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Previous cross-sectional studies have shown that sympathetic nervous system (SNS) arousal is positively associated with posttraumatic stress disorder (PTSD) symptoms in children with trauma exposure. One of the ways that SNS activity is measured is through skin conductance response (SCR), which has been shown to predict future PTSD severity in adults. In this study, we explored the utility of a novel, low-cost mobile SCR device, eSense, to predict future PTSD symptom severity in trauma exposed children. We recruited children (N = 43, age 9 years at initial visit) for a longitudinal study in which SCR was recorded at baseline visit, and PTSD symptoms were assessed two years later. Results indicated an interaction between SCR and trauma exposure, such that children with lower trauma exposure who demonstrated greater SCR reported higher PTSD severity two years later. This association remained significant even after controlling for baseline PTSD symptoms. Children with higher levels of trauma exposure did not show this association, potentially due to ceiling effects of PTSD symptoms. Together these findings suggest the utility of SCR as a biomarker for predicting trauma related disorders in children, and that it may be a valuable tool in clinical interventions targeting sympathetic arousal.

Although there is an established link between smaller hippocampal volume and anxiety, the longitudinal relations between hippocampus structure and anxiety in diverse youth are not well understood. The present longitudinal study investigated hippocampal volumes related to anxiety symptoms in a sample of Black 8–14-year-old youth (N = 64), a population historically underrepresented in neuroimaging research. Smaller hippocampal volumes were associated with greater anxiety symptoms independent of age, sex, intracranial volume and trauma exposure. Exploratory longitudinal analyses showed smaller hippocampal volume as a predictor for anxiety symptoms (n = 37) and not a consequence of anxiety symptoms (n = 32), however results were inconclusive as this finding was no longer significant after correcting for baseline anxiety symptoms. Overall, this data increases our understanding of potential neurobiological mechanisms for anxiety in a high-risk sample of Black youth and suggests future directions into studying trajectories of developmental risk.

Abstract Background Traumatic events experienced in childhood can lead to increased risk of cardiovascular disorders in adulthood. Black Americans are disproportionately affected, as they are at increased risk for experiencing childhood trauma and cardiovascular diseases in adulthood. One of the hypothesized mechanisms of this association is through long-lasting dysregulation of the autonomic nervous system, a hallmark physiological biomarker of posttraumatic stress disorder (PTSD), which is twice as prevalent in women compared to men. Methods Ninety-one, majority Black American children, aged 9 were recruited to be a part of our longitudinal study of child development at research centers in Atlanta, GA and Detroit, MI. Resting HR was measured through a electrocardiogram (ECG) recording using the Biopac MP150. Self-report measures of violence exposure and PTSD symptoms were administered by research staff. Results Children with more violence exposure reported increased PTSS as well as lower resting HR. Regression analysis showed evidence of sex modifying this relationship, (B = -0.64, p

Background: The prevalence of posttraumatic stress disorder (PTSD) among people living with HIV (PLWH) is higher than in the general population and can impact health behaviors. The influence of HIV on PTSD psychophysiology requires further investigation due to implications for the treatment of PTSD in PLWH. Objective: Utilizing fear-potentiated startle (FPS), we aimed to interrogate the influence of PTSD and HIV on fear responses. Materials and Methods: Women (18?65 years of age) recruited from the Women's Interagency HIV Study in Atlanta, GA (n?=?70, 26 without HIV and 44 with HIV), provided informed consent and completed a semistructured interview to assess trauma exposure and PTSD symptom severity. Participants also underwent an FPS paradigm to assess fear acquisition and extinction: Psychophysiological indices that measure how individuals learn new fear and then subsequently attempt to suppress this fear. Results: Women with PTSD, who did not have HIV, exhibited a greater startle response compared to women without PTSD or HIV during late acquisition to both the danger cue, reinforced conditioned stimulus (CS+, p?=?0.013)), and the safety cue, non-reinforced conditioned stimulus (CS?, p?=?0.046)), whereas women living with HIV (WLH) and PTSD demonstrated blunted fear responses compared to women with PTSD only. During extinction, WLH comorbid with PTSD exhibited an increased fear response during the extinction period in comparison to all other groups (p?=?0.023). Women without PTSD demonstrated a reduction in the fear response during extinction regardless of HIV status. Conclusion: Our findings indicate that HIV further modifies fear psychophysiology in WLH with comorbid PTSD, highlighting the importance of considering HIV status in conjunction with PTSD treatment.

AbstractObjective People living with HIV (PLWH) experience high rates of childhood maltreatment, which increases risk for posttraumatic stress disorder (PTSD). Thus, it is important to understand how HIV status interacts with childhood maltreatment to influence PTSD symptom severity and underlying psychophysiology.Methods The current study assessed whether HIV status interacts with childhood maltreatment to influence PTSD symptom severity and heart rate variability during a dark-enhanced startle (DES) task in 88 Black women with (n=30) and without HIV (n=58).Results HIV was associated with greater PTSD symptom severity only in women with low levels of childhood maltreatment (p=.024). Startle potentiation during DES was highest in women living without HIV and with high childhood maltreatment (p=.018). In women who had experienced low levels of childhood maltreatment, respiratory sinus arrhythmia (RSA) was lower during the dark phase of DES in women living without HIV than women living with HIV (WLWH), (p=.046). RSA during the light phase of DES was lower in WLWH than in women living without HIV (p=.042).Conclusion In the current sample of Black women, HIV status was associated with PTSD symptom severity in a manner dependent on level of childhood maltreatment, suggesting that HIV status may be an important factor to consider for behavioral and pharmacological treatment strategies for PTSD. Additionally, HIV status is associated with lower percent potentiation to darkness and lower RSA during the light phase of DES, suggesting physiological mechanisms by which HIV may contribute to PTSD symptoms in individuals exposed to low levels of childhood maltreatment.

During the war time dysregulation of negative emotions such as fear, anger, hatred, frustration, sadness, humiliation, and hopelessness can overrule normal societal values, culture, and endanger global peace and security, and mental health in affected societies. Therefore, it is understandable that the range and power of negative emotions may play important roles in consideration of human behavior in any armed conflict. The estimation and assessment of dominant negative emotions during war time are crucial but are challenged by the complexity of emotions’ neuro-psycho-physiology. Currently available natural language processing (NLP) tools have comprehensive computational methods to analyze and understand the emotional content of related textual data in war-inflicted societies. Innovative AI-driven technologies incorporating machine learning, neuro-linguistic programming, cloud infrastructure, and novel digital therapeutic tools and applications present an immense potential to enhance mental health care worldwide. This advancement could make mental health services more cost-effective and readily accessible. Due to the inadequate number of psychiatrists and limited psychiatric resources in coping with mental health consequences of war and traumas, new digital therapeutic wearable devices supported by AI tools and means might be promising approach in psychiatry of future. Transformation of negative dominant emotional maps might be undertaken by the simultaneous combination of online cognitive behavioral therapy (CBT) on individual level, as well as usage of emotionally based strategic communications (EBSC) on a public level. The proposed positive emotional transformation by means of CBT and EBSC may provide important leverage in efforts to protect mental health of civil population in war-inflicted societies. AI-based tools that can be applied in design of EBSC stimuli, like Open AI Chat GPT or Google Gemini may have great potential to significantly enhance emotionally based strategic communications by more comprehensive understanding of semantic and linguistic analysis of available text datasets of war-traumatized society. Human in the loop enhanced by Chat GPT and Gemini can aid in design and development of emotionally annotated messages that resonate among targeted population, amplifying the impact of strategic communications in shaping human dominant emotional maps into a more positive by CBT and EBCS.

