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Abstract Digital twins represent a key technology for precision health. Medical digital twins consist of computational models that represent the health state of individual patients over time, enabling optimal therapeutics and forecasting patient prognosis. Many health conditions involve the immune system, so it is crucial to include its key features when designing medical digital twins. The immune response is complex and varies across diseases and patients, and its modelling requires the collective expertise of the clinical, immunology, and computational modelling communities. This review outlines the initial progress on immune digital twins and the various initiatives to facilitate communication between interdisciplinary communities. We also outline the crucial aspects of an immune digital twin design and the prerequisites for its implementation in the clinic. We propose some initial use cases that could serve as “proof of concept” regarding the utility of immune digital technology, focusing on diseases with a very different immune response across spatial and temporal scales (minutes, days, months, years). Lastly, we discuss the use of digital twins in drug discovery and point out emerging challenges that the scientific community needs to collectively overcome to make immune digital twins a reality.

Kleibsiella pneumoniae Kpn555, isolated from coffee waste pulp showed high level of tolerance to lead with a minimum inhibitory concentration of 900 mg/L. On its growth in nutrient broth supplemented with lead, brown clumps were visualised at the bottom of the flask. On scanning and transmission electron microscopic studies the brown clumps were corroborated to be bacterial cells with lead biosorbed on the cell surface and accumulated inside the cytoplasm. Biochemical and FT-IR analysis of the extracellular polymeric substance produced on exposure to lead revealed its chemical nature as glycolipid with protein moieties. Purified EPS (100 mg/L) could remove 50% of lead from aqueous solution (200 mg/L). Isolation of plasmid from Klebsiella pneumoniae Kpn555 revealed the presence of a plasmid of size 30–40 kb. This capability of the bacteria was proven to be plasmid mediated as the Escherichia coli DH5α cells transformed with the plasmid of Klebsiella pneumoniae Kpn555 also could tolerate 900 mg/L of lead and form brown clumps. This study shows that these bacteria, aided by EPS could serve as an effective agent for the removal of lead from contaminated water environmental samples.

DNA supercoiling acts as a global and ancestral regulator of bacterial gene expression. In this review, we advocate that it plays a pivotal role in host-pathogen interactions by transducing environmental signals to the bacterial chromosome and coordinating its transcriptional response. We present available evidence that DNA supercoiling is modulated by environmental stress conditions relevant to the infection process according to ancestral mechanisms, in zoopathogens as well as phytopathogens. We review the results of transcriptomics studies obtained in widely distant bacterial species, showing that such structural transitions of the chromosome are associated to a complex transcriptional response affecting a large fraction of the genome. Mechanisms and computational models of the transcriptional regulation by DNA supercoiling are then discussed, involving both basal interactions of RNA Polymerase with promoter DNA, and more specific interactions with regulatory proteins. A final part is specifically focused on the regulation of virulence genes within pathogenicity islands of several pathogenic bacterial species. Keywords: DNA supercoiling, Transcription, Pathogenesis, Genetic regulation

Capoterra Pond in southern Sardinia is described and analyzed with respect to its morphological, meteorological, physical and chemical characteristics, and its zoobenthic, zooplankton, and phytoplankton biocenoses. The birdlife, flora, and riparian associations of vegetation are studied in order to draw international attention to the importance of this lagoon, the precariousness of its ecosystem, the seriousness of current attempts to destabilize it, and the need to encourage the Sardinian authorities to initiate conservation measures, especially as rare birds have found their niches there. [ABSTRACT FROM AUTHOR]

