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Background: Psychiatric disorders have been associated with advanced epigenetic age in DNA methylation, yet this relationship has not been studied in the brain transcriptome. We examined transcriptomic age using an RNA-based algorithm recently developed by Ren and Kuan ("RNAAgeCalc") and the associations between posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and alcohol use disorder with age-adjusted RNA age ("RNA age residuals") in three brain regions: dorsolateral prefrontal cortex, ventromedial prefrontal cortex (vmPFC), and motor cortex., Methods: RNA sequencing was used to measure gene expression in postmortem brain tissue from the VA National PTSD Brain Bank (n = 94; 59% male)., Results: Linear models revealed that diagnoses of PTSD and/or MDD were positively associated with RNA age residuals in vmPFC only (p-adj = 0.012). Three genes in the RNAAgeCalc algorithm (KCNJ16, HYAL2, and CEBPB) were also differentially expressed in association with PTSD/MDD in vmPFC (p-adj = 6.45E-05 to 0.02). Enrichment analysis revealed that inflammatory and immune-related pathways were overrepresented (p-adj < 0.05) among the 43 genes in RNAAgeCalc that were also at least nominally associated with PTSD/MDD in vmPFC relative to the 448 RNAAgeCalc genes. Endothelial and mural cells were negatively associated with RNA age residuals in vmPFC (both p-adj = 0.028) and with PTSD/MDD (both p-adj = 0.017)., Conclusions: Results highlight the importance of inflammation and immune system dysregulation in the link between psychopathology and accelerated cellular aging and raise the possibility that blood-brain barrier degradation may play an important role in stress-related accelerated brain aging., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA.)

The COVID-19 pandemic has had unprecedented effects on lifestyle stability and physical and mental health. We examined the impact of preexisting posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), and depression on biopsychosocial responses to the pandemic, including psychiatric symptoms, COVID-19 exposure, and housing/financial stability, among 101 U.S. military veterans enrolled in a longitudinal study of PTSD, a population of particular interest given veterans' trauma histories and defense-readiness training. Participants (83.2% male, 79.2% White, M age  = 59.28 years) completed prepandemic, clinician-administered psychiatric diagnostic interviews and a phone-based assessment between May and September 2020 using a new measure, the Rapid Assessment of COVID-19-Related Experiences (RACE), which was used to assess pandemic responses and its effects on mental and physical health; COVID-19 diagnosis and testing were also extracted from electronic medical records. Multivariate regressions showed that, controlling for demographic characteristics, prepandemic PTSD, β = .332; p = .003, and AUD symptoms, β = .228; p = .028, were associated with increased pandemic-related PTSD symptoms. Prepandemic AUD was associated with increased substance use during the pandemic, β = .391; p < .001, and higher rates of self-reported or medical record-based COVID-19 diagnosis, β = .264; p = .019. Minority race was associated with pandemic-related housing/financial instability, β = -.372; p < .001, raising concerns of population inequities. The results suggest that preexisting PTSD and AUD are markers for adverse pandemic-related psychiatric outcomes and COVID-19 illness. These findings carry implications for the importance of targeting prevention and treatment efforts for the highest-risk individuals., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Posttraumatic stress disorder (PTSD) is associated with inflammation and various forms of chronic disease. The Absent in Melanoma 2 (AIM2) gene has been implicated in mechanisms of inflammation and anxiety, and methylation at a particular locus in this gene (cg10636246) has previously been shown to influence the association between PTSD and elevated C-reactive protein levels in blood., Method: We tested if this association might extend to other indicators of inflammation and to plasma-based measures of neuropathology in a cohort of post-9/11 US military veterans. Using a Bayesian approach, mediation models were tested cross-sectionally (n = 478) and longitudinally (n = 298). Peripheral markers of inflammation and neuropathology were measured with ultra-sensitive Single Molecule Array (Simoa®) technology., Results: Analyses revealed indirect effects of PTSD symptom severity on peripheral indices of both inflammation (interleukin [IL]6, IL-10, tumor necrosis factor-α; indirect standardized [std.] ß range = 0.018-0.023, all p-values adjusted for multiple testing [p adj ] < 0.05) and neuropathology (neurofilament light [NFL]; indirect std. ß = -0.018, p adj  = 0.02) via AIM2 methylation. This indirect effect was also evident when predicting IL-10 at a follow-up assessment (indirect std. ß = -0.018, p adj  = 0.04) controlling for baseline IL-10., Conclusions: Given that AIM2 methylation mediated the association between PTSD symptoms and multiple inflammatory and neuropathology markers, our results suggest that AIM2 methylation may offer clinical utility for indexing risk for adverse health outcomes associated with these peripheral indices of inflammation and neuropathology. Results also suggest a possible shared etiology underlying the frequent co-occurrence of inflammation and neuropathology., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA.)

