This study is the first prospective study of posttraumatic stress disorder showing skin conductance response in the immediate aftermath of trauma predicts subsequent development of chronic posttraumatic stress disorder. This finding points to an easily obtained, and neurobiologically informative, biomarker in emergency departments that can be disseminated to predict the development of posttraumatic stress disorder.

Background This investigation involved an in-depth examination of psychophysiological responses during exposure to the trauma memory across 10 sessions among active duty soldiers with combat-related posttraumatic stress disorder (PTSD) treated by Prolonged Exposure (PE) or Virtual Reality Exposure (VRE). We compared psychophysiological changes, session-by-session, between VRE and traditional imaginal exposure. Methods Heart rate (HR), galvanic skin response (GSR), and peripheral skin temperature were collected every 5 min during exposure sessions with 61 combat veterans of Iraq/Afghanistan and compared to the PTSD Checklist (PCL-C) and Clinician-Administered PTSD Scale (CAPS) outcomes using multilevel modeling. Results Over the course of treatment, participants in the PE group had higher HR arousal compared to participants in the VRE group. With reference to GSR, in earlier sessions, participants demonstrated a within-session increase, whereas, in later sessions, participants showed a within-session habituation response. A significant interaction was found for GSR and treatment assignment for within-session change, within-person effect, predicting CAPS (d = 0.70) and PCL-C (d = 0.66) outcomes. Conclusion Overall, these findings suggest that exposure to traumatic memories activates arousal across sessions, with GSR being most associated with reductions in PTSD symptoms for participants in the PE group.

The societal burden of anxiety disorders is enormous in the United States and in many other countries. A quarter of the US population will experience an anxiety disorder at some point in their lives. Although cognitive-behavioral therapy is effective at treating anxiety disorders, most individuals with anxiety disorders will go untreated as a consequence of several barriers to accessing treatment. Technology may serve as a means of addressing such barriers. This chapter reviews the application of technology for psychoeducation, training, screening, tracking, treatment, homework, and aftercare in anxiety disorders. More research is needed to evaluate the efficacy of these applications in controlled trials, but preliminary evidence is promising.

Posttraumatic stress disorder (PTSD) is characterized by increased risk for developing hypertension and cardiovascular disease. We recently showed that device-guided slow breathing (DGB) acutely lowers blood pressure (BP) and muscle sympathetic activity (MSNA) and improves baroreflex sensitivity (BRS) in PTSD. The aim of this study was to assess the long-term benefits of DGB on autonomic function at rest and during stress. We hypothesized that long-term DGB improves arterial BRS and lowers BP and MSNA in PTSD. Twenty-five veterans with PTSD were studied and randomized to either 8 wk of daily DGB ( n = 12) or 8 wk of sham device (Sham; n = 13). BP, heart rate (HR), and MSNA were measured at rest and during mental math. Arterial BRS was assessed using the modified Oxford technique. Resting MSNA, BP, and heart rate (HR) remained comparable before and after 8 wk in both groups (DGB and Sham). Likewise, the change in sympathetic and cardiovagal BRS was not different between the groups. Interestingly, DGB significantly decreased MSNA reactivity to mental math when expressed as burst frequency ( P = 0.012) or burst incidence ( P = 0.008) compared with Sham, suggesting a sustained effect of DGB on sympathetic reactivity to stress in PTSD. Contrary to our hypothesis, long-term DGB did not lower systolic BP, diastolic BP, or HR responses to stress compared with Sham. Likewise, pulse pressure reactivity after 8 wk ( P = 0.121) was also comparable. In summary, these data suggest that long-term use of DGB may lead to a sustained dampening of sympathetic reactivity to mental stress in PTSD.