Abstract Caregivers may play an essential role in buffering and/or exacerbating coronavirus disease 2019 (COVID‐19) fears and behaviors in youth. However, few studies have examined these associations in children from racial or ethnic minority groups, who have been historically marginalized and may be disproportionately susceptible to psychological consequences. Here, we examined the associations among caregivers and children in COVID‐19‐related fears, behaviors, and impact in a majority Black (71.9%) sample of children. Children (N = 64, 24 females, ages 7–10 years) were recruited from three Detroit, Michigan‐area schools during the 2019–2020 school year. Following school shutdowns in March 2020, children and their caregivers were invited to complete remote surveys in May and August 2020. We examined the associations among child and caregiver COVID‐19‐related fears, preventive behaviors, and perceived impact. We also examined whether aspects of the caregiver–child relationship (i.e., closeness, conflicts) moderated these associations. Caregiver–child fears about social distancing, preventive behaviors, and the perceived impact of COVID‐19 were positively correlated. The positive correlation between caregiver–child preventive behaviors strengthened over time and was moderated by caregiver–child closeness. These findings suggest that caregivers may impact fear as well as preventive behaviors and perceived impact of the pandemic in marginalized youth.

BackgroundPost-traumatic stress disorder (PTSD) and substance use (tobacco, alcohol, and cannabis) are highly comorbid. Many factors affect this relationship, including sociodemographic and psychosocial characteristics, other prior traumas, and physical health. However, few prior studies have investigated this prospectively, examining new substance use and the extent to which a wide range of factors may modify the relationship to PTSD.MethodsThe Advancing Understanding of RecOvery afteR traumA (AURORA) study is a prospective cohort of adults presenting at emergency departments (N = 2,943). Participants self-reported PTSD symptoms and the frequency and quantity of tobacco, alcohol, and cannabis use at six total timepoints. We assessed the associations of PTSD and future substance use, lagged by one timepoint, using the Poisson generalized estimating equations. We also stratified by incident and prevalent substance use and generated causal forests to identify the most important effect modifiers of this relationship out of 128 potential variables.ResultsAt baseline, 37.3% (N = 1,099) of participants reported likely PTSD. PTSD was associated with tobacco frequency (incidence rate ratio (IRR): 1.003, 95% CI: 1.00, 1.01, p = 0.02) and quantity (IRR: 1.01, 95% CI: 1.001, 1.01, p = 0.01), and alcohol frequency (IRR: 1.002, 95% CI: 1.00, 1.004, p = 0.03) and quantity (IRR: 1.003, 95% CI: 1.001, 1.01, p = 0.001), but not with cannabis use. There were slight differences in incident compared to prevalent tobacco frequency and quantity of use; prevalent tobacco frequency and quantity were associated with PTSD symptoms, while incident tobacco frequency and quantity were not. Using causal forests, lifetime worst use of cigarettes, overall self-rated physical health, and prior childhood trauma were major moderators of the relationship between PTSD symptoms and the three substances investigated.ConclusionPTSD symptoms were highly associated with tobacco and alcohol use, while the association with prospective cannabis use is not clear. Findings suggest that understanding the different risk stratification that occurs can aid in tailoring interventions to populations at greatest risk to best mitigate the comorbidity between PTSD symptoms and future substance use outcomes. We demonstrate that this is particularly salient for tobacco use and, to some extent, alcohol use, while cannabis is less likely to be impacted by PTSD symptoms across the strata.

BackgroundMood disorders such as major depressive and bipolar disorders, along with posttraumatic stress disorder (PTSD), schizophrenia (SCZ), and other psychotic disorders, constitute serious mental illnesses (SMI) and often lead to inpatient psychiatric care for adults. Risk factors associated with increased hospitalization rate in SMI (H-SMI) are largely unknown but likely involve a combination of genetic, environmental, and socio-behavioral factors. We performed a genome-wide association study in an African American cohort to identify possible genes associated with hospitalization due to SMI (H-SMI).MethodsPatients hospitalized for psychiatric disorders (H-SMI; n=690) were compared with demographically matched controls (n=4467). Quality control and imputation of genome-wide data were performed following the Psychiatric Genetic Consortium (PGC)-PTSD guidelines. Imputation of the Human Leukocyte Antigen (HLA) locus was performed using the HIBAG package.ResultsGenome-wide association analysis revealed a genome-wide significant association at 6p22.1 locus in the ubiquitin D (UBD/FAT10) gene (rs362514, p=9.43x10-9) and around the HLA locus. Heritability of H-SMI (14.6%) was comparable to other psychiatric disorders (4% to 45%). We observed a nominally significant association with 2 HLA alleles: HLA-A*23:01 (OR=1.04, p=2.3x10-3) and HLA-C*06:02 (OR=1.04, p=1.5x10-3). Two other genes (VSP13D and TSPAN9), possibly associated with immune response, were found to be associated with H-SMI using gene-based analyses.ConclusionWe observed a strong association between H-SMI and a locus that has been consistently and strongly associated with SCZ in multiple studies (6p21.32-p22.1), possibly indicating an involvement of the immune system and the immune response in the development of severe transdiagnostic SMI.

Background: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. Methods: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. Results: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. Conclusion: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

Introduction: Cytomegalovirus (CMV) infection is a major clinical issue after allogeneic hematopoietic stem cell transplantation (HSCT). The CMV envelope glycoproteins are key in viral pathogenesis; the glycoprotein B (gB) encoded by the UL55 gene might be an important determinant of viral virulence and disease severity marker in patients treated with allogeneic HSCT. Our aim was to investigate the molecular diversity of CMV gB and inquire into the associations between UL55 gene variations and clinical manifestations in adult patients treated with allogeneic HSCT. Results: The most prevalent genotypes were gB1 and gB4 (11/27, 40.7%). Patients with genotype gB1 infection had earlier platelet engraftment (p < 0.033) and less frequent minimal/measurable residual disease post HSCT than those without this genotype. Patients with gB4 glycoprotein infection had a significantly lower CD4+/CD8+ ratio at D90 (p < 0.026). Interestingly, patients with gB5 glycoprotein infection had shorter overall survival from base condition diagnosis (p < 0.042), as well as shorter overall survival after HSCT (p < 0.036). Acute GvHD was noted more frequently in those with mixed-genotype infection (p = 0.047). Material and Methods: The study included fifty-nine adult patients treated with allogeneic HSCT. Peripheral venous blood was sampled typically per week, with detection of CMV performed by quantitative real-time PCR. Multiplex nested PCR was used to determine specific gB genotypes, which were then statistically compared vis-à-vis specific clinical variables. Conclusions: Our study points to variations in the viral UL55 locus imparting both beneficial (earlier platelet engraftment, less frequent MRD post HSCT) and adverse effects (shorter overall survival, more frequent acute GvHD, less frequent 100% chimerism at day 90) to the transplanted host. Comprehensive molecular investigations are necessary to validate this apparent duality, as the potential benefits of CMV could perhaps be utilized for the benefit of the patient in the future.

The oncogenicity of the human cytomegalovirus (CMV) is currently being widely debated. Most recently, mounting clinical evidence suggests an anti-cancer effect via CMV-induced T cell-mediated tumor destruction. However, the data were mostly obtained from single-center studies and in vitro experiments. Broad geographic coverage is required to offer a global perspective. Our study examined the correlation between country-specific CMV seroprevalence (across 73 countries) and the age-standardized incidence rate (of 34 invasive tumors). The populations studied were stratified according to decadal age periods as the immunologic effects of CMV seropositivity may depend upon age at initial infection. The International Agency for Research on Cancer of the World Health Organization (IARC WHO) database was used. The multivariate linear regression analysis revealed a worldwide inverse correlation between CMV seroprevalence and the incidences of 62.8% tumors. Notably, this inverse link persists for all cancers combined (Spearman’s ρ = −0.732, p < 0.001; β = −0.482, p < 0.001, adjusted R2 = 0.737). An antithetical and significant correlation was also observed in particular age groups for the vast majority of tumors. Our results corroborate the conclusions of previous studies and indicate that this oncopreventive phenomenon holds true on a global scale. It applies to a wide spectrum of cancer histologies, additionally supporting the idea of a common underlying mechanism—CMV-stimulated T cell tumor targeting. Although these results further advance the notion of CMV-based therapies, in-depth investigation of host–virus interactions is still warranted.