Many Veterans who served in Iraq and Afghanistan struggle with posttraumatic stress disorder (PTSD) and the effects of traumatic brain injuries (TBI). Some people with a history of TBI report a constellation of somatic, cognitive, and emotional complaints that are often referred to as postconcussive symptoms (PCS). Research suggests these symptoms may not be specific to TBI. This study examined the impact of PTSD treatment on PCS in combat Veterans seeking treatment for PTSD. As part of a larger randomized control trial, 198 Operation Iraqi Freedom, Operation Enduring Freedom, Operation New Dawn (OIF/OEF/OND) Veterans with PTSD received Prolonged Exposure Therapy, sertraline, or the combination. Potential deployment related TBI, PCS, PTSD and depression symptoms were assessed throughout treatment. Linear mixed models were used to predict PCS change over time across the full sample and treatment arms, and the association of change in PTSD and depression symptoms on PCS was also examined. Patterns of change for the full sample and the subsample of those who reported a head injury were examined. Results showed that PCS decreased with treatment. There were no significant differences across treatments. No significant differences were found in the pattern of symptom change based on TBI screening status. Shifts in PCS were predicted by change PTSD and depression. Results suggest that PCS reduced with PTSD treatment in this population and are related to shift in depression and PTSD severity, further supporting that reported PCS symptoms may be better understood as non-specific symptoms., Competing Interests: Declaration of competing interest Disclosures: This work was supported by the U.S. Department of Defense through the U.S. Army Medical Research and Materiel Command (MRMC; Randomized Controlled Trial of Sertraline, Prolonged Exposure Therapy, and Their Combination in OEF/OIF Combat Veterans with PTSD; Grant #W81XWH-11-1-0073); the National Center for Advancing Translational Sciences of the National Institutes of Health (Grant #UL1TR000433). The views expressed in this article presentation are solely those of the author(s) and do not reflect an endorsement by or the official policy of the Department of Veterans Affairs, Department of Defense, or the U.S. Government, or the official views of the National Institutes of Health. The contents do not represent the views of the US Department of Veterans Affairs (DVA), Department of Defense (DOD), or the United States Government. Dr. Rauch receives support from Wounded Warrior Project (WWP), DVA, National Institute of Health (NIH), Woodruff Foundation, and DOD and royalties from Oxford University Press and American Psychological Association Press. In the past 3 years Dr. Simon reports receiving grants from the National Institutes of Health (NIH), U.S. Department of Defense, American Foundation for Suicide Prevention, Patient-Centered Outcomes Research Institute, Ananda Scientific and support from Cohen Veterans Network and MindMed; receiving personal fees from Vanda Pharmaceuticals, Praxis Therapeutics, Genomind, Bionomics Limited, BehavR LLC, Cerevel, Engrail Therapeutics Inc; receiving fees or royalties from Wiley (Deputy Editor Depression and Anxiety), Wolters Kluwyer (UpToDate) and APA Publishing (Textbook of Anxiety, Trauma and OCD Related Disorders, 2020); and having spousal stock from G1 Therapeutics and Zentalis outside the submitted work. ClinicalTrials.gov: NCT01524133., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Suicide is a leading cause of death worldwide. Whereas some studies have suggested that a direct measure of common genetic liability for suicide attempts (SA), captured by a polygenic risk score for SA (SA-PRS), explains risk independent of parental history, further confirmation would be useful. Even more unsettled is the extent to which SA-PRS is associated with lifetime non-suicidal self-injury (NSSI)., Methods: We used summary statistics from the largest available GWAS study of SA to generate SA-PRS for two non-overlapping cohorts of soldiers of European ancestry. These were tested in multivariable models that included parental major depressive disorder (MDD) and parental SA., Results: In the first cohort, 417 (6.3 %) of 6573 soldiers reported lifetime SA and 1195 (18.2 %) reported lifetime NSSI. In a multivariable model that included parental history of MDD and parental history of SA, SA-PRS remained significantly associated with lifetime SA [aOR = 1.26, 95%CI:1.13-1.39, p < 0.001] per standardized unit SA-PRS]. In the second cohort, 204 (4.2 %) of 4900 soldiers reported lifetime SA, and 299 (6.1 %) reported lifetime NSSI. In a multivariable model that included parental history of MDD and parental history of SA, SA-PRS remained significantly associated with lifetime SA [aOR = 1.20, 95%CI:1.04-1.38, p = 0.014]. A combined analysis of both cohorts yielded similar results. In neither cohort or in the combined analysis was SA-PRS significantly associated with NSSI., Conclusions: PRS for SA conveys information about likelihood of lifetime SA (but not NSSI, demonstrating specificity), independent of self-reported parental history of MDD and parental history of SA., Limitations: At present, the magnitude of effects is small and would not be immediately useful for clinical decision-making or risk-stratified prevention initiatives, but this may be expected to improve with further iterations. Also critical will be the extension of these findings to more diverse populations., Competing Interests: Declaration of competing interest Dr. Kessler has in the past three years received support for his epidemiological studies from Sanofi Aventis; and was a consultant for Datastat, Inc., Sage Pharmaceuticals, and Takeda. Dr. Stein has in the past three years been a paid consultant for Aptinyx, BigHealth, Biogen, Bionomics, Boehringer-Ingelheim, Cerevel Therapeutics, EmpowerPharm, Engrail Therapeutics, Genentech/Roche, GW Pharma, Janssen, Jazz Pharmaceuticals, Otsuka, Oxeia Biopharmaceuticals, PureTech Health, and Sage Therapeutics. Dr. Smoller is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity), and has received grant support from Biogen, Inc., is PI of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments. The remaining authors have no disclosures., (Published by Elsevier B.V.)