Background: A better understanding of the extent to which prior occurrences of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) predict psychopathological reactions to subsequent traumas might be useful in targeting posttraumatic preventive interventions., Methods: Data come from 1306 patients presenting to 29 U.S. emergency departments (EDs) after a motor vehicle collision (MVC) in the advancing understanding of recovery after trauma study. Patients completed self-reports in the ED and 2-weeks, 8-weeks, and 3-months post-MVC. Associations of pre-MVC probable PTSD and probable MDE histories with subsequent 3-months post-MVC probable PTSD and probable MDE were examined along with mediation through intervening peritraumatic, 2-, and 8-week disorders., Results: 27.6% of patients had 3-month post-MVC probable PTSD and/or MDE. Pre-MVC lifetime histories of these disorders were not only significant (relative risk = 2.6-7.4) but were dominant (63.1% population attributable risk proportion [PARP]) predictors of this 3-month outcome, with 46.6% prevalence of the outcome among patients with pre-MVC disorder histories versus 9.9% among those without such histories. The associations of pre-MVC lifetime disorders with the 3-month outcome were mediated largely by 2- and 8-week probable PTSD and MDE (PARP decreasing to 22.8% with controls for these intervening disorders). Decomposition showed that pre-MVC lifetime histories predicted both onset and persistence of these intervening disorders as well as the higher conditional prevalence of the 3-month outcome in the presence of these intervening disorders., Conclusions: Assessments of pre-MVC PTSD and MDE histories and follow-ups at 2 and 8 weeks could help target early interventions for psychopathological reactions to MVCs., (© 2021 Wiley Periodicals LLC.)

Traumatic stress is thought to be associated with shortened telomere length (TL) in leukocytes, an age-related marker of increased risk for cellular senescence, although findings thus far have been mixed. We assessed associations between posttraumatic stress disorder (PTSD) symptom severity, temperament, and TL in a sample of 453 White, non-Hispanic, middle-aged, trauma-exposed male and female veterans and civilians. Given that prior research has suggested an association between PTSD and accelerated cellular age, we also examined associations between TL and an index of accelerated cellular age derived from DNA methylation data (DNAm age). Analyses revealed that, controlling for chronological age, PTSD was not directly associated with TL but rather this association was moderated by age, β = -.14, p = .003, ΔR 2 = .02. Specifically, PTSD severity evidenced a stronger negative association with TL among relatively older participants (≥ 55 years of age). In a subset of veterans with data pertaining to temperament (n = 150), positive emotionality, and, specifically, a drive toward achievement, β = .26, p = .002, ΔR 2 = .06, were positively associated with TL. There was no evidence of an association between age-adjusted TL and accelerated DNAm age. Collectively, these results indicate that older adults may be more vulnerable to the negative health effects of PTSD but that traits such as achievement, resilience, and psychological hardiness may be protective. These findings underscore the importance of identifying reliable biomarkers of cellular aging and senescence and of determining the biological mechanisms that contribute to stress-related disease and decline., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Longitudinal studies have demonstrated transactional associations between psychopathology and stressful life events (SLEs), such that psychopathology predicts the occurrence of new SLEs, and SLEs in turn predict increasing symptom severity. The association between posttraumatic stress disorder (PTSD), specifically, and stress generation remains unclear. This study used temporally sequenced data from 116 veterans (87.9% male) to examine whether PTSD symptoms predicted new onset SLEs, and if these SLEs were associated with subsequent PTSD severity. The SLEs were objectively rated, using a clinician-administered interview and consensus-rating approach, to assess the severity, frequency, and personal dependence (i.e., if the event was due to factors that were independent of or dependent on the individual) of new-onset SLEs. A series of mediation models were tested, and results provided evidence for moderated mediation whereby baseline PTSD severity robustly predicted personally dependent SLEs, B = 0.03, p = .006, and dependent SLEs predicted increases in follow-up PTSD symptom severity, B = -0.04, p = .003, among participants with relatively lower baseline PTSD severity. After we controlled for baseline PTSD severity, personality traits marked by low constraint (i.e., high impulsivity) were also associated with an increased number of dependent SLEs. Our results provide evidence for a stress-generative role of PTSD and highlight the importance of developing interventions aimed at reducing the occurrence of personally dependent stressors., (Copyright © 2018 International Society for Traumatic Stress Studies.)