IntroductionExposure to traumatic events and stressful life experiences are associated with a wide range of adverse mental and physical health outcomes. Studies have found post-traumatic stress disorder (PTSD), depression, and anxiety sensitivity occurrence to be common in addition to inflammatory diseases like asthma, especially in women. Moreover, overlapping neurobiological mechanisms have been linked to both PTSD and asthma.MethodsIn the current study, n = 508 women reported on presence of lifetime asthma diagnosis and symptoms of trauma-related psychopathology including PTSD and depression. A separate group of female participants (n = 64) reported on asthma, PTSD, depression and anxiety sensitivity, and underwent functional MRI scans during a fearful faces task, and their anterior insula responses were analyzed.ResultsOverall, PTSD and depression severity were significantly higher in those with asthma versus those without asthma. There was a positive association between anterior insula response to social threat cues and depression symptoms only among individuals without a lifetime presence of asthma.DiscussionThese findings provide continued evidence on the interactions between stress, neural mechanisms involved in interoception and salience detection, and trauma-related psychopathology.

Abstract The authors sought to characterize adverse posttraumatic neuropsychiatric sequelae (APNS) symptom trajectories across ten symptom domains (pain, depression, sleep, nightmares, avoidance, re-experiencing, anxiety, hyperarousal, somatic, and mental/fatigue symptoms) in a large, diverse, understudied sample of motor vehicle collision (MVC) survivors. More than two thousand MVC survivors were enrolled in the emergency department (ED) and completed a rotating battery of brief smartphone-based surveys over a 2-month period. Measurement models developed from survey item responses were used in latent growth curve/mixture modeling to characterize homogeneous symptom trajectories. Associations between individual trajectories and pre-trauma and peritraumatic characteristics and traditional outcomes were compared, along with associations within and between trajectories. APNS across all ten symptom domains were common in the first two months after trauma. Many risk factors and associations with high symptom burden trajectories were shared across domains. Both across and within traditional diagnostic boundaries, APNS trajectory intercepts, and slopes were substantially correlated. Across all domains, symptom severity in the immediate aftermath of trauma (trajectory intercepts) had the greatest influence on the outcome. An interactive data visualization tool was developed to allow readers to explore relationships of interest between individual characteristics, symptom trajectories, and traditional outcomes ( http://itr.med.unc.edu/aurora/parcoord/ ). Individuals presenting to the ED after MVC commonly experience a broad constellation of adverse posttraumatic symptoms. Many risk factors for diverse APNS are shared. Individuals diagnosed with a single traditional outcome should be screened for others. The utility of multidimensional categorizations that characterize individuals across traditional diagnostic domains should be explored.

Abstract Visual components of trauma memories are often vividly re-experienced by survivors with deleterious consequences for normal function. Neuroimaging research on trauma has primarily focused on threat-processing circuitry as core to trauma-related dysfunction. Conversely, limited attention has been given to visual circuitry which may be particularly relevant to posttraumatic stress disorder (PTSD). Prior work suggests that the ventral visual stream is directly related to the cognitive and affective disturbances observed in PTSD and may be predictive of later symptom expression. The present study used multimodal magnetic resonance imaging data (n = 278) collected two weeks after trauma exposure from the AURORA study, a longitudinal, multisite investigation of adverse posttraumatic neuropsychiatric sequelae. Indices of gray and white matter were combined using data fusion to identify a structural covariance network (SCN) of the ventral visual stream 2 weeks after trauma. Participant’s loadings on the SCN were positively associated with both intrusion symptoms and intensity of nightmares. Further, SCN loadings moderated connectivity between a previously observed amygdala-hippocampal functional covariance network and the inferior temporal gyrus. Follow-up MRI data at 6 months showed an inverse relationship between SCN loadings and negative alterations in cognition in mood. Further, individuals who showed decreased strength of the SCN between 2 weeks and 6 months had generally higher PTSD symptom severity over time. The present findings highlight a role for structural integrity of the ventral visual stream in the development of PTSD. The ventral visual stream may be particularly important for the consolidation or retrieval of trauma memories and may contribute to efficient reactivation of visual components of the trauma memory, thereby exacerbating PTSD symptoms. Potentially chronic engagement of the network may lead to reduced structural integrity which becomes a risk factor for lasting PTSD symptoms.

Abstract Posttraumatic stress disorder (PTSD) is a significant public health issue. Yet, there are limited treatment options and no data to suggest which treatment will work for whom. We tested the efficacy of virtual reality exposure (VRE) or prolonged imaginal exposure (PE), augmented with D-cycloserine (DCS) for combat-related PTSD. As an exploratory aim, we examined whether brain-derived neurotrophic factor (BDNF) and fatty acid amide hydrolase (FAAH) moderated treatment response. Military personnel with PTSD (n = 192) were recruited into a multisite double-blind randomized controlled trial to receive nine weeks of VRE or PE, with DCS or placebo. Primary outcome was the improvement in symptom severity. Randomization was stratified by comorbid depression (MDD) and site. Participants in both VRE and PE showed similar meaningful clinical improvement with no difference between the treatment groups. A significant interaction (p = 0.45) suggested VRE was more effective for depressed participants (CAPS difference M = 3.51 [95% CI 1.17–5.86], p = 0.004, ES = 0.14) while PE was more effective for nondepressed participants (M = −8.87 [95% CI −11.33 to −6.40], p

Objective Although several risk factors for stroke-induced posttraumatic stress disorder (PTSD) have been identified, objective risk measures that can be detected in the acute aftermath of these events are needed. This study is the first to collect an objective measure of psychophysiological arousal—skin conductance (SC) reactivity to a trauma interview—in patients after stroke or transient ischemic attack (TIA) and investigate correlates of SC reactivity. Methods Mobile SC measurement during a resting baseline and standardized trauma interview was performed in-hospital in 98 individuals following stroke/TIA. We examined associations between several stroke-induced PTSD risk factors (sociodemographic, psychosocial, and medical characteristics) and SC reactivity to a trauma interview involving a free-response recalling of the stroke/TIA event. Results Of the sociodemographic, psychosocial, medical characteristics examined as correlates to SC reactivity to recalling the stroke/TIA event, 2 factors reflecting aspects of prior and in-hospital experience were significantly associated with this indicator of sympathetic nervous system activation. A greater cumulative trauma burden was significantly associated with greater SC reactivity ( r = .23, P = .04). Additionally, individuals administered benzodiazepines in-hospital had significantly greater SC reactivity to recalling the stroke/TIA event ( M = 1.51, SD = 1.52) than those who were not ( M = 0.76, SD = 1.16; P = .01). Greater cumulative trauma burden remained significantly associated with greater SC reactivity when adjusting for age and in-hospital benzodiazepine administration ( β =0.22, P = .04). Conclusion This study demonstrated that SC reactivity was related to both behavioral and psychological risk factors for PTSD after a stroke/TIA event. Additionally, we demonstrated the feasibility of a low-cost, mobile measurement of SC that can be conducted in-hospital in a novel patient population: individuals with a medical trauma. With this measure, we were able to identify those individuals with the greatest trauma-related sympathetic nervous system reactivity in the days following a medical trauma. Future research is needed to determine whether SC reactivity may be leveraged in the development of brief, noninvasive screening measures for enhancing PTSD risk prediction.