High rates of drop-out from treatment of PTSD have challenged implementation. Care models that integrate PTSD focused psychotherapy and complementary interventions may provide benefit in retention and outcome. The first 80 veterans with chronic PTSD enrolled in a 2-week intensive outpatient program combining Prolonged Exposure (PE) and complementary interventions completed symptom and biological measures at baseline and posttreatment. We examined trajectories of symptom change, mediating and moderating effects of a range of patient characteristics. Of the 80 veterans, 77 completed (96.3%) treatment and pre- and posttreatment measures. Self-reported PTSD (p < .001), depression (p < .001) and neurological symptoms (p < .001) showed large reductions with treatment. For PTSD, 77% (n = 59) showed clinically significant reductions. Satisfaction with social function (p < .001) significantly increased. Black veterans and those with a primary military sexual trauma (MST) reported higher baseline severity than white or primary combat trauma veterans respectively but did not differ in their trajectories of treatment change. Greater cortisol response to the trauma potentiated startle paradigm at baseline predicted smaller reductions in PTSD over treatment while greater reductions in this response from baseline to post were associated with better outcomes. Intensive outpatient prolonged exposure combined with complementary interventions shows excellent retention and large, clinically significant reduction in PTSD and related symptoms in two weeks. This model of care is robust to complex presentations of patients with varying demographics and symptom presentations at baseline. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Objective Interhospital patient transfer (IHT) of patients is common and accounts for a significant portion of health care costs, yet the variables driving neurosurgical IHT have not been systematically described. We analyzed variables that distinguished spine surgery patients who underwent IHT from patients who did not undergo IHT to report on the effect of frailty on IHT. Methods A retrospective chart review was performed to collect data on consecutive patients undergoing spinal procedures during 2015–2017. IHT patients were identified and compared with non–interhospital patient transfer (n-IHT) patients to identify factors that distinguished the 2 patient groups using multivariate regression analysis. Studied variables included case complexity, frailty (modified frailty index), age, insurance status, and baseline demographic variables. Postoperative outcomes affected by transfer status were identified in binary regression analysis. Results During 2015–2017, there were 595 n-IHT and 76 IHT spine surgery patients (N = 671). Increased frailty (modified frailty index ≥3; odds ratio = 2.4, P = 0.01) and increased spine surgery complexity (spine surgery complexity score ≥2; odds ratio = 2.57, P = 0.002) were independent risk factors associated with IHT. IHT was an independent risk factor for increased hospital length of stay and increased postoperative complications (Clavien-Dindo scale; P Conclusions IHT patients comprise a more frail and surgically complex surgical spine population compared with n-IHT patients. IHT was also an independent risk factor for increased complications and length of stay after spine surgery. Patients' insurance status and age did not distinguish between IHT and n-IHT groups. This is the first report in any specialty to demonstrate increasing frailty is associated with IHT.

This chapter presents the rationale for why Prolonged Exposure for Intensive Outpatient Programs (PE-IOP) was created through an examination of some of the barriers to care that may appear in traditional outpatient psychotherapy for posttraumatic stress disorder (PTSD). Evidence for efficacy and effectiveness of PE-IOP for PTSD and related issues across patient populations is summarized, including those areas still in need of examination.

Foundations of prolonged exposure (PE) include (1) education about common reactions to trauma, what maintains trauma-related symptoms, and how PE reduces posttraumatic stress disorder (PTSD) symptoms; (2) repeated in vivo confrontation with situations, people, or objects that the patient is avoiding because they are trauma-related and cause emotional distress such as anxiety, shame, or guilt; and (3) repeated, prolonged imaginal exposure to the trauma memories followed by processing the details of the event, the emotions, and the thoughts that the patient experienced during the trauma. The aim of in vivo and imaginal exposure is to enhance emotional processing of traumatic events by helping the patient face the trauma memories and reminders and process the emotions and thoughts, as well as the details of the trauma that emerge during revisiting experiences.