Background: To examine shared genetic and environmental risk factors across PTSD symptoms and resilience., Methods: Classical twin study of 2010-2012 survey data conducted among 3,318 male twin pairs in the Vietnam Era Twin Registry. Analyses included: (a) estimates of genetic and environmental influences on PTSD symptom severity (as measured by the PTSD Checklist) and resilience (assessed with the Connor-Davidson Resilience Scale-10); (b) development of a latent model of traumatic stress, spanning both PTSD and resilience; and (c) estimates of genetic and environmental influences on this spectrum., Results: The heritability of PTSD was 49% and of resilience was 25%. PTSD and resilience were correlated at r = -.59, and 59% of this correlation was attributable to a single genetic factor, whereas the remainder was due to a single non-shared environment factor. Resilience was also influenced by common and unique environmental factors not shared with PTSD, but there was no genetic factor specific to resilience. Confirmatory factor analysis supported the Development of a revised phenotype reflecting the broader dimension of traumatic stress, with biometric models suggesting increased heritability (66%) of this spectrum compared to PTSD or resilience individually., Conclusions: Genetic factors contribute to a single spectrum of traumatic stress reflecting resilience at one end and high symptom severity at the other. This carries implications for phenotype refinement in the search for molecular genetic markers of trauma-related psychopathology. Rather than focusing only on genetic risk for PTSD, molecular genetics research may benefit from evaluation of the broader spectrum of traumatic stress., (© 2017 Wiley Periodicals, Inc.)

Background: Accumulating evidence suggests that posttraumatic stress disorder (PTSD) is associated with disrupted default mode network (DMN) connectivity, but findings across studies have not been uniform. Individual differences in relevant genes may account for some of the reported variability in the relationship between DMN connectivity and PTSD. In this study, we investigated this possibility using genome-wide association study (GWAS) derived polygenic risk scores (PRSs) for relevant psychiatric traits. We hypothesized that the association between PTSD and DMN connectivity would be moderated by genetic risk for one or more psychiatric traits such that individuals with elevated polygenic risk for psychopathology and severe PTSD would exhibit disrupted DMN connectivity., Methods: Participants were 156 white, non-Hispanic veterans of the wars in Iraq and Afghanistan who were genotyped and underwent resting state functional magnetic resonance imaging and clinical assessment. PRSs for neuroticism, anxiety, major depressive disorder, and cross-disorder risk (based on five psychiatric disorders) were calculated using summary statistics from published large-scale consortia-based GWASs., Results: Cross-disorder polygenic risk influenced the relationship between DMN connectivity and PTSD symptom severity such that individuals at greater genetic risk showed a significant negative association between PTSD symptom severity and connectivity between the posterior cingulate cortex and right middle temporal gyrus. Polygenic risk for neuroticism, anxiety, and major depressive disorder did not influence DMN connectivity directly or through an interaction with PTSD., Conclusions: Findings illustrate the potential power of genome-wide PRSs to advance understanding of the relationship between PTSD and DMN connectivity, a putative neural endophenotype of the disorder., (© 2017 Wiley Periodicals, Inc.)

The addition of self-destructive and reckless behavior as a symptom of posttraumatic stress disorder (PTSD) in DSM-5 has stimulated renewed interest in understanding relationships between these behaviors and trauma-related psychopathology. This study examined the relationship between reckless and self-destructive behaviors (RSDB), intervening exposure to new adverse events, and later PTSD severity in a sample of trauma-exposed veterans. At baseline, participants were assessed for RSDB (past 5 years) and current PTSD severity (N = 222). PTSD severity was then reassessed approximately 4 years later (N = 148). Overall, RSDB were reported by 74.4% of the sample, with 61.3% engaging in multiple forms of RSDB. The most commonly endorsed behaviors included alcohol/drug abuse (42.8%), driving while intoxicated (29.4%), gambling (24.7%), and aggression (23.1%). There was a positive correlation between RSDB and PTSD severity at both the baseline (r = .16, p = .031) and follow-up assessment (r = .24, p = .005). Path models indicated that exposure to new adverse events fully mediated the effect of Time 1 RSDB on PTSD symptoms at Time 2 (indirect association: β = .05, p = .046). Results suggest that RSDB are common among trauma-exposed veterans and may perpetuate PTSD symptoms by increasing exposure to new adverse events., (Copyright © 2017 International Society for Traumatic Stress Studies.)

Background: DNA methylation of the SKA2 gene has recently been implicated as a biomarker of suicide risk and posttraumatic stress disorder (PTSD). To examine the specificity and reliability of these findings, we examined associations between SKA2 DNA methylation, broad dimensions of psychiatric symptoms, and suicide phenotypes in adults with high levels of trauma exposure., Methods: A total of 466 White, non-Hispanic veterans and their intimate partners (65% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. DNA methylation of the CpG locus cg13989295 and genotype at the methylation-associated single-nucleotide polymorphism (SNP) rs7208505 were examined in relation to current and lifetime PTSD, internalizing and externalizing psychopathology, and suicide phenotypes (ideation, plans, and attempts)., Results: DNA methylation at the previously implicated SKA2 CpG locus (cg13989295) was associated with current and lifetime symptoms of internalizing (but not externalizing) disorders. SKA2 methylation levels also predicted higher rates of current suicidal thoughts and behaviors, even after including well-established psychiatric risk factors for suicide in the model. Associations between PTSD and SKA2 were not significant, and genetic variation at the methylation-associated SNP (rs7208505) was not related to any of the phenotypes examined., Conclusions: SKA2 methylation may index a general propensity to experience stress-related psychopathology, including internalizing disorders and suicidal thoughts and behaviors. This study demonstrates that SKA2 methylation levels explain unique variance in suicide risk not captured by clinical symptom interviews, providing further evidence of its potential utility as a biomarker of suicide risk and stress-related psychopathology., (© 2016 Wiley Periodicals, Inc.)