Background: Individuals with posttraumatic stress disorder (PTSD) are more likely to present with metabolic diseases such as type-2 diabetes mellitus (T2DM), and cardiovascular dysfunction has been implicated in this link. These diseases disproportionately affect women and individuals exposed to chronic environmental stressors (e.g., community violence, poverty). We examined associations among PTSD, cardiovascular indices, and metabolic function in highly trauma-exposed Black women with T2DM. Methods: Participants (N = 80) were recruited for a follow-up study of stress and T2DM as part of the Grady Trauma Project. PTSD symptoms were assessed with the Clinician Administered PTSD Scale (CAPS-IV). Cardiovascular indices included heart rate (HR), blood pressure (BP), respiratory sinus arrhythmia (RSA), and endothelial function (assessed via flow-mediated dilation; FMD). An oral glucose tolerance test was used as an indicator of metabolic function. Results: Of the cardiovascular indices, only FMD was significantly associated with PTSD symptoms (CAPS Avoidance symptoms; β = −0.37, p = .042), and glucose tolerance (β = −0.44, p = .019), controlling for age and body mass index. The association between FMD and PTSD Avoidance was moderated by RSA such that the effect of FMD was only significant at low levels of RSA (simple slopes β = −0.87, p = .004). Conclusions: Our results indicate that endothelial function is significantly related to PTSD and glucose tolerance, over and above other cardiovascular measures (HR, BP, RSA). Further, our results suggest that low RSA may be a risk factor for the link between poor endothelial function and PTSD in women with T2DM.

Abstract Background Post-traumatic stress disorder (PTSD) is a significant public health problem, affecting approximately 7% of the general population and 13–18% of the combat Veteran population. The first study using acupuncture for PTSD in a civilian population showed large pre- to post-treatment effects for an empirically developed verum protocol, which was equivalent to group cognitive behavior therapy and superior to a wait-list control. The primary objective of this study is to determine both clinical and biological effects of verum acupuncture for combat-related PTSD in treatment-seeking US Veterans. Methods This is a two-arm, parallel-group, prospective randomized placebo-controlled clinical trial. The experimental condition is verum acupuncture and the placebo control is sham (minimal) acupuncture in 1-h sessions, twice a week for 12 weeks. Ninety subjects will provide adequate power and will be allocated to group by an adaptive randomization procedure. The primary outcome is change in PTSD symptom severity from pre- to post-treatment. The secondary biological outcome is change from pre- to post-treatment in psychophysiological response, startle by electromyographic (EMG) eyeblink. Assessments will be conducted at pre-, mid-, post-, and 1-month post-treatment, blind to group allocation. Intent-to-treat analyses will be conducted. Discussion The study results will be definitive because both clinical and biological outcomes will be assessed and correlated. Issues such as the number needed for recruitment and improvement, use of sham acupuncture, choice of biological measure, and future research need will be discussed. Trial registration ClinicalTrials.gov NCT02869646 . Registered on 17 August 2016.

A National Immunization Technical Advisory Group (NITAG) is a multi-disciplinary body of national experts that provide evidence-based recommendations to policy-makers to assist them in making informed immunization policy and programme decisions. During the COVID-19 pandemic, NITAGs faced many challenges in making evidence-based recommendations for COVID-19 vaccines due to the rapidly evolving situation with new vaccine products available in a short time period and limited data on vaccine effectiveness. The authors reviewed the process used by Serbia's NITAG, which is called the Serbian Expert Committee on Immunization, to develop COVID-19 vaccine recommendations during the pandemic. The article examines the challenges and successes faced by the committee. Serbia's expert committee used the best available evidence to develop over forty recommendations on all aspects of COVID-19 vaccination. These expert committee recommendations facilitated the early procurement and successful roll-out of COVID-19 vaccines, guidance for vaccination of individuals at the highest risk, and high COVID-19 vaccination coverage in the country. The availability of five COVID-19 vaccines in Serbia was an advantage for the successful roll-out but posed challenges for the expert committee. Serbia's expert committee plans to use the experience and best practices developed during the pandemic to improve and expand its work moving forward.

Adverse social exposures (ASEs) such as low income, low educational attainment, and childhood/adult trauma exposure are associated with variability in brain region measurements of gray matter volume (GMV), surface area (SA), and cortical thickness (CT). These CNS morphometries are associated with stress-related psychiatric illnesses and represent endophenotypes of stress-related psychiatric illness development. Epigenetic mechanisms, such as 5-methyl-cytosine (5mC), may contribute to the biological embedding of the environment but are understudied and not well understood. How 5mC relates to CNS endophenotypes of psychiatric illness is also unclear. In 97 female, African American, trauma-exposed participants from the Grady Trauma Project, we examined the associations of childhood trauma burden (CTQ), adult trauma burden, low income, and low education with blood-derived 5mC clusters and variability in brain region measurements in the amygdala, hippocampus, and frontal cortex subregions. To elucidate whether peripheral 5mC indexes central nervous system (CNS) endophenotypes of psychiatric illness, we tested whether 73 brain/blood correlated 5mC clusters, defined by networks of correlated 5mC probes measured on Illumina’s HumanMethylation Epic Beadchip, mediated the relationship between ASEs and brain measurements. CTQ was negatively associated with rostral middle frontal gyrus (RMFG) SA (β =−0.231, p = 0.041). Low income and low education were also associated with SA or CT in a number of brain regions. Seven 5mC clusters were associated with CTQ (pmin = 0.002), two with low education (pmin = 0.010), and three with low income (pmin = 0.007). Two clusters fully mediated the relation between CTQ and RMFG SA, accounting for 47 and 35% of variability, respectively. These clusters were enriched for probes falling in DNA regulatory regions, as well as signal transduction and immune signaling gene ontology functions. Methylome-network analyses showed enrichment of macrophage migration (p = 9 × 10–8), T cell receptor complex (p = 6 × 10–6), and chemokine-mediated signaling (p = 7 × 10–4) pathway enrichment in association with CTQ. Our results support prior work highlighting brain region variability associated with ASEs, while informing a peripheral inflammation-based epigenetic mechanism of biological embedding of such exposures. These findings could also serve to potentiate increased investigation of understudied populations at elevated risk for stress-related psychiatric illness development.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2–81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3–85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Introduction Childhood trauma is strongly associated with fear-related psychopathology, like anxiety and posttraumatic stress disorder (PTSD). Atypical fear extinction and neural responses to social threat (i.e., negative emotional faces) may serve as intermediate phenotypes preceding the emergence of fear-related psychopathology during childhood and adolescence. However, few studies have examined associations among these phenotypes in trauma-exposed youth. Methods 29 9-year-old children with high rates of trauma exposure (Mdn = 4, min = 0, max= 14 total events) completed a fear-potentiated startle paradigm assessing fear conditioning and extinction and an emotional faces functional magnetic resonance imaging (fMRI) task assessing neural responses to fearful and neutral faces. Results Overall amygdala response was positively associated with anxiety (peak coordinates: x = −30, y = −6, z = −24; Z = 3.54; pFWE corrected = 0.011; k = 24 voxels) and fear-potentiated startle during early extinction (peak coordinates x = 28, y = −6, z = −18; Z = 3.50; pFWE corrected = 0.012; k = 19 voxels). Across the session, amygdala reactivity to fearful faces increased (F(1, 29) = 4.427, p = .044) and was positively associated with fear-potentiated startle during early extinction (r = .56, p = .002). Conclusions We found a positive association between increasing amygdala response to threatening faces and fear load, that is, heightened fear-potentiated startle during early extinction, in trauma-exposed children. These fear-based intermediate phenotypes may share underlying amygdala circuits, such that hyperactivity may represent an early marker of anxiety risk in trauma-exposed youth.