Background Exposure-based psychotherapy is a first-line treatment for posttraumatic stress disorder (PTSD), but its mechanisms are poorly understood. Functional brain connectivity is a promising metric for identifying treatment mechanisms and biosignatures of therapeutic response. To this end, we assessed amygdala and insula treatment–related connectivity changes and their relationship to PTSD symptom improvements. Methods Individuals with a primary PTSD diagnosis (N = 66) participated in a randomized clinical trial of prolonged exposure therapy (n = 36) versus treatment waiting list (n = 30). Task-free functional magnetic resonance imaging was completed prior to randomization and 1 month following cessation of treatment/waiting list. Whole-brain blood oxygenation level–dependent responses were acquired. Intrinsic connectivity was assessed by subregion in the amygdala and insula, limbic structures key to the disorder pathophysiology. Dynamic causal modeling assessed evidence for effective connectivity changes in select nodes informed by intrinsic connectivity findings. Results The amygdala and insula displayed widespread patterns of primarily subregion-uniform intrinsic connectivity change, including increased connectivity between the amygdala and insula; increased connectivity of both regions with the ventral prefrontal cortex and frontopolar and sensory cortices; and decreased connectivity of both regions with the left frontoparietal nodes of the executive control network. Larger decreases in amygdala–frontal connectivity and insula–parietal connectivity were associated with larger PTSD symptom reductions. Dynamic causal modeling evidence suggested that treatment decreased left frontal inhibition of the left amygdala, and larger decreases were associated with larger symptom reductions. Conclusions PTSD psychotherapy adaptively attenuates functional interactions between frontoparietal and limbic brain circuitry at rest, which may reflect a potential mechanism or biosignature of recovery.

Now freely downloadable on the Anxiety and Depression Association of America website (https://adaa.org/sites/default/files/PhasedApproachtoCovid‐19.ver1.1%20(002).pdf) is a framework for COVID‐19 mental health response (see Table 1). This framework of phased interventions and resources is intended to assist health systems and programs impacted by the pandemic to plan for how to address current mental health issues arising as well as to prepare and plan for the continued needs of their communities, patients, and staff. This article is protected by copyright. All rights reserved.

Posttraumatic stress disorder (PTSD) is often a clinically complex disorder, frequently presenting with comorbid clinical conditions. Individuals with PTSD may also present with high-risk symptoms such as substance misuse and suicidal ideation. The clinical complexity of PTSD has precluded some clinicians from providing gold-standard trauma-focused treatment due to concern of iatrogenic effects. However, evidence to date suggests that trauma-focused treatments are safe and effective for PTSD even when higher-risk comorbidity presents. Occasionally, while some patients present with clinical concerns that may benefit from modifications to standard recommended treatment protocols, research suggests there are few absolute contraindications to trauma-focused treatment. The present manuscript provides a review of evidence-based assessment and treatment recommendations for PTSD. A clinical decision-making guide for PTSD across areas of clinical complexity is provided.

Objective A key symptom of posttraumatic stress disorder (PTSD) is hyperreactivity to trauma-relevant stimuli. Though physiological arousal is reliably elevated in PTSD, the question remains whether this arousal responds to treatment. Virtual reality (VR) has been posited to increase emotional engagement during prolonged exposure therapy (PE) for PTSD by augmenting imaginal exposures with trauma-relevant sensory information. However, the comparative effects of VR exposure therapy (VRE) have received limited empirical inquiry. Method Ninety active-duty soldiers with combat-related PTSD participating in a randomized-controlled trial to receive PE, VRE, or a waitlist-control (WL) condition had their physiological reactivity, indexed by galvanic skin response (GSR), to their trauma memories assessed at pre-, mid-, and posttreatment. Results Although both VRE and PE conditions showed reduced GSR reactivity to trauma memories from pre- to posttreatment, only the VRE group differed significantly from WL. Across the sample, reductions in GSR were significantly correlated with reductions in self-reported PTSD and anxiety symptoms. Conclusions This was the first study comparing effects of VRE and PE on psychophysiological variables. Given previous research finding limited differences between VRE and PE in PTSD symptom reduction, these findings lend support to the rationale for including VR in exposure therapy protocols while raising important questions about the potential benefits of VRE. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Evidence-based psychotherapies such as prolonged exposure therapy (PE) are recommended by clinical practice guidelines as first-line treatments for post-traumatic stress disorder (PTSD) and are safe and acceptable for use with older adults. One third to one half of all patients do not achieve a clinically meaningful response to standard outpatient PE and recent research suggests that older adults in particular may experience barriers to full engagement and response. Standard treatment may be challenging in older adults due to cognitive, medical, and psychosocial barriers. This article reviews the current state of the evidence on adjunctive and second-tier interventions that show promise for increasing response and/or engagement in evidence-based psychotherapy for PTSD, including medications such as d-cycloserine and 3,4-methylenedioxy-methamphetamine, neuromodulation techniques such as repetitive transcranial magnetic stimulation, and augmentations to the structure and content of psychotherapy, such as intensive outpatient formats. A case illustration of successful application of multiple augmentations to PE with an initially nonresponsive older adult patient is presented. A creative interdisciplinary approach based in available research may be beneficial for older adults who do not respond to first-line treatments.