Objective/Background: Intravenous (IV) ketamine is effective for reducing symptoms of major depressive disorder in short-term clinical trials; this study characterized clinical outcomes of repeated infusions in routine clinical practice and the frequency and number of infusions used to sustain symptom improvement., Methods: Records of IV ketamine infusions for depression and associated Patient Health Questionnaire-9 (PHQ-9) scores were identified from Veterans Health Administration (VA) electronic medical records for patients treated in Fiscal Year 2020 and up to 12 months following the date of their first infusion., Results: Sample patients (n = 215) had a mean baseline PHQ-9 score of 18.6 and a mean of 2.1 antidepressant medication trials in the past year and 6.1 antidepressant trials in the 20 years prior to their first ketamine infusion. Frequency of infusions decreased from every 5 days to every 3-4 weeks over the first 5 months of infusions, with a mean of 18 total infusions over 12 months. After 6 weeks of treatment, 26% had a 50% improvement in PHQ-9 score (response) and 15% had PHQ-9 score ≤ 5 (remission). These improvements were similar at 12 and 26 weeks. No demographic characteristics or comorbid diagnoses were associated with 6-week PHQ-9 scores., Conclusions: While only a minority of patients treated with IV ketamine for depression experienced response or remission, symptom improvements achieved within the first 6 weeks were sustained over at least 6 months with decreasing infusion frequency. Further study is needed to determine optimal infusion frequency and potential for adverse effects with repeated ketamine infusions for depression., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Objectives: Two commonly used forms of repetitive transcranial magnetic stimulation (rTMS) were recently shown to be equivalent for the treatment of depression: high-frequency stimulation (10 Hz), a protocol that lasts between 19 and 38 minutes, and intermittent theta burst stimulation (iTBS), a protocol that can be delivered in just three minutes. However, it is unclear whether iTBS treatment offers the same benefits as those of standard 10-Hz rTMS for comorbid symptoms such as those seen in posttraumatic stress disorder (PTSD)., Materials and Methods: In this retrospective case series, we analyzed treatment outcomes in veterans from the Veterans Affairs San Diego Healthcare System who received 10-Hz (n = 47) or iTBS (n = 51)-rTMS treatments for treatment-resistant depression between February 2018 and June 2022. We compared outcomes between these two stimulation protocols in symptoms of depression (using changes in the Patient Health Questionnaire-9 [PHQ-9]) and PTSD (using changes in the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, or Patient Checklist [PCL]-5)., Results: There was an imbalance of sex between groups (p < 0.05). After controlling for sex, we found no significant difference by stimulation protocol for depression (PHQ-9, F [1,94] = 0.16, p = 0.69, eta-squared = 0.002), confirming the original study previously noted. We also showed no difference by stimulation protocol of changes in PTSD symptoms (PCL-5, F [1,94] = 3.46, p = 0.067, eta-squared = 0.036). The iTBS group showed a decrease from 41.9 ± 4.4 to 25.1 ± 4.9 (a difference of 16.8 points) on the PCL-5 scale whereas the 10-Hz group showed a decrease from 43.6 ± 2.9 to 35.2 ± 3.2 on this scale (a difference of 8.4 points). Follow-up analyses restricting the sample in various ways did not meaningfully change these results (no follow-up analyses showed that there was a significant difference between stimulation protocols)., Conclusions: Although limited by small sample size, nonblind, and pseudorandomized assignment, our data suggest that iTBS is similar to 10-Hz stimulation in inducing reductions in PTSD symptoms and depression in military veterans., (Published by Elsevier Inc.)