Background Inhibition is a critical executive control process and an established neurobiological phenotype of PTSD, yet to our knowledge, no prospective studies have examined this using a contextual cue task that enables measurement of behavioural response and neural activation patterns across proactive and reactive inhibition. Objective The current longitudinal study utilised functional magnetic resonance imaging (fMRI) to examine whether deficits in proactive and reactive inhibition predicted PTSD symptoms six months after trauma. Method Twenty-three (65% males) medical patients receiving emergency medical care from a level 1 trauma centre were enrolled in the study and invited for an MRI scan 1-2-months post-trauma. PTSD symptoms were measured using self-report at scan and 6-months post-trauma. A stop-signal anticipation task (SSAT) during an fMRI scan was used to test whether impaired behavioural proactive and reactive inhibition, and reduced activation in right inferior frontal gyrus (rIFG), ventromedial prefrontal cortex (vmPFC), and bilateral hippocampus, were related to PTSD symptoms. We predicted that lower activation levels of vmPFC and rIFG during reactive inhibition and lower activation of hippocampus and rIFG during proactive inhibition would relate to higher 6-month PTSD symptoms. Results No significant associations were found between behavioural measures and 6-month PTSD. Separate linear regression analyses showed that reduced rIFG activation (F1,21 = 9.97, R2 = .32, p = .005) and reduced vmPFC activation (F1,21 = 5.19, R2 = .20, p = .03) significantly predicted greater 6-month PTSD symptoms; this result held for rIFG activation controlling for demographic variables and baseline PTSD symptoms (β = −.45, p = .04) and Bonferroni correction. Conclusion Our findings suggest that impaired rIFG and, to a lesser extent, vmPFC activation during response inhibition may predict the development of PTSD symptoms following acute trauma exposure. Given the small sample size, future replication studies are needed. HIGHLIGHTS Impaired inhibition may be an important risk factor for the development of PTSD following trauma, with less right inferior frontal gyrus and ventromedial prefrontal cortex activation during response inhibition predicting PTSD development.

Background: Posttraumatic stress symptoms (PTSS) include a constellation of physical and emotional profiles that youth exposed to trauma may experience. An estimated 20% of youth are exposed to trauma, and in refugee populations, up to 54% experience posttraumatic stress. Given the physical and mental health consequences associated with trauma exposure and subsequent psychopathology, identifying biomarkers of symptom severity is a top research priority. Objective: Previous research in adults found that skin conductance responses to trauma interview predicted current and future PTSS. We extended this method to refugee youth exposed to civilian war trauma and forced migration, to examine associations between PTSS and skin conductance in this uniquely vulnerable child and adolescent population. Methods: 86 refugee youth ages 7–17 years completed a trauma interview and assessment of self-reported PTSS. The mobile eSense app on a iPad was used to obtain continuous recordings of skin conductance level (SCL) during a trauma interview (trauma SCL). Skin conductance response (SCR) was calculated by subtracting the baseline SCL from the maximum amplitude of the trauma SCL. Results: SCL during trauma was significantly greater than baseline SCL, Trauma exposure was significantly associated with SCR to trauma interview, R2 = .084, p = .042. SCR to trauma interview was positively correlated with reexperiencing (R2 = .127, p = .028), and hyperarousal symptoms (R2 = .123, p = .048). Conclusions: The present study provides evidence for feasibility of SCR to trauma interview as a candidate biomarker of PTSS in youth. This is the first study to look at SCR to trauma interview in youth resettled as refugees and is part of the limited but growing body of research to look at biomarkers in refugee cohorts more broadly. As the number of forcibly displaced persons surges, early detection and prevention of trauma-related psychology is becoming more important than ever. HIGHLIGHTS Using the mobile eSense app, we demonstrate that skin conductance is measurable in a variety of research settings and that skin conductance response may be a biological indicator of trauma and related psychopathology – namely re-experiencing symptoms – in youth resettled as refugees.

Background: Type 2 diabetes mellitus (T2DM) is a major public health problem in the United States. Although cardiovascular autonomic functioning, blood glucose control, and inflammation are known to play a role in T2DM, the interaction between these variables remains largely unexplored, particularly in the context of stress. To address this gap, we examined the relationship between these variables in a sample that is uniquely vulnerable to the health consequences of T2DM. Methods: Participants were 37 trauma-exposed Black women with a diagnosis of T2DM. High frequency heart rate variability (HF-HRV), blood glucose control (HbA1c), and a stressor-evoked biomarker of inflammation (interleukin 6; IL-6) were obtained as part of a larger study of the genetic risk factors for and consequences of trauma exposure. Results: The interaction of HbA1c and HF-HRV was significantly associated with IL-6 response calculated as area under the curve with respect to ground. Post-hoc simple slopes analyses revealed HbA1c, rather than HF-HRV, as the moderator in this association such that higher HF-HRV conferred higher circulating levels of IL-6 only in the presence of lower HbA1c, (β ​= ​0.60, t ​= ​3.51, p ​= ​.001). Conclusions: Cardiovascular autonomic functioning and blood glucose control were significantly associated with stressor-evoked IL-6 responses when controlling for BMI and age. Moreover, the association between cardiovascular autonomic functioning and inflammation varied at different levels of HbA1c. This highlights the possibility that individuals with trauma exposure and T2DM may benefit from stratification by HbA1c levels for research analysis and treatment decision making.

BackgroundMen who have sex with men (MSM) are at a disproportionate risk for HIV infection and common mental disorders worldwide. In the context of HIV, common mental disorders are important and are frequent drivers of suboptimal prevention and treatment outcomes. Mobile ecological momentary assessments (EMAs), or the repeated sampling of people’s behaviors and psychological states in their daily lives using mobile phones, can clarify the triggers and HIV-related sequelae of depressive-anxious symptoms and contribute toward the design of ecological momentary interventions (EMIs) that cater to the contextually varying needs of individuals to optimize prevention and treatment outcomes. ObjectiveThis study aims to characterize the feasibility and acceptability of mobile EMA among high-risk MSM in Hanoi, Vietnam. It aims to evaluate the perceived relevance, usability, and concerns of this group with regard to the content and delivery of mobile EMA and the potential of leveraging such platforms in the future to deliver EMIs. MethodsBetween January and April 2018, a total of 46 participants were recruited. The participants completed 6 to 8 mobile EMA surveys daily for 7 days. Surveys occurred once upon waking, 4 to 6 times throughout the day, and once before sleeping. All surveys queried participants’ perceived safety, social interactions, psychological state, and mental health symptoms. The morning survey further queried on sleep and medication use within the past 24 hours, whereas the night survey queried on sexual activity and substance use and allowed participants to share an audio recording of a stressful experience they had that day. At the end of the week, participants were interviewed about their experiences with using the app. ResultsParticipants completed an average of 21.7 (SD 12.7) prompts over the 7-day period. Excluding nonresponders, the average compliance rate was 61.8% (SD 26.6%). A thematic analysis of qualitative interviews suggested an overall positive reception of the app and 5 recurring themes, which were centered on the relevance of psychological and behavioral items to daily experiences (eg, mental health symptoms and audio recording), benefits of using the app (eg, increased self-understanding), worries and concerns (eg, privacy), usability (eg, confusion about the interface), and recommendations for future design (eg, integrating more open-ended questions). ConclusionsMobile EMA is feasible and acceptable among young MSM in Vietnam; however, more research is needed to adapt EMA protocols to this context and enhance compliance. Most participants eagerly provided information about their mental health status and daily activities. As several participants looked toward the app for further mental health and psychosocial support, EMIs have the potential to reduce HIV and mental health comorbidity among MSM.

Abstract Background Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. Method Adult subjects (N = 2229; 56.2% male) aged 18–69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA‐PGC PTSD sites underwent T1‐weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel‐wise (brainageR) and region‐of‐interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age − chronological age) controlling for chronological age, sex, and scan site. Results BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three‐way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. Discussion Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age‐related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan.