Posttraumatic stress disorder (PTSD) is characterized by increased sympathetic nervous system (SNS) activity, blunted parasympathetic nervous system (PNS) activity, and impaired baroreflex sensitivity (BRS), which contribute to accelerated cardiovascular disease. Patients with PTSD also have chronic stress-related elevations in resting blood pressure (BP), often in the prehypertensive range; yet, it is unclear if elevated resting blood pressure (ERBP) augments these autonomic derangements in PTSD. We hypothesized that compared with normotensive PTSD (N-PTSD), those with ERBP (E-PTSD) have further increased SNS, decreased PNS activity, and impaired BRS at rest and exaggerated SNS reactivity, PNS withdrawal, and pressor responses during stress. In 16 E-PTSD and 17 matched N-PTSD, we measured continuous BP, ECG, muscle sympathetic nerve activity (MSNA), and heart rate variability (HRV) markers reflecting cardiac PNS activity [standard deviation of R-R intervals (SDNN), root mean square of differences in successive R-R intervals (RMSSD), and high frequency power (HF)] during 5 min of rest and 3 min of mental arithmetic. Resting MSNA ( P = 0.943), sympathetic BRS ( P = 0.189), and cardiovagal BRS ( P = 0.332) were similar between groups. However, baseline SDNN (56 ± 6 vs. 78 ± 8 ms, P = 0.019), RMSSD (39 ± 6 vs. 63 ± 9 ms, P = 0.018), and HF (378 ± 103 vs. 693 ± 92 ms2, P = 0.015) were lower in E-PTSD versus N-PTSD. During mental stress, the systolic blood pressure response ( P = 0.011) was augmented in E-PTSD. Although MSNA reactivity was not different ( P > 0.05), the E-PTSD group had an exaggerated reduction in HRV during mental stress ( P < 0.05). PTSD with ERBP have attenuated resting cardiac PNS activity, coupled with exaggerated BP reactivity and PNS withdrawal during stress.

Background We have previously evaluated the efficacy of the CRF1 receptor antagonist GSK561679 in female PTSD patients. While GSK561679 was not superior to placebo overall, it was associated with a significantly stronger symptom reduction in a subset of patients with probable CRF system hyperactivity, i.e., patients with child abuse and CRHR1 SNP rs110402 GG carriers. Here, we test whether blood-based DNA methylation levels within CRHR1 and other PTSD-relevant genes would be associated with treatment outcome, either overall or in the high CRF activity subgroup. Results Therefore, we measured CRHR1 genotypes as well as baseline and post-treatment DNA methylation from the peripheral blood in the same cohort of PTSD-diagnosed women treated with GSK561679 (N = 43) or placebo (N = 45). In the same patients, we assessed DNA methylation at the PTSD-relevant genes NR3C1 and FKBP5, shown to predict or associate with PTSD treatment outcome after psychotherapy. We observed significant differences in CRHR1 methylation after GSK561679 treatment in the subgroup of patients with high CRF activity. Furthermore, NR3C1 baseline methylation significantly interacted with child abuse to predict PTSD symptom change following GSK561679 treatment. Conclusions Our results support a possible role of CRHR1 methylation levels as an epigenetic marker to track response to CRF1 antagonist treatment in biologically relevant subgroups. Moreover, pre-treatment NR3C1 methylation levels may serve as a potential marker to predict PTSD treatment outcome, independent of the type of therapy. However, to establish clinical relevance of these markers, our findings require replication and validation in larger studies. Trial registration NCT01018992. Registered 6 November 2009. Electronic supplementary material The online version of this article (10.1186/s13148-018-0569-x) contains supplementary material, which is available to authorized users.