As nitrogen discharge limits are becoming more stringent, short-cut nitrogen systems and tertiary nitrogen polishing steps are gaining popularity. For partial nitritation or nitritation-denitritation systems, anaerobic ammonia oxidation (anammox) polishing may be feasible to remove residual ammonia and nitrite from the effluent. Nitrogen polishing of mainstream nitritation-denitritation system effluent via anammox was studied at 25°C in a fully anoxic moving bed bioreactor (MBBR) (V = 0.45 m(3) ) over 385 days. Unlike other anammox based processes, a very fast startup of anammox MBBR was demonstrated, despite nitrite limited feeding conditions (influent nitrite = 0.7 ± 0.59 mgN/L, ammonia = 6.13 ± 2.86 mgN/L, nitrate = 3.41 ± 1.92 mgN/L). The nitrogen removal performance was very stable within a wide range of nitrogen inputs. Anammox bacteria (AMX) activity up to 1 gN/m(2) /d was observed which is comparable to other biofilm-based systems. It is generally believed that nitrate production limits nitrogen removal through AMX metabolism. However, in this study, anammox MBBR demonstrated ammonia, nitrite, and nitrate removal at limited chemical oxygen demand (COD) availability. AMX and heterotrophs contributed to 0.68 ± 0.17 and 0.32 ± 0.17 of TIN removal, respectively. It was speculated that nitrogen removal might be aided by denitratation which could be due to heterotrophs or the recently discovered ability for AMX to use short-chain fatty acids to reduce nitrate to nitrite. This study demonstrates the feasibility of anammox nitrogen polishing in an MBBR is possible for nitritation-denitration systems., (© 2015 Wiley Periodicals, Inc.)

Diabetes affects more than 330 million people worldwide and causes elevated cardiovascular disease risk. Mitochondria are critical for vascular function, generate cellular reactive oxygen species (ROS), and are perturbed by diabetes, representing a novel target for therapeutics. We hypothesized that adaptive mitochondrial plasticity in response to nutrient stress would be impaired in diabetes cellular physiology via a nitric oxide synthase- (NOS-) mediated decrease in mitochondrial function. Primary smooth muscle cells (SMCs) from aorta of the nonobese, insulin resistant rat diabetes model Goto-Kakizaki (GK) and the Wistar control rat were exposed to high glucose (25 mM). At baseline, significantly greater nitric oxide evolution, ROS production, and respiratory control ratio (RCR) were observed in GK SMCs. Upon exposure to high glucose, expression of phosphorylated eNOS, uncoupled respiration, and expression of mitochondrial complexes I, II, III, and V were significantly decreased in GK SMCs (p < 0.05). Mitochondrial superoxide increased with high glucose in Wistar SMCs (p < 0.05) with no change in the GK beyond elevated baseline concentrations. Baseline comparisons show persistent metabolic perturbations in a diabetes phenotype. Overall, nutrient stress in GK SMCs caused a persistent decline in eNOS and mitochondrial function and disrupted mitochondrial plasticity, illustrating eNOS and mitochondria as potential therapeutic targets.

This work describes the development of an intermittently aerated pilot-scale process (V = 0.45 m(3) ) operated for optimized efficient nitrogen removal in terms of volume, supplemental carbon and alkalinity requirements. The intermittent aeration pattern was controlled using a strategy based on effluent ammonia concentration set-points. The unique feature of the ammonia-based aeration control was that a fixed dissolved oxygen (DO) set-point was used and the length of the aerobic and anoxic time (anoxic time ≥25% of total cycle time) were changed based on the effluent ammonia concentration. Unlike continuously aerated ammonia-based aeration control strategies, this approach offered control over the aerobic solids retention time (SRT) to deal with fluctuating ammonia loading without solely relying on changes to the total SRT. This approach allowed the system to be operated at a total SRT with a small safety factor. The benefits of operating at an aggressive SRT were reduced hydraulic retention time (HRT) for nitrogen removal. As a result of such an operation, nitrite oxidizing bacteria (NOB) out-selection was also obtained (ammonia oxidizing bacteria [AOB] maximum activity: 400 ± 79 mgN/L/d, NOB maximum activity: 257 ± 133 mgN/L/d, P < 0.001) expanding opportunities for short-cut nitrogen removal. The pilot demonstrated a total inorganic nitrogen (TIN) removal rate of 95 ± 30 mgN/L/d at an influent chemical oxygen demand: ammonia (COD/NH4 (+) -N) ratio of 10.2 ± 2.2 at 25°C within the hydraulic retention time (HRT) of 4 h and within a total SRT of 5-10 days. The TIN removal efficiency up to 91% was observed during the study, while effluent TIN was 9.6 ± 4.4 mgN/L. Therefore, this pilot-scale study demonstrates that application of the proposed on-line aeration control is capable of relatively high nitrogen removal without supplemental carbon and alkalinity addition at a low HRT., (© 2015 Wiley Periodicals, Inc.)