ObjectiveWhether short-term, low-potency opioid prescriptions for acute pain lead to future at-risk opioid use remains controversial and inadequately characterized. Our objective was to measure the association between emergency department (ED) opioid analgesic exposure after a physical, trauma-related event and subsequent opioid use. We hypothesized ED opioid analgesic exposure is associated with subsequent at-risk opioid use.MethodsParticipants were enrolled in AURORA, a prospective cohort study of adult patients in 29 U.S., urban EDs receiving care for a traumatic event. Exclusion criteria were hospital admission, persons reporting any non-medical opioid use (e.g., opioids without prescription or taking more than prescribed for euphoria) in the 30 days before enrollment, and missing or incomplete data regarding opioid exposure or pain. We used multivariable logistic regression to assess the relationship between ED opioid exposure and at-risk opioid use, defined as any self-reported non-medical opioid use after initial ED encounter or prescription opioid use at 3-months.ResultsOf 1441 subjects completing 3-month follow-up, 872 participants were included for analysis. At-risk opioid use occurred within 3 months in 33/620 (5.3%, CI: 3.7,7.4) participants without ED opioid analgesic exposure; 4/16 (25.0%, CI: 8.3, 52.6) with ED opioid prescription only; 17/146 (11.6%, CI: 7.1, 18.3) with ED opioid administration only; 12/90 (13.3%, CI: 7.4, 22.5) with both. Controlling for clinical factors, adjusted odds ratios (aORs) for at-risk opioid use after ED opioid exposure were: ED prescription only: 4.9 (95% CI 1.4, 17.4); ED administration for analgesia only: 2.0 (CI 1.0, 3.8); both: 2.8 (CI 1.2, 6.5).ConclusionsED opioids were associated with subsequent at-risk opioid use within three months in a geographically diverse cohort of adult trauma patients. This supports need for prospective studies focused on the long-term consequences of ED opioid analgesic exposure to estimate individual risk and guide therapeutic decision-making.

The COVID-19 pandemic has adverse consequences on human psychology and behavior long after initial recovery from the virus. These COVID-19 health sequelae, if undetected and left untreated, may lead to more enduring mental health problems, and put vulnerable individuals at risk of developing more serious psychopathologies. Therefore, an early distinction of such vulnerable individuals from those who are more resilient is important to undertake timely preventive interventions. The main aim of this article is to present a comprehensive multimodal conceptual approach for addressing these potential psychological and behavioral mental health changes using state-of-the-art tools and means of artificial intelligence (AI). Mental health COVID-19 recovery programs at post-COVID clinics based on AI prediction and prevention strategies may significantly improve the global mental health of ex-COVID-19 patients. Most COVID-19 recovery programs currently involve specialists such as pulmonologists, cardiologists, and neurologists, but there is a lack of psychiatrist care. The focus of this article is on new tools which can enhance the current limited psychiatrist resources and capabilities in coping with the upcoming challenges related to widespread mental health disorders. Patients affected by COVID-19 are more vulnerable to psychological and behavioral changes than non-COVID populations and therefore they deserve careful clinical psychological screening in post-COVID clinics. However, despite significant advances in research, the pace of progress in prevention of psychiatric disorders in these patients is still insufficient. Current approaches for the diagnosis of psychiatric disorders largely rely on clinical rating scales, as well as self-rating questionnaires that are inadequate for comprehensive assessment of ex-COVID-19 patients’ susceptibility to mental health deterioration. These limitations can presumably be overcome by applying state-of-the-art AI-based tools in diagnosis, prevention, and treatment of psychiatric disorders in acute phase of disease to prevent more chronic psychiatric consequences.

Background: Cross-sectional studies have found that individuals with posttraumatic stress disorder (PTSD) exhibit deficits in autonomic functioning. While PTSD rates are twice as high in women compared to men, sex differences in autonomic functioning are relatively unknown among trauma-exposed populations. The current study used a prospective design to examine sex differences in posttraumatic autonomic functioning. Methods: 192 participants were recruited from emergency departments following trauma exposure (Mean age = 35.88, 68.2% female). Skin conductance was measured in the emergency department; fear conditioning was completed two weeks later and included measures of blood pressure (BP), heart rate (HR), and high frequency heart rate variability (HF-HRV). PTSD symptoms were assessed 8 weeks after trauma. Results: 2-week systolic BP was significantly higher in men, while 2-week HR was significantly higher in women, and a sex by PTSD interaction suggested that women who developed PTSD demonstrated the highest HR levels. Two-week HF-HRV was significantly lower in women, and a sex by PTSD interaction suggested that women with PTSD demonstrated the lowest HF-HRV levels. Skin conductance response in the emergency department was associated with 2-week HR and HF-HRV only among women who developed PTSD. Conclusions: Our results indicate that there are notable sex differences in autonomic functioning among trauma-exposed individuals. Differences in sympathetic biomarkers (BP and HR) may have implications for cardiovascular disease risk given that sympathetic arousal is a mechanism implicated in this risk among PTSD populations. Future research examining differential pathways between PTSD and cardiovascular risk among men versus women is warranted.

Recent research has linked early life stress (ELS), such as trauma exposure, with early puberty. Early puberty has also been identified as a risk factor for poor mental health outcomes. However, these two paths have primarily been examined independently. In addition, more studies have examined these associations in girls than boys, and findings for boys remain mixed. We hypothesized that early puberty (relative to peers) would be positively associated with both prior trauma exposure and concurrent anxiety symptoms. We anticipated that these associations might differ by sex. We tested these hypotheses within a cross-sectional sample of 133 8- to 13-year-old Black girls and boys with trauma exposure. The association between trauma and accelerated pubertal timing was sex-specific: it was positive for girls and negative for boys. We stratified subsequent analyses by sex. Regression analyses indicated that early puberty relative to peers predicted more anxiety symptoms for girls but not boys, after accounting for trauma exposure. A statistical mediation analysis indicated that, for girls, the positive association between trauma exposure and anxiety was partially mediated by pubertal timing. These results indicate that trauma exposure may have sex-specific effects on pubertal timing and anxiety risk in Black children. We also found that, for girls, trauma may increase risk for adverse outcomes by prompting earlier puberty, which is linked to higher anxiety. These findings are consistent with cascading effects of trauma across development, and highlight the need for further study of sex-specific mechanisms.

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.

Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.

Schizophrenia (SCZ) is an etiologically heterogeneous disease with genetic and environmental risk factors (e.g., Toxoplasma gondii infection) differing among affected individuals. Distinguishing such risk factors may point to differences in pathophysiological pathways and facilitate the discovery of individualized treatments. Toxoplasma gondii (TOXO) has been implicated in increasing the risk of schizophrenia. To determine whether TOXO-positive individuals with SCZ have a different polygenic risk burden than uninfected people, we applied the SCZ polygenic risk score (SCZ-PRS) derived from the Psychiatric GWAS Consortium separately to the TOXO-positive and TOXO-negative subjects with the diagnosis of SCZ as the outcome variable. The SCZ-PRS does not include variants in the major histocompatibility complex.Of 790 subjects assessed for TOXO, the 662 TOXO-negative subjects (50.8% with SCZ) reached a Bonferroni corrected significant association (p = 0.00017, R2 = 0.023). In contrast, the 128 TOXO-positive individuals (53.1% with SCZ) showed no significant association (p = 0.354) for SCZ-PRS and had a much lower R2 (R2 = 0.007). To account for Type-2 error in the TOXO-positive dataset, we performed a random sampling of the TOXO-negative subpopulation (n = 130, repeated 100 times) to simulate equivalent power between groups: the p-value was 0.354.We found intriguing evidence that the SCZ-PRS predicts SCZ in TOXO-negative subjects, as expected, but not in the TOXO-positive individuals. This result highlights the importance of considering environmental risk factors to distinguish a subgroup with independent or different genetic components involved in the development of SCZ.