OBJECTIVE: In addition to clinical symptoms, patients with posttraumatic stress disorder (PTSD) often experience considerable disability and may evidence minor impairments in performance on measures of cognition and functional capacity (FC). The objective of the present study was to determine if cognitive and functional skills manifest temporal stability as observed in other neuropsychiatric conditions in the presence of greater fluctuations in clinical symptoms. METHOD: Assessments of cognition, FC, and clinical symptoms were conducted over two time points as part of a pre- and post-treatment assessment in a placebo-controlled clinical trial in 96 women with PTSD. The goal of these analyses was to examine the relative stability of scores and intercorrelations of measures of cognition, FC, and clinical symptoms. RESULTS: Cognitive and FC performance manifested considerably greater cross-temporal stability compared to clinical symptoms. FC performance did not change over time. Similar to previous findings in patients with schizophrenia and bipolar disorder measures of symptoms and self-reported disability did not correlate with measures of functional skills or cognitive performance. CONCLUSIONS: Cognitive performance and functional capacity were temporally stable in women with PTSD. In contrast, clinical symptoms had much more cross-temporal fluctuation. Self-reported disability was correlated with current symptomatology but unrelated to objective measures of performance. Similar to other neuropsychiatric conditions, mood symptoms likely influence estimates of current level of functioning more than cognitive or functional skills.

BACKGROUND: In rodents, context specificity of Pavlovian extinction is attenuated by manipulations that impair hippocampal function, including systemic administration of scopolamine, a muscarinic-cholinergic receptor antagonist. Context renewal translates into return of fear following exposure therapy to feared situations. We evaluated the effectiveness of scopolamine for attenuating context renewal of phobic fear in humans. METHODS: A total of 60 participants (35 female, 22 male, 1 transgender, 2 undeclared) with social anxiety disorder and fear of public speaking were randomized to placebo, 0.5 mg scopolamine, or 0.6 mg scopolamine. They completed seven exposure sessions in an exposure context and subsequently tested in the exposure context (extinction retest) versus a different context (context renewal test), which were counterbalanced. Testing 1 month later occurred in the exposure context (long-term extinction retest). Fear measures included skin conductance and self-reported distress during speeches. Hippocampus-dependent cognitive tasks were completed as well. RESULTS: Scopolamine augmented extinction across exposure sessions on skin conductance response and skin conductance level. Lower skin conductance response at context renewal in scopolamine groups relative to the placebo group was constrained to simple effects and complicated by unexpected outcomes within placebo and on self-reported fear. Scopolamine led to lower skin conductance response at long-term extinction retest. Scopolamine impaired performance on a cognitive task of hippocampal function. CONCLUSIONS: Noninvasive and well-tolerated scopolamine impaired hippocampal processes and augmented extinction during exposure. Drug-free effects persisted 1 month later. Findings at context renewal were limited and suggestive only. Further investigation is warranted with varying scopolamine dosages.