Trauma-informed beliefs often decrease during posttraumatic stress disorder (PTSD) treatment. This may also extend to anxiety sensitivity (AS), defined as a fear of anxiety-related sensations and beliefs that anxiety is dangerous and/or intolerable. However, little is known about how AS changes during exposure-based and psychopharmacological PTSD treatments. Further, high AS may be a risk factor for diminished PTSD symptom improvement and increased treatment dropout. To better understand how AS impacts and is impacted by PTSD treatment, we conducted a secondary analysis of a randomized clinical trial with a sample of 223 veterans (87.0% male, 57.5% White) with PTSD from four U.S. sites. Veterans were randomized to receive prolonged exposure (PE) plus placebo (n = 74), sertraline plus enhanced medication management (n = 74), or PE plus sertraline (n = 75). Veterans answered questions about PTSD symptoms and AS at baseline and 6-, 12-, 24-, 36-, and 52-week follow-ups. High baseline AS was related to high levels of PTSD severity at 24 weeks across all conditions, β = .244, p = .013, but did not predict dropout from exposure-based, β = .077, p = .374, or psychopharmacological therapy, β = .009, p = .893. AS also significantly decreased across all three treatment arms, with no between-group differences; these reductions were maintained at the 52-week follow-up. These findings suggest that high AS is a risk factor for attenuated PTSD treatment response but also provide evidence that AS can be improved by both PE and an enhanced psychopharmacological intervention for PTSD., (© 2022 The Authors. Journal of Traumatic Stress published by Wiley Periodicals LLC on behalf of International Society for Traumatic Stress Studies.)

Background: ( S )-ketamine is a glutamatergic drug with potent and rapid acting effects for the treatment of depression. Little is known about the effectiveness of intranasal ( S )-ketamine for treating patients with comorbid depression and post-traumatic stress disorder (PTSD)., Methods: We performed a retrospective case series analysis of clinical outcomes in 35 Veterans with co-morbid depression and PTSD who were treated with intranasal ( S )-ketamine treatments at the VA San Diego Neuromodulation Clinic between Jan 2020 and March 2021. Veterans were not randomized or blinded to treatment. The primary outcome measured was a change in patient health questionnaire-9 (PHQ-9) and PTSD Checklist for DSM-5 (PCL-5) scores across the first 8 treatments (induction period) using a repeated measures analysis of variance (ANOVA). In a smaller sub-group ( n  = 19) of Veterans who received at least 8 additional treatments, we analyzed whether intranasal ( S )-ketamine continued to show treatment effects. Finally, we performed a sub-group and correlation analyses to understand how changes in PHQ-9 and PCL-5 scores were related across treatments., Findings: During the induction phase of treatment there was an absolute reduction of 5.1 (SEM 0.7) on the patient health questionnaire-9 (PHQ-9) rating scale for depression, from 19.8 (SEM 0.7) at treatment 1 to 14.7 (SEM 0.8) at treatment 8 (week 4) (F(7238) = 8.3, p  = 1e-6, partial η 2  = 0.2). Five Veterans (14%) showed a clinically meaningful response (50% reduction in PHQ-9 score) at treatment 8. There was an absolute reduction of 15.5 +/- 2.4 on the patient checklist 5 (PCL-5) rating scale for PTSD, from 54.8 (SEM 2) at treatment 1 down to 39.3 (SEM 2.5) at treatment 8 (F(7238) = 15.5, p  = 2e-7, partial η 2  = 0.31). Sixteen Veterans (46%) showed a clinically meaningful response (reduction in PCL-5 of > 30%) in PTSD. Change in PHQ-9 correlated with change in PCL-5 at treatment 8 ( r  = 0.47, p  = 0.005), but a decrease in PTSD symptoms were observable in some individuals with minimal anti-depressant response., Interpretations: While this is an open-label retrospective analysis, our results indicate that both depression and PTSD symptoms in Veterans with dual-diagnoses may improve with repeated intranasal ( S )-ketamine treatment. The effects of ( S )-ketamine on PTSD symptoms were temporally and individually distinct from those on depression, suggesting potentially different modes of action on the two disorders. This work may warrant formal randomized controlled studies on the effects of intranasal ( S )-ketamine for individuals with co-morbid MDD and PTSD., Funding: VA Center of Excellence in Stress and Mental Health, VA ORD (Career Development Award to DSR), Burroughs-Wellcome Fund Award (DSR), NIMH (EL)., Competing Interests: The views expressed here are our own and do not represent the opinion of the VA., (© 2022 Published by Elsevier Ltd.)

Loneliness is associated with increased morbidity and mortality. Deeper understanding of neurobiological mechanisms underlying loneliness is needed to identify potential intervention targets. We did not find any systematic review of neurobiology of loneliness. Using MEDLINE and PsycINFO online databases, we conducted a search for peer-reviewed publications examining loneliness and neurobiology. We identified 41 studies (n = 16,771 participants) that had employed various methods including computer tomography (CT), structural magnetic resonance imaging (MRI), functional MRI (fMRI), electroencephalography (EEG), diffusion tensor imaging (DTI), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and post-mortem brain tissue RNA analysis or pathological analysis. Our synthesis of the published findings shows abnormal structure (gray matter volume or white matter integrity) and/or activity (response to pleasant versus stressful images in social versus nonsocial contexts) in the prefrontal cortex (especially medial and dorsolateral), insula (particularly anterior), amygdala, hippocampus, and posterior superior temporal cortex. The findings related to ventral striatum and cerebellum were mixed. fMRI studies reported links between loneliness and differential activation of attentional networks, visual networks, and default mode network. Loneliness was also related to biological markers associated with Alzheimer's disease (e.g., amyloid and tau burden). Although the published investigations have limitations, this review suggests relationships of loneliness with altered structure and function in specific brain regions and networks. We found a notable overlap in the regions involved in loneliness and compassion, the two personality traits that are inversely correlated in previous studies. We have offered recommendations for future research studies of neurobiology of loneliness., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Objective: Suicide rates have been of increasing concern across the United States, particularly among military veterans. The Veterans Health Administration has initiated multiple suicide prevention initiatives, but little research has examined the impact of these programs. The purpose of this study was to test the hypothesis that more frequent contact with suicide prevention clinicians would predict lower odds of suicidal behavior., Method: Retrospective medical record review was performed for 1364 veterans identified as high risk for suicide during 2012-2018. Logistic regression was used to test whether the number of suicide prevention contacts predicted the odds of suicide attempt, any self-directed violence, or reactivation of high-risk status in the next year, accounting for age, sex, length of high-risk episode, and other mental health contacts., Results: Each additional suicide prevention coordinator contact was associated with 4%-5% lower odds of suicide attempt, suicidal behavior, and reactivation of high-risk status in the next year (ps < 0.05). For suicide attempt and self-directed violence, associations were stronger when considering only initial high-risk episodes (8%-10% lower odds, ps < 0.05)., Conclusions: Findings suggest ongoing support from suicide prevention clinicians can have a significant protective effect. Additional research is needed to identify mechanisms by which this support reduces risk., (© 2021 The American Association of Suicidology.)

Objective: The current study is an analysis of predictors of posttraumatic stress disorder (PTSD) treatment response in a clinical trial comparing (1) prolonged exposure plus placebo (PE + PLB), (2) PE + sertraline (PE + SERT), and (3) sertraline + enhanced medication management (SERT + EMM) with predictors including time since trauma (TST), self-report of pain, alcohol use, baseline symptoms, and demographics., Methods: Participants (N = 196) were veterans with combat-related PTSD ( DSM-IV-TR ) of at least 3 months' duration recruited between 2012 and 2016 from 4 sites in the 24-week PROlonGed ExpoSure and Sertraline (PROGrESS) clinical trial (assessments at weeks 0 [intake], 6, 12, 24, 36, and 52)., Results: Across treatment conditions, (1) longer TST was predictive of greater week 24 PTSD symptom improvement (β = 1.72, P  = .01) after adjusting for baseline, (2) higher baseline pain severity was predictive of smaller symptom improvement (β = -2.96, P  = .003), and (3) Hispanic patients showed greater improvement than non-Hispanic patients (β = 12.33, P  = .03). No other baseline characteristics, including alcohol consumption, were significantly predictive of week 24 improvement. Comparison of TST by treatment condition revealed a significant relationship only in those randomized to the PE + SERT condition (β = 2.53, P  = .03). Longitudinal analyses showed similar results., Conclusions: The finding that longer TST shows larger symptom reductions is promising for PTSD patients who might not seek help for years following trauma. Higher baseline pain severity robustly predicted attenuated and slower response to all treatment conditions, suggesting a common neuropathologic substrate. Finally, in the current study, alcohol use did not impede the effectiveness of pharmacotherapy for PTSD., Trial Registration: ClinicalTrials.gov identifier: NCT01524133., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Although prolonged exposure (PE) and SSRI antidepressants are effective in treating posttraumatic stress disorder (PTSD), previous studies have shown that some symptoms tend to persist. The current study compared sertraline hydrochloride plus enhanced medication management (EMM), PE plus placebo, or PE plus sertraline hydrochloride in the likelihood of each individual PTSD symptom persisting in veterans with a PTSD diagnosis. We compared the likelihood of individual PTSD symptoms persisting in those with versus without a PTSD diagnosis at posttreatment. We found no significant differences across conditions in which symptoms were likely to persist posttreatment. Among those without a PTSD diagnosis at posttreatment, sleeping difficulties (63.0%), hypervigilance (47.3%), and nightmares (45.0%) were most likely to persist. Findings indicate no consistent differences in residual symptoms between PE and medications, and shared decision making with patients is encouraged in selecting treatments. Gold standard treatments (e.g., CBT-I) may be warranted for residual symptoms like insomnia., Competing Interests: Declaration of Competing Interests No other disclosures were reported. For the remaining authors, no conflicts of interest were declared., (Published by Elsevier B.V.)

Chronic Posttraumatic stress disorder (PTSD), characterized by symptoms of re-experiencing, hyperarousal, and avoidance, is challenging to treat as a significant proportion of patients remain symptomatic following even empirically supported interventions. The current case series investigated the effects of up to 10 sessions of high definition transcranial direct current stimulation (HD-tDCS) on symptoms of PTSD. Participants received HD-tDCS that targeted the right lateral temporal cortex (LTC; center cathode placed over T8), given this region's potential involvement in symptoms of re-experiencing and, possibly, hyperarousal. Five of the six enrolled patients completed at least 8 sessions. Of these five, four showed improvement in symptoms of re-experiencing after HD-tDCS. This improvement was accompanied by connectivity change in the right LTC as well as a larger extended fear network but not a control network that consisted of visual cortex regions; however, the nature of the change varied across participants as some showed increased connectivity whereas others showed decreased connectivity. These preliminary data suggest that HD-tDCS may be beneficial for treatment of specific PTSD symptoms, in at least some individuals, and warrants further investigation., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Published by Elsevier B.V.)

Abiotic and biotic properties of soil can influence growth and chemical composition of plants. Although it is well-known that soil microbial composition can vary greatly spatially, how this variation affects plant chemical composition is poorly understood. We grew genetically identical Jacobaea vulgaris in sterilized soil inoculated with live soil collected from four natural grasslands and in 100% sterilized soil. Within each grassland we sampled eight plots, totalling 32 different inocula. Two samples per plot were collected, leading to three levels of spatial variation: within plot, between and within grasslands. The leaf metabolome was analysed with 1 H Nuclear magnetic resonance spectroscopy (NMR) to investigate if inoculation altered the metabolome of plants and how this varied between and within grasslands. Inoculation led to changes in metabolomics profiles of J. vulgaris in two out of four sites. Plants grown in sterilized and inoculated soils differed in concentrations of malic acid, tyrosine, trehalose and two pyrrolizidine alkaloids (PA). Metabolomes of plants grown in inoculated soils from different sites varied in glucose, malic acid, trehalose, tyrosine and in one PA. The metabolome of plants grown in soils with inocula from the same site was more similar than with inocula from distant sites. We show that soil influences leaf metabolomes. Performance of aboveground insects often depends on chemical composition of plants. Hence our results imply that soil microbial communities, via affecting aboveground plant metabolomes, can impact aboveground plant-insect food chains but that it is difficult to make general predictions due to spatial variation in soil microbiomes.

Background: Posttraumatic stress disorder (PTSD) has been associated with exaggerated threat processing and deficits in emotion modulation circuitry. It remains unknown how neural circuits are associated with response to evidence-based treatments for PTSD., Method: We examined associations between PTSD symptoms and indicators of neural response in key emotion processing and modulation regions. Fifty-six military Veterans with PTSD were randomly assigned to one of three evidence-based treatments (prolonged exposure, sertraline, and PE plus sertraline) in a randomized clinical trial ("PROGrESS"; 2018, Contemp Clin Trials, 64, 128-138). Twenty-seven combat-exposed controls (CCs) served as a comparison group at pretreatment. Before and after PTSD treatment, functional magnetic resonance imaging was used to assess brain activation and connectivity during the validated Shifted Attention Emotion Appraisal Task (2003, J Neurosci, 23, 5627-5633; 2013, Biol Psychiatry, 73, 1045-1053)., Results: Greater activation in emotion processing (anterior insula) and modulation (prefrontal cortex) regions and increased connectivity between attentional control (dorsolateral prefrontal cortex and superior parietal cortex) and emotion processing (amygdala) regions, at pretreatment, were associated with subsequent PTSD symptom improvement., Conclusions: This study is one of the first to examine task-based activation and functional connectivity in a PTSD treatment trial, and provides evidence to suggest that activation in and connectivity between emotion processing and modulation regions are important predictors of treatment response., (© 2020 Wiley Periodicals, Inc.)

Posttraumatic Stress Disorder (PTSD) is a debilitating condition often associated with difficulty in emotion regulation, including reappraising negative emotions. This study assessed neural mechanisms associated with emotion regulation in veterans prior to and following treatment for PTSD. Participants with PTSD and combat exposed controls (CC) completed diagnostic evaluation and underwent fMRI scanning while completing Emotion Regulation Task (ERT) and Emotional Faces Assessment Task (EFAT). Participants with PTSD were randomly assigned to Prolonged Exposure plus placebo (PE+PLB), Sertraline plus enhanced medication management (SERT+EMM), or PE plus SERT (PE+SERT) and repeated diagnostic evaluation and MRI scanning following treatment. The amygdala, dmPFC, and dlPFC were examined as regions of interest. On ERT, veterans with PTSD showed significantly less dmPFC activation than CCs during reappraisal vs emotional maintenance. Within the PTSD group, results demonstrated a significant association between less activation in the dmPFC during emotion reappraisal vs maintenance trials before treatment and greater reductions in symptoms from pre- to post-treatment. During the EFAT, there were no group differences between participants with PTSD and CCs in brain activation, and no relationships between brain function and PTSD symptoms. These findings suggest that less emotional reactivity might potentially reflect less need for recruitment of prefrontal regions when reappraising negative emotion, and is an individual factor associated with better treatment outcome., Competing Interests: Declaration of Competing Interest Dr. Duval reports in past 24 months funding from NIH, the Michigan Institute for Clinical Health Research, Cohen Veterans Bioscience, and One Mind Institute. Dr. King reports in past 24 months funding from NIH and the Michigan Institute for Clinica Health Research. Dr. Liberzon reports in past 24 months speaking or consulting with: Department of Defense, NIH, VA, Cohen Veteran Bioscience, ARMGO Pharma Inc., Sunovion Pharmaceuticals Inc. Aptinyx Inc., Heptares Therapeutics Ltd., Nobilis Therapeutics, Inc., Astrotide, Inc. Dr. Rauch reports in past 24 months speaking or consulting with Department of Defense, NIH, VA, Woodruff Foundation, McCormick Foundation, Wounded Warrior Project, Cohen Veteran Bioscience, and The Pennsylvania State University. Dr. Rauch receives royalties from Oxford University Press. Ms. Joshi and Drs. Sheynin, Phan, Martis, and Porter report no disclosures. The views expressed in this article are solely those of the authors and do not reflect an endorsement by or the official policy of the Department of Veterans Affairs, or the U.S. Government., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Importance: Meta-analyses of treatments for posttraumatic stress disorder (PTSD) suggest that trauma-focused psychotherapies produce greater benefits than antidepressant medications alone., Objective: To determine the relative efficacy of prolonged exposure therapy plus placebo, prolonged exposure therapy plus sertraline hydrochloride, and sertraline plus enhanced medication management in the treatment of PTSD., Design, Setting, and Participants: The Prolonged Exposure and Sertraline Trial was a randomized, multisite, 24-week clinical trial conducted at the Veterans Affairs Ann Arbor Healthcare System, Veterans Affairs San Diego Healthcare System, Ralph H. Johnson Veterans Affairs Medical Center, and Massachusetts General Hospital Home Base Veterans Program between January 26, 2012, and May 9, 2016. Participants and clinicians were blinded to pill condition, and outcome evaluators were blinded to assignment. Participants completed assessments at weeks 0 (intake), 6, 12, 24, and 52 (follow-up). Participants (N = 223) were service members or veterans of the Iraq and/or Afghanistan wars with combat-related PTSD and significant impairment (Clinician-Administered PTSD Scale score, ≥50) of at least 3 months' duration. Analyses were on an intent-to-treat basis., Intervention: Participants completed up to thirteen 90-minute sessions of prolonged exposure therapy by week 24. Sertraline dosage was titrated during a 10-week period and continued until week 24; medication management was manualized., Main Outcomes and Measures: The primary outcome was symptom severity of PTSD in the past month as assessed by the Clinician-Administered PTSD Scale score at week 24., Results: Of 223 randomized participants, 149 completed the study at 24 weeks, and 207 (180 men and 27 women; mean [SD] age, 34.5 [8.3 years]) were included in the intent-to-treat analysis. Modified intent-to-treat analysis using a mixed model of repeated measures showed that PTSD symptoms decreased significantly during the 24 weeks (sertraline plus enhanced medication management, 33.8 points; prolonged exposure therapy plus sertraline, 32.7 points; and prolonged exposure therapy plus placebo, 29.4 points; β,-9.39; 95% CI, -11.62 to -7.16; P < .001); however, slopes did not differ by treatment group (prolonged exposure therapy plus placebo group, -9.39; sertraline plus enhanced medication management group, -10.37; and prolonged exposure therapy plus sertraline group, -9.99; P = .81)., Conclusions and Relevance: No difference in change in PTSD symptoms or symptom severity at 24 weeks was found between sertraline plus enhanced medication management, prolonged exposure therapy plus placebo, and prolonged exposure therapy plus sertraline., Trial Registration: ClinicalTrials.gov Identifier: NCT01524133.

Introduction: Traumatic brain injury (TBI), pain, and post-traumatic stress disorder (PTSD) commonly co-occur in Veteran populations, particularly among Veterans returning from the recent conflicts in Iraq and Afghanistan. Extant research indicates that both TBI and PTSD can negatively impact pain broadly; however, less is known about how these variables impact one another. The current study examines the impact of self-reported post-concussive symptoms on both pain severity and pain interference among Veterans with PTSD who screened positive for a possible TBI, and subsequently, evaluates the potential mediating role of PTSD in these relationships., Materials and Methods: Participants were 126 combat Veterans that served in Operation Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn who were being evaluated for participation in a multisite treatment outcomes study. As part of an initial evaluation for inclusion in the study, participants completed several self-report measures and interviews, including the Brief Traumatic Brain Injury Screen, Neurobehavioral Symptom Inventory, Brief Pain Inventory, and the Clinician Administered PTSD Scale, which were utilized in these analyses., Results: For pain severity, greater post-concussive symptoms significantly predicted increased pain severity with a significant indirect effect of post-concussive symptoms on pain severity through PTSD (indirect effect = 0.03; 95% confidence interval = 0.0094-0.0526). Similar results were found for pain interference (indirect effect = 0.03; 95% confidence interval = 0.0075-0.0471)., Conclusions: These findings replicate and extend previous findings regarding the relationship between TBI, pain, and PTSD. Self-reported post-concussive symptoms negatively impact both pain severity and pain interference among Veterans with probable TBI, and PTSD serves as a mediator in these relationships. Clinically, these results highlight the importance of fully assessing for PTSD symptoms in Veterans with a history of TBI presenting with pain. Further, it is possible that providing effective PTSD treatment to reduce PTSD severity may provide some benefit in reducing post-concussive and pain symptoms.

Mild traumatic brain injury (mTBI) is commonly reported in recent combat Veterans. While the majority resolve, some Veterans develop postconcussive symptoms (PCS). Previous research suggests these symptoms are not specific to head injury and are often associated with psychiatric symptoms. The current study examines the relative contributions of posttraumatic stress, depressive symptoms, and TBI on postconcussive symptoms, and explores whether the relationship remains after controlling for symptom overlap. Two hundred eighteen combat Veterans from Operation Iraqi Freedom (OIF), Operation Enduring Freedom (OEF), and Operation New Dawn (OND) provided the data for this study as part of a baseline evaluation for inclusion into larger treatment study for