17β-estradiol (E2) levels in women correlate with multiple neuropsychiatric symptoms, including those that are stress-related. Furthermore, prior work from our group has demonstrated that E2 status influences DNA methylation (DNAm) across the genome. We developed and validated a DNAm-based predictor of E2 (one of four naturally occurring estrogens) using a training set of 183 females and a test set of 79 females from the same traumatized cohort. We showed that predicted E2 levels were highly correlated with measured E2 concentrations in our testing set (r ​= ​0.75, p ​= ​1.8e-15). We further demonstrated that predicted E2 concentrations, in combination with measured values, negatively correlated with current post-traumatic stress disorder (PTSD) (β ​= ​−0.38, p ​= ​0.01) and major depressive disorder (MDD) diagnoses (β ​= ​−0.45, p ​= ​0.02), as well as a continuous measure of PTSD symptom severity (β ​= ​−2.3, p ​= ​0.007) in females. Finally, we tested our predictor in an independent data set (n ​= ​85) also comprised of recently traumatized female subjects to determine if the predictor would generalize to a different population than the one on which it was developed. We found that the correlation between predicted and actual E2 concentrations in the external validation data set was also high (r ​= ​0.48, p ​= ​3.0e-6). While further validation is warranted, a DNAm predictor of E2 concentrations will advance our understanding of hormone-epigenetic interactions. Furthermore, such a DNAm predictor may serve as an epigenetic proxy for E2 concentrations and thus provide an important biomarker to better evaluate the contribution of E2 to current and potentially future psychiatric symptoms in samples for which E2 is not measured.

Summary: To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.

Background: Approximately three quarters of men who have sex with men (MSM) in Vietnam have used a phone or tablet to search for sexual health information online, and over half of these men have used it to locate nearby service providers. As HIV prevalence continues to rise in Vietnamese MSM, smartphones and other electronic media may provide an ideal platform for HIV research and intervention. Here, we describe a pilot study of an ecological momentary assessment (EMA) application (app) and a wearable device (MC10 BioStamp) to monitor risk-taking behaviours and mental health symptomatology and assess the feasibility and acceptability of the app, and mobile health (mHealth) needs of MSM in Vietnam. Methods: We recruited 50 participants from outpatient clinics and community-based organisations for MSM in Hanoi, Vietnam. For 1 week, participants completed brief surveys on their smartphone at six to eight random time-points every day. At each time-point, participants answered questions assessing: current mood; stress level; qualities of their current environment (including who they were with); mental health symptoms since last notification; risk behaviours; and GPS location (automatically recorded). They additionally wore two sensors on their chest and thigh, monitoring ambulatory heart rate and physical activity. After the week, participants were interviewed about their experiences using the application and were asked survey questions about what features they wanted in future mHealth-related apps. Findings: Participants were identified from an existing dataset of MSM (n=198) and invited to return for the study between January and April 2019. Overall, participants reported few issues with the sensors; however, they had more concerns about the app. The most frequent complaints participants had were that the assessments were too repetitive, too frequent, and did not provide enough opportunity for in-depth qualitative responses. What participants most enjoyed about the app was that it provided an opportunity to share and to reflect on their moods and social interactions. To improve, participants felt the messaging needed to be more MSM-friendly and visually appealing, while providing occasional statistics on their weekly moods or behaviours. The most popular app features desired were the ability to talk directly to a service provider about ongoing health concerns (91%; 40/44), locate nearby PrEP providers (82%; 36/44), and locate a nearby HIV/STD testing centre (82%; 36/44). Interpretation: This study found that mobile EMA apps and wearable technology are a feasible and acceptable way of monitoring mental distress and HIV risk among MSM in Vietnam. Given that many were already looking towards the app as a means to self-manage and acquire more health-related information, mobile technologies may be a natural platform for bridging research and intervention among this population. Funding: PHRMA Foundation; Global Health Institute and Center for Culture, Mind, Brain at Emory University; Robert Lemelson Foundation, Society for Psychological Anthropology; Healthcare Innovation Program/Georgia CTSA; American Society of Tropical Medicine & Hygiene; Ben Kean Fellowship Committee.

Maladaptive patterns of attention to emotional stimuli are a common feature of posttraumatic stress disorder (PTSD), with growing evidence supporting sustained attention to threatening stimuli across trauma samples. However, it remains unclear how different PTSD symptom clusters are associated with attentional bias patterns, particularly in urban civilian settings with high rates of trauma exposure and PTSD. The present study examined associations among these variables in 70 traumatized primarily African American women. PTSD was measured using the Clinician Administered PTSD Scale, and eye tracking was used to measure patterns of attention as participants engaged in an attention bias (dot probe) task to emotional faces; average initial fixation (1 s) and dwell duration (overall time spent looking at emotional face versus neutral face across the 5 s task) were used to assess attention bias patterns toward emotional faces. Women with PTSD showed significantly longer dwell duration toward angry faces than women without PTSD (F = 5.16, p

Accelerated epigenetic aging, the difference between the DNA methylation-predicted age (DNAm age) and the chronological age, is associated with a myriad of diseases. This study investigates the relationship between epigenetic aging and risk and protective factors of PTSD. Genome-wide DNA methylation analysis was performed in 211 individuals including combat-exposed Australian veterans (discovery cohort, n = 96 males) and trauma-exposed civilian males from the Grady Trauma Project (replication cohort, n = 115 males). Primary measures included the Clinician Administered PTSD Scale for DSM-5 and the Connor-Davidson Resilience Scale (CD-RISC). DNAm age prediction was performed using the validated epigenetic clock calculator. Veterans with PTSD had increased PTSD symptom severity (P-value = 3.75 × 10−34) and lower CD-RISC scores (P-value = 7.5 × 10−8) than veterans without PTSD. DNAm age was significantly correlated with the chronological age (P-value = 3.3 × 10−6), but DNAm age acceleration was not different between the PTSD and non-PTSD groups (P-value = 0.24). Evaluating potential protective factors, we found that DNAm age acceleration was significantly associated with CD-RISC resilience scores in veterans with PTSD, these results remained significant after multiple testing correction (P-value = 0.023; r = 0.32). This finding was also replicated in an independent trauma-exposed civilian cohort (P-value = 0.02; r = 0.23). Post-hoc factor analyses revealed that this association was likely driven by “self-efficacy” items within the CD-RISC (P-value = 0.015; r = 0.35). These results suggest that among individuals already suffering from PTSD, some aspects of increased resilience might come at a biological cost. Keywords: Epigenetic aging, Biomarkers, Veterans, Stress, PTSD, Resilience

Hippocampal structure is particularly sensitive to trauma and other stressors. However, previous findings linking hippocampal function with trauma-related psychopathology have been mixed. Heterogeneity in psychological responses to trauma has not been considered with respect to hippocampal function and may contribute to mixed findings. To address these issues, we examined associations between data-driven symptom dimensions and episodic memory formation, a key function of the hippocampus, in a trauma-exposed sample. Symptom dimensions were defined using principal components analysis (PCA) in 3881 trauma-exposed African-American women recruited from primary care waiting rooms of a large urban hospital. Hippocampal and amygdala function were subsequently investigated in an fMRI study of episodic memory formation in a subset of 54 women. Participants viewed scenes with neutral, negative, and positive content during fMRI, and completed a delayed cued recall task. PCA analysis produced five symptom dimensions interpreted as reflecting negative affect, somatic symptoms, re-experiencing, hyper-arousal, and numbing. Re-experiencing was the only symptom type associated with hippocampal function, predicting increased memory encoding-related activation in the hippocampus as well as the amygdala. In contrast, the negative affect component predicted lower amygdala activation for subsequently recalled scenes, and lower functional coupling with other important memory-related regions including the precuneus, inferior frontal gyrus, and occipital cortex. Symptom dimensions were not related to hippocampal volume. The fMRI findings for re-experiencing versus negative affect parallel differences in behavioral memory phenomena in PTSD versus MDD, and highlight a need for more complex models of trauma-related pathology. Keywords: Trauma, Ptsd, Hippocampus, Amygdala, Episodic memory, Symptom dimensions

Abstract Epigenetic processes, including DNA methylation, change reliably with age across the lifespan, such that DNA methylation can be used as an “epigenetic clock”. This epigenetic clock can be used to predict age and age acceleration, which occurs when methylation-based prediction of age exceeds chronological age and has been associated with increased mortality. In the current study we examined epigenetic age acceleration using saliva samples collected from children between ages 6–13 (N = 101). Children’s exposure to neighborhood violence and heart rate during a stressful task were assessed. Age acceleration was associated with children’s direct experience of violence (p = 0.004) and with decreased heart rate (p = 0.002). Children who were predicted to be older than their chronological age had twice as much violence exposure as other children and their heart rate was similar to that of adults. The results remained significant after controlling for demographic variables, such as sex, income and education. This is the first study to show the effects of direct violence exposure on epigenetic aging in children using salivary DNA. Although longitudinal studies are needed to determine whether accelerated epigenetic aging leads to adverse health outcomes later in life, these data point to DNA methylation during childhood as a putative biological mechanism.