Introduction Patients (pts) with MF who discontinue ruxolitinib due to resistance or progression have a poor prognosis (median OS, 14 months; Kuykendall et al. Ann Hematol. 2018). Available therapies provide symptom control and reduce spleen volumes, but do not address the underlying pathophysiology of disease, underscoring a need for disease-modifying treatments. Murine double minute 2 (MDM2), a key negative regulator of the tumor suppressor protein p53, is overexpressed in CD34+ cells in MF. Elevated MDM2 attenuates p53 activity resulting in proliferation of malignant CD34+ cells. Navtemadlin (KRT-232), a potent, selective, orally available MDM2 inhibitor, restores p53 function and mediates apoptosis of malignant cells, suggesting a potential for disease-modification. As previously reported in relapsed/refractory (R/R) MF, once-daily navtemadlin at 240 mg (Day 1-7/28-day cycle) yielded a best spleen volume reduction (SVR) ≥35% by central review in 16% of pts, best total symptom score (TSS) response >50% in 30% of pts, and an 87% reduction of peripheral CD34+ cells at Week 24 (Al-Ali et al. EHA 2020). Aims To evaluate the correlations between changes in biomarkers of disease burden (variant allele frequency [VAF] of driver mutation and high-molecular risk (HMR) genes, peripheral blood CD34+ cells, serum cytokine levels, and bone marrow fibrosis) and clinical benefits (spleen volume reduction and symptom response). Methods Pts with R/R MF were treated in a phase 2 trial with different doses/schedules of navtemadlin (NCT03662126). Peripheral blood samples were collected at baseline and after 12 and 24 weeks of navtemadlin. Analysis of driver and HMR mutations (ASXL1, EZH2, SRSF2, IDH1/2, U2AF1) and VAF measurements from peripheral blood were determined by next-generation sequencing. Serum TNFα was analyzed by ELISA. Bone marrow biopsies were collected at baseline and after 24 weeks of treatment; fibrosis was assessed by a central pathology review. Correlations were investigated by calculating Spearman's rank-correlation coefficients. Results As of April 15, 2021, of 113 pts treated with navtemadlin, 111 were evaluable for mutation analyses. At baseline, 108 pts had ≥1 driver mutation and 75 pts had ≥1 mutation in an HMR gene Driver mutations in JAK2, CALR, or MPL were reported in 81 (73%), 22 (19%) and 13 (12%) of pts, respectively; 28 (25%) carried mutations in ≥2 HMR genes. Of 65 pts evaluable for driver gene or HMR VAF reductions, a best driver gene reduction ≥20% after navtemadlin was observed in 22 (34%) pts and 19 (29%) showed a complete VAF reduction (below the limit of detection) in HMR or driver genes (Fig 1). Reduction in driver allele VAF at any time on study significantly correlated with SVR (Fig 2A); SVR responses were noted in more pts with ≥20% vs Reductions in circulating CD34+ cells in peripheral blood observed with navtemadlin treatment correlated significantly with best SVR (Fig 2B). Navtemadlin induced reductions in serum TNFα with a median best decrease from baseline of 41%. Reductions in TNFα correlated with best SVR and TSS responses (Fig 2C and 2D). Of 45 pts who had bone marrow biopsies at baseline and Week 24, 41 (91%) had baseline fibrosis scores ≥1, with 31 (69%) and 4 (9%) having Grade 2 and 3 fibrosis, respectively. After navtemadlin treatment, 12 (27%) showed improved fibrosis scores of ≥1 grade and 23 (51%) had stable fibrosis scores. Among responders, fibrosis scores were improved or stable in 67% of pts with SVR ≥35% and 100% of pts with TSS improvement ≥50%. Fibrosis scores were also associated with improvements in mutation burden; of 14 patients with VAF reductions ≥20% and bone marrow assessments, 4 (29%) showed improvements in fibrosis and 8 (57%) had stable fibrosis scores. Conclusion Among pts with R/R MF treated with navtemadlin, spleen responses correlated with reductions of MPN-driver mutation burden, decreased peripheral CD34+ cell counts, improvements in bone marrow fibrosis scores, and reduction in inflammatory cytokine, TNFα. Improvement in symptom burden significantly correlated with reductions in TNFα. The reduction in mutation burden and CD34+ cells, together with an improvement in bone marrow fibrosis, suggest that navtemadlin has a disease-modifying effect in MF. These correlations will be explored further in BOREAS, a global phase 3 study in MF that is R/R to JAK inhibitors (NCT03662126). Figure 1 Figure 1. Disclosures Vachani: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Delgado: Novartis: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy. Al-Ali: Incyte: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy, Honoraria. Hernández-Rivas: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kiladjian: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Vannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Perkins: Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy; Abbvie: Honoraria, Speakers Bureau. Valmeekam: Telios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company, Other: travel, accommodations, expenses. Krejsa: Seattle Genetics: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Kartos Therapeutics: Current Employment, Current holder of stock options in a privately-held company, Other: travel, accommodations, expenses; AstraZeneca: Current equity holder in publicly-traded company; Acerta Pharma: Current holder of individual stocks in a privately-held company. Uyei: Kartos Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company; Genentech/Roche: Ended employment in the past 24 months; Gilead Sciences: Current equity holder in publicly-traded company; Telios Pharma: Current holder of individual stocks in a privately-held company. McGreivy: Kartos Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Rothbaum: Quogue Capital: Current Employment; Iovance Biotherapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Acerta Pharma/Astra Zeneca: Current equity holder in publicly-traded company; Kartos Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Patents & Royalties; Telios Pharma: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Patents & Royalties; Quogue IP Holdings: Patents & Royalties. Mascarenhas: PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forbius: Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merus: Research Funding; Geron: Consultancy; Galecto: Consultancy; Prelude: Consultancy. Verstovsek: CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; Roche: Research Funding; Ital Pharma: Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: Navtemadlin (KRT-232) is an investigational agent that is being evaluated in a clinical trial setting.