Deficits in impulse control are increasingly recognized in association with posttraumatic stress disorder (PTSD). To our further understanding of the neurobiology of PTSD-related disinhibition, we examined alterations in brain morphology and network connectivity associated with response inhibition failures and PTSD severity. The sample consisted of 189 trauma-exposed Operation Enduring Freedom/Operation Iraqi Freedom veterans (89% male, ages 19-62) presenting with a range of current PTSD severity. Disinhibition was measured using commission errors on a Go/No-Go (GNG) task with emotional stimuli, and PTSD was assessed using a measure of current symptom severity. Whole-brain vertex-wise analyses of cortical thickness revealed two clusters associated with PTSD-related disinhibition (Monte Carlo cluster corrected P < 0.05). The first cluster included portions of right inferior and middle frontal gyri and frontal pole. The second cluster spanned portions of left medial orbital frontal, rostral anterior cingulate, and superior frontal gyrus. In both clusters, commission errors were associated with reduced cortical thickness at higher (but not lower) levels of PTSD symptoms. Resting-state functional magnetic resonance imaging analyses revealed alterations in the functional connectivity of the right frontal cluster. Together, study findings suggest that reductions in cortical thickness in regions involved in flexible decision-making, emotion regulation, and response inhibition contribute to impulse control deficits in PTSD. Furthermore, aberrant coupling between frontal regions and networks involved in selective attention, memory/learning, and response preparation suggest disruptions in functional connectivity may also play a role., (© 2015 Wiley Periodicals, Inc.)

Objective: A large body of factor analytic research supports the idea that common mental disorders are organized along correlated latent dimensions termed internalizing and externalizing. Eating disorders (EDs) have been associated with both internalizing (mood and anxiety disorders) and externalizing (substance use, antisocial personality disorder) forms of psychopathology. Previous studies found that EDs are most strongly related to internalizing disorders. However, no previous factor analytic studies of EDs and the internalizing/externalizing dimensions have evaluated if EDs align with these spectra similarly for men and women. We examined the location of anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED) symptoms within this model of psychopathology among a sample of veterans, a population traditionally understudied in EDs., Method: Data were from two studies of veterans and their intimate partners (N = 453 men and 307 women). Participants were administered the Structured Clinical Interview for DSM-IV without skip-outs. Lifetime symptom severity scores were used in confirmatory factor analytic models., Results: A model with AN, BN, and BED symptoms loading onto the distress subfactor of the internalizing domain fit the data best in the full sample and the male and female subsamples. This model was statistically equivalent for men and women., Discussion: All three EDs loaded onto distress, indicating that these conditions overlap with psychopathology characterized by negative affect. Investigating latent dimensions of psychopathology is one approach to identifying common factors that partially account for patterns of comorbidity among psychiatric disorders, which may aid in translating research findings into clinical practice., (© 2014 Wiley Periodicals, Inc.)

The dopamine D3 receptor (DRD3) gene has been implicated in schizophrenia, autism, and substance use-disorders and is related to emotion reactivity, executive functioning, and stress-responding, processes impaired in posttraumatic stress disorder (PTSD). The aim of this candidate gene study was to evaluate DRD3 polymorphisms for association with PTSD. The discovery sample was trauma-exposed White, non-Hispanic U.S. veterans and their trauma-exposed intimate partners (N = 491); 60.3% met criteria for lifetime PTSD. The replication sample was 601 trauma-exposed African American participants living in Detroit, Michigan; 23.6% met criteria for lifetime PTSD. Genotyping was based on high-density bead chips. In the discovery sample, 4 single nucleotide polymorphisms (SNPs), rs2134655, rs201252087, rs4646996, and rs9868039, showed evidence of association with PTSD and withstood correction for multiple testing. The minor alleles were associated with reduced risk for PTSD (OR range = 0.59 to 0.69). In the replication sample, rs2251177, located 149 base pairs away from the most significant SNP in the discovery sample, was nominally associated with PTSD in men (OR = 0.32). Although the precise role of the D3 receptor in PTSD is not yet known, its role in executive functioning and emotional reactivity, and the sensitivity of the dopamine system to environmental stressors could potentially explain this association., (Published 2014. This article is a US Government work and is in the public domain in the USA.)

Background: Recent work suggests that a subset of individuals with posttraumatic stress disorder (PTSD) exhibit marked dissociative symptoms, as defined by derealization and depersonalization. A dissociative subtype of PTSD was added to the diagnostic criteria listed in the Diagnostic and Statistical Manual of Mental Disorders, Version 5 (DSM-5) to capture this presentation of PTSD. This study examined genetic polymorphisms for association with the symptoms that define the dissociative subtype of PTSD using a genome-wide approach., Methods: The sample comprised 484 White, non-Hispanic, trauma-exposed veterans and their partners who were assessed for lifetime PTSD and dissociation using a structured clinical interview. The prevalence of PTSD was 60.5%. Single-nucleotide polymorphisms (SNPs) from across the genome were obtained from a 2.5 million SNP array., Results: Ten SNPs evidenced suggestive association with dissociation (P < 10(-5)). No SNPs met genome-wide significance criteria (P < 5 × 10(-8)). The peak SNP was rs263232 (β = 1.4, P = 6.12 × 10(-7)), located in the adenylyl cyclase 8 (ADCY8) gene; a second SNP in the suggestive range was rs71534169 (β = 1.63, P = 3.79 × 10(-6)), located in the dipeptidyl-peptidase 6 (DPP6) gene., Conclusions: ADCY8 is integral for long-term potentiation and synaptic plasticity and is implicated in fear-related learning and memory and long-term memory consolidation. DPP6 is critical for synaptic integration and excitation. These genes may exert effects on basic sensory integration and cognitive processes that underlie dissociative phenomena., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

Subtypes of posttraumatic psychopathology were replicated and extended in 254 female veterans with posttraumatic stress disorder (PTSD). Cluster analyses on Minnesota Multiphasic Personality Inventory-2 and Personality Psychopathology Five scales (Harkness, McNulty, & Ben-Porath, ) yielded internalizing and externalizing psychopathology dimensions, with a third low psychopathology group (simple PTSD). Externalizers were higher than the internalizers and the simple PTSD groups on the antisocial, substance, and aggression scales; internalizers were higher on depression and anxiety scales. Further validation included an independent measure of psychopathology to examine anger (Buss-Durkee Hostility Inventory, [BDHI]; Buss & Durkee, ). Externalizers were higher on extreme behavioral anger scales (assault and verbal hostility); and externalizers and internalizers were higher than the simple PTSD subjects on other anger scales. Positive correlations between the BDHI scales and the PTSD symptom of "irritability and anger outbursts" were found across scales in the total sample (range: r = .19-.36), on the assault scale in externalizers (r = .59), and the verbal hostility scale in both internalizers (r = .30) and simple PTSD (r = .37) groups, suggesting the broad utility of the symptom in the diagnosis. The results demonstrate the generalizability of the internalizing/externalizing typology to the female veteran population and highlight clinically relevant distinctions in anger expression within PTSD., (Copyright © 2014 International Society for Traumatic Stress Studies.)

This study examined the psychological impact of the Boston Marathon bombing using data from an ongoing longitudinal study of Boston-area veterans with posttraumatic stress disorder (PTSD; N = 71). Participants were assessed by telephone within 1 week of the end of the event; 42.3% of participants reported being personally affected by the bombings and/or the manhunt that followed. The majority of them reported that the bombing reminded them of their own traumas and/or caused other emotional distress. Examination of change in posttraumatic stress disorder (PTSD) symptoms from a prebombing assessment an average of 2 months earlier to 1 week after the event revealed no significant change in symptoms across the sample as a whole. However, examination of patterns of change at the individual level revealed significant correlations (r = .33; p = .005) between distress at the time of the event and change in total PTSD symptom severity, with this effect accounted for primarily by increases in intrusion and avoidance symptoms (rs = .35 and .31, ps = .002 and .008, respectively). Findings of this study should raise awareness of the potential impact of terror attacks, mass shootings, and other events of this type on the well-being of individuals with histories of trauma and/or pre-existing PTSD., (Published 2013. This article is a US Government work and is in the public domain in the USA.)

Background: The corticotropin releasing hormone (CRH) system has been implicated in a variety of anxiety and mood-based symptoms and disorders. CRH receptor-2 (CRHR-2) plays a role in attenuating biological responses to stressful life events and trauma, making the CRHR-2 gene a strong candidate to study in relationship to PTSD., Methods: The sample was 491 trauma-exposed white non-Hispanic veterans and their cohabitating intimate partners assessed via structured interview for lifetime DSM-IV PTSD; just over 60% met criteria for the disorder. Thirty-one single nucleotide polymorphisms (SNPs) in and near CRHR-2, obtained from an array of 2.5 million markers, were tested for association with PTSD diagnosis and symptom severity in the whole sample and in men and women separately., Results: Ten SNPs showed nominally significant evidence of association with PTSD in the full sample and two SNPs (rs8192496 and rs2190242) were significant after permutation-based multiple testing correction (uncorrected ps = .0004 and .0005, odds ratios = .60 and .58, respectively). Analyses stratified by sex revealed that the effect was specific to women, who comprised 35% of the sample (uncorrected ps = .0003 and .0002, odds ratios = .41 and .35, respectively). Two additional SNPs (rs2267715 and rs2284218) also showed significant association with PTSD in women (both uncorrected ps = .001, both odds ratios = .48)., Conclusions: Results suggest that CRHR-2 variants may affect risk for PTSD in women by attenuating the stress response and reducing symptoms of the disorder., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA.)

Prevalence of posttraumatic stress disorder (PTSD) defined according to the American Psychiatric Association's Diagnostic and Statistical Manual fifth edition (DSM-5; 2013) and fourth edition (DSM-IV; 1994) was compared in a national sample of U.S. adults (N = 2,953) recruited from an online panel. Exposure to traumatic events, PTSD symptoms, and functional impairment were assessed online using a highly structured, self-administered survey. Traumatic event exposure using DSM-5 criteria was high (89.7%), and exposure to multiple traumatic event types was the norm. PTSD caseness was determined using Same Event (i.e., all symptom criteria met to the same event type) and Composite Event (i.e., symptom criteria met to a combination of event types) definitions. Lifetime, past-12-month, and past 6-month PTSD prevalence using the Same Event definition for DSM-5 was 8.3%, 4.7%, and 3.8% respectively. All 6 DSM-5 prevalence estimates were slightly lower than their DSM-IV counterparts, although only 2 of these differences were statistically significant. DSM-5 PTSD prevalence was higher among women than among men, and prevalence increased with greater traumatic event exposure. Major reasons individuals met DSM-IV criteria, but not DSM-5 criteria were the exclusion of nonaccidental, nonviolent deaths from Criterion A, and the new requirement of at least 1 active avoidance symptom., (Published 2013. This article is a US Government work and is in the public domain in the USA.)

This study used structural equation modeling to evaluate a mediation model of the relationship between trauma exposure, posttraumatic stress disorder (PTSD) symptoms, and perpetration of intimate partner physical and psychological aggression in trauma-exposed veterans and their cohabitating spouses (n = 286 couples; 88% male veteran and female spouse, 80.8% White, non-Hispanic). Dyadic data analyses were used to simultaneously evaluate actor and partner effects using the actor-partner interdependence model (Kashy & Kenny, 2000). The primary hypothesis was that PTSD would mediate the association between trauma exposure and intimate partner physical and psychological aggression with these effects evident both within and across members of a couple (i.e., actor and partner effects). The best-fitting model included (a) equivalent actor and partner direct effects of trauma on veterans' acts of psychological aggression (β = .17 to .20, p = .001), and (b) equivalent actor and partner indirect effects via PTSD on veterans' acts of physical aggression (β = .08 to .10, p < .001). There were no direct or indirect effects predicting the spouses' aggression. Results suggest it is important to consider the trauma histories and possible presence of PTSD in both partners as this may be a point of intervention when treating distressed couples., (Published 2013. This article is a US Government work and is in the public domain in the USA.)

This study examined the relative influences of posttraumatic stress disorder (PTSD), other psychopathology, and intimate partner alcohol and drug use on substance-related problems in U.S. veterans (242 couples, N = 484). Hierarchical regression analyses revealed that partner alcohol and drug use severity explained more variance in veteran alcohol use and drug use (20% and 13%, respectively) than did veteran PTSD, adult antisocial behavior, or depression symptoms combined (6% for veteran alcohol use; 7% for veteran drug use). Findings shed new light on the influence of relationship factors on veteran alcohol and drug use and underscore the importance of couples-oriented approaches to treating veterans with comorbid PTSD and substance abuse., (Published 2013. This article is a US Government work and is in the public domain in the USA.)

Background: The nature of the relationship between dissociation and posttraumatic stress disorder (PTSD) has clinical and nosological importance. The aim of this study was to evaluate the evidence for a dissociative subtype of PTSD in two independent samples and to examine the pattern of personality disorder (PD) comorbidity associated with the dissociative subtype of PTSD., Methods: Latent profile analyses were conducted on PTSD and dissociation items reflecting derealization and depersonalization in two samples of archived data: Study 1 included 360 male Vietnam War Veterans with combat-related PTSD; Study 2 included 284 female Veterans and active duty service personnel with PTSD and a high base rate of exposure to sexual trauma., Results: The latent profile analysis yielded evidence for a three-class solution in both samples: the model was defined by moderate and high PTSD classes and a class marked by high PTSD severity coupled with high levels of dissociation. Approximately 15% of the male sample and 30% of the female sample were classified into the dissociative class. Women (but not men) in the dissociative group exhibited higher levels of comorbid avoidant and borderline PD diagnoses., Conclusions: Results provide support for a dissociative subtype of PTSD and also suggest that dissociation may play a role in the frequent co-occurrence of PTSD and borderline PD among women. These results are pertinent to the on-going revisions to the DSM and suggest that consideration should be given to incorporating a dissociative subtype into the revised PTSD criteria., (© 2012 Wiley Periodicals, Inc.)

Objective: The results of sentinel lymph node biopsy (SLNB) can be useful for staging and deciding on adjuvant treatment for patients with head and neck melanoma. False-negative SLNB can result in treatment delay. This study aimed to evaluate the characteristics and outcome of patients with false-negative SLNB in cutaneous melanoma of the head and neck., Study Design: Longitudinal cohort study using a prospective institutional tumor registry., Setting: Academic health center., Subjects and Methods: Data from 153 patients who underwent SLNB for melanoma of the head and neck were analyzed. False-negative biopsy was defined as recurrence of tumor in a previously identified negative nodal basin. Statistical analysis was performed on registry data., Results: Positive sentinel lymph nodes were identified in 19 (12.4%) patients. False-negative SLNB was noted in 9 (5.9%) patients, with a false-negative SLNB rate of 32.1%. Using multivariate regression analysis, only examination of a single sentinel lymph node was a significant predictor of false-negative SLNB (P = .01). The mean treatment delay for the false-negative SLNB group was 470 days compared with 23 days in the positive SLNB group (P < .001). The 2-year overall survival of patients with false-negative SLNB was 75% compared with 84% and 98% in positive and negative SLNB groups, respectively (P = .02)., Conclusions: False-negative SLNB is more likely to occur when a single sentinel lymph node is harvested. There is significant treatment delay in patients with false-negative SLNB. False-negative SLNB is associated with poor outcome in patients with melanoma of the head and neck.

Research on the structure of posttraumatic stress disorder (PTSD) symptoms has yielded support for two 4-factor models: the King (King, Leskin, King, & Weathers, 1998) and Simms/Watson models (Simms, Watson, & Doebbeling, 2002). This study evaluated them using data drawn from 1,128 Vietnam veterans by comparing associations with a latent internalizing comorbidity variable and five scales from the MMPI-2 Restructured Clinical (RC) Scales (Tellegen et al., 2003). The Simms/Watson dysphoria factor failed to show evidence of superior convergent or discriminant validity in association with external measures relative to the numbing or hyperarousal factors of the King model. Findings raise questions about proposals to abandon the distinction between numbing and hyperarousal symptoms in favor of a dysphoria-based model.

Using latent class analysis (LCA) the typology of personality profiles of veterans with posttraumatic stress disorder (PTSD) was examined based on internalizing/externalizing dimensions of psychopathology. Latent class analysis on Minnesota Multiphasic Personality Inventory-2 (MMPI-2) Personality Psychopathology-5 (PSY-5) scale data from 299 Australian combat veterans with PTSD supported the model, identifying an optimal 4-class solution, with PTSD externalizing class defined by aggressiveness and disconstraint, high and moderate internalizing classes differentiated on the extent of elevations in introversion and negative emotionality and elevation of psychoticism in the high internalizing class and a simple PTSD class with normal range scores. The model was validated using external self-report and psychiatric-interview-derived diagnoses. A second exploratory LCA using broader comorbidity indicators (MMPI-2 Restructured Clinical scales) demonstrated some support for, although limitations in, using nonpersonality measures to identify these classes directly.

The authors examine the question of whether posttraumatic stress disorder (PTSD) should continue to be classified with the anxiety disorders in the upcoming revision of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V; American Psychiatric Association) classification system. They examine four areas of research that challenge the placement of PTSD among the anxiety disorders: research on peritraumatic emotions and their association with later PTSD symptoms, the role of emotions over the course of PTSD, physiological reactivity and emotional responses, and comorbidity patterns. The authors conclude with the recommendation that PTSD be included among a new category of traumatic stress disorders in DSM-V., (Copyright © 2009 International Society for Traumatic Stress Studies.)

This study examined the latent structure of psychiatric disorders in a sample with a high prevalence of PTSD. A series of confirmatory factor analyses tested competing models for the covariation between Structured Clinical Interview for DSM-III-R diagnoses among 1,325 Vietnam veterans. The best-fitting solution was a 3-factor model that included two correlated internalizing factors: anxious-misery, defined by PTSD and major depression, and fear, defined by panic disorder/agoraphobia and obsessive-compulsive disorder. The third factor, externalizing, was defined by antisocial personality disorder, alcohol abuse/dependence, and drug abuse/dependence. Both substance-related disorders also showed significant, albeit smaller, cross-loadings on the anxious-misery factor. These findings shed new light on the structure of psychiatric comorbidity in a treatment-seeking sample characterized by high rates of PTSD.