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

Aim: This study tested sex differences in the association between hippocampal volume and working memory of a national sample of 9–10-year-old children in the US. As the hippocampus is functionally lateralized (especially in task-related activities), we explored the results for the right and the left hippocampus. Methods: This is a cross-sectional study using the Adolescent Brain Cognitive Development (ABCD) Study data. This analysis included baseline ABCD data (n = 10,093) of children between ages 9 and 10 years. The predictor variable was right and left hippocampal volume measured by structural magnetic resonance imaging (sMRI). The primary outcome, list sorting working memory, was measured using the NIH toolbox measure. Sex was the moderator. Age, race, ethnicity, household income, parental education, and family structure were the covariates. Results: In the overall sample, larger right (b = 0.0013; p < 0.001) and left (b = 0.0013; p < 0.001) hippocampal volumes were associated with higher children’s working memory. Sex had statistically significant interactions with the right (b = −0.0018; p = 0.001) and left (b = −0.0012; p = 0.022) hippocampal volumes on children’s working memory. These interactions indicated stronger positive associations between right and left hippocampal volume and working memory for females compared to males. Conclusion: While right and left hippocampal volumes are determinants of children’s list sorting working memory, these effects seem to be more salient for female than male children. Research is needed on the role of socialization, sex hormones, and brain functional connectivity as potential mechanisms that may explain the observed sex differences in the role of hippocampal volume as a correlate of working memory.

Approximately 30 million people currently live with HIV worldwide and the incidence of stress-related disorders, such as post-traumatic stress disorder (PTSD), is elevated among people living with HIV as compared to those living without the virus. PTSD is a severely debilitating, stress-related psychiatric illness associated with trauma exposure. Patients with PTSD experience intrusive and fearful memories as well as flashbacks and nightmares of the traumatic event(s) for much of their lives, may avoid other people, and may be constantly on guard for new negative experiences. This review will delineate the information available to date regarding the comorbidity of PTSD and HIV and discuss the biological mechanisms which may contribute to the co-existence, and potential interaction of, these two disorders. Both HIV and PTSD are linked to altered neurobiology within areas of the brain involved in the startle response and altered function of the hypothalamic-pituitary-adrenal axis. Collectively, the data highlighted suggest that PTSD and HIV are more likely to actively interact than to simply co-exist within the same individual. Multi-faceted interactions between PTSD and HIV have the potential to alter response to treatment for either independent disorder. Therefore, it is of great importance to advance the understanding of the neurobiological substrates that are altered in comorbid PTSD and HIV such that the most efficacious treatments can be administered to improve both mental and physical health and reduce the spread of HIV.

The development of PTSD after military deployment is influenced by a combination of biopsychosocial risk and resilience factors. In particular, physiological factors may mark risk for symptom progression or resiliency. Research in civilian populations suggests elevated catecholamines after trauma are associated with PTSD months following the trauma. However, less is known regarding physiological markers of PTSD resilience among post-deployment service members (SM). We therefore assessed whether catecholamines obtained shortly after deployment were associated with combat-related PTSD symptoms three months later. Eighty-seven SMs completed the Clinician-Administered PTSD Scale for DSM-IV and blood draws within two months after return from deployment to Iraq or Afghanistan (“Time 1” or “T1”) and three months later (“Time 2” or “T2”). Linear regression analyses demonstrated that lower norepinephrine at T1 was associated with lower PTSD symptoms at T2. In particular, T1 norepinephrine was positively associated with T2 symptom intensity and avoidance symptoms. The present findings represent a biologically-informed method of assessing PTSD resilience after deployment, which may aid clinicians in providing tailored treatments for those in the greatest need. Further research is needed to validate these findings and incorporate physiological measures within an assessment battery.

Latency of the acoustic startle response is the time required from the presentation of startling auditory stimulus until the startle response is elicited and provides an index of neural processing speed. Latency is prolonged in subjects with schizophrenia compared to controls in some but not all studies and is 68–90% heritable in baseline startle trials. In order to determine the genetic association with latency as a potential inroad into genetically based vulnerability to psychosis, we conducted a gene-based study of latency followed by an independent replication study of significant gene findings with a single-nucleotide polymorphism (SNP)-based analysis of schizophrenia and control subjects. 313 subjects from an urban population of low socioeconomic status with mixed psychiatric diagnoses were included in the gene-based study. Startle testing was conducted using a Biopac M150 system according to our published methods. Genotyping was performed with the Omni-Quad 1M or the Omni Express BeadChip. The replication study was conducted on 154 schizophrenia subjects and 123 psychiatric controls. Genetic analyses were conducted with Illumina Human Omni1-Quad and OmniExpress BeadChips. Twenty-nine SNPs were selected from four genes that were significant in the gene-based analysis and also associated with startle and/or schizophrenia in the literature. Linear regressions on latency were conducted, controlling for age, race, and diagnosis as a dichotomous variable. In the gene-based study, 2,870 genes demonstrated the evidence of association after correction for multiple comparisons (false discovery rate

Both childhood trauma and a functional COMT genetic polymorphism have been associated with PTSD and depression; however, it is still unclear whether the two interact and how this interaction relates to long-term risk or resilience. Imaging and genotype data were collected on 73 highly traumatized women. DNA extracted from saliva was used to determine COMT genotype (Val/Val, n=38, Met carriers, n=35). Functional MRI data were collected during a Go/NoGo task to investigate the neurocircuitry underlying response inhibition. Self-report measures of adult and childhood trauma exposure, PTSD and depression symptom severity, and resilience were collected. Childhood trauma was found to interact with COMT genotype to impact inhibition-related hippocampal activation. In Met carriers, more childhood trauma was associated with decreased hippocampal activation, whereas in the Val/Val group childhood trauma was related to increased hippocampal activation. Second, hippocampal activation correlated negatively with PTSD and depression symptoms, and positively with trait resilience. Moreover, hippocampal activation mediated the relationship between childhood trauma and psychiatric risk or resilience in the Val/Val, but not in the Met-carrier group. These data reveal a potential mechanism by which childhood trauma and COMT genotype interact to increase risk for trauma-related psychopathology or resilience. Hippocampal recruitment during inhibition may improve the ability to use contextual information to guide behavior, thereby enhancing resilience in trauma-exposed individuals. This finding may contribute to early identification of individuals at risk, and suggests a mechanism that can be targeted in future studies aiming to prevent or limit negative outcomes.

C-reactive protein (CRP), a marker of systemic inflammation, has been associated with major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Emotion dysregulation is a transdiagnostic risk factor for many psychological disorders associated with chronic inflammatory state. The objective of this study was to determine whether inflammation is associated with emotion dysregulation in women with type 2 diabetes mellitus (T2DM). We examined associations between trauma exposure, MDD, PTSD, emotion dysregulation, and CRP among 40 African-American women with T2DM recruited from an urban hospital. Emotion dysregulation was measured using the Difficulties in Emotion Regulation Scale. PTSD and MDD were measured with structured clinical interviews. Child abuse and lifetime trauma load were also assessed. Analyses showed that both emotion dysregulation and current MDD were significantly associated with higher levels of CRP (p