Increased emphasis on mechanisms of treatment effectiveness, biomarker predictors, and objective indicators of treatment response has sparked interest in integrated, translational treatment outcomes trials. The PROlonGed ExpoSure and Sertraline Trial (PROGrESS) is one such randomized controlled trial (RCT) focused on a key question in clinical management of posttraumatic stress disorder (PTSD) - the comparative and combined effectiveness of medication and psychotherapy. PROGrESS employs a state of the art trial design to examine psychotherapy and medication effects across three conditions: 1) Prolonged Exposure (PE) plus pill placebo, 2) Sertraline (SERT) plus Enhanced Medication Management (EMM), and 3) Combined treatment (PE/SERT). Innovative measures will capture potential biomarker predictors and indicators of treatment response within and across these three treatment conditions in Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) service members and veterans with PTSD. Assessments include clinician-rated measures, self-report outcome measures, saliva for salivary cortisol and cortisol response to awakening at six assessment points, blood at baseline and week 24 for genetic and genomic analysis, as well as resting state connectivity and emotion processing and regulation using functional Magnetic Resonance Imaging (fMRI) paradigms in a subsample of veterans. Accordingly, the current study is designed to provide pragmatic clinical direction for the delivery of PTSD treatment through its primary outcomes in an effectiveness design, and will also provide informative results to elucidate underlying mechanisms and biomarkers involved in PTSD treatment response.

Surgical-site infections (SSIs) account for 20% of all healthcare-associated infections, are the most common nosocomial infection among surgical patients, and are a focus of quality improvement initiatives. Despite implementation of many quality care measures (e.g. prophylactic antibiotics), SSIs remain a significant cause of morbidity, mortality, and economic burden, particularly in the field of neurosurgery. Topical vancomycin is increasingly utilized in instrumented spinal and cardiothoracic procedures, where it has been shown to reduce the risk of SSIs. However, a randomized controlled trial assessing its efficacy in the general neurosurgical population has yet to be done. The principle aim of "Topical Vancomycin for Neurosurgery Wound Prophylaxis" (NCT02284126) is to determine whether prophylactic, topical vancomycin reduces the risk of SSIs in the adult neurosurgical population. This prospective, multicenter, patient-blinded, randomized controlled trial will enroll patients to receive the standard of care plus topical vancomycin, or the standard of care alone. The primary endpoint of this study is a SSI by postoperative day (POD) 30. Patients must be over 18years of age. Patients are excluded for renal insufficiency, vancomycin allergy, and some ineligible procedures. Univariate analysis and logistic regression will determine the effect of topical vancomycin on SSIs at 30days. A randomized controlled trial is needed to determine the efficacy of this treatment. Results of this trial are expected to directly influence the standard of care and prevention of SSIs in neurosurgical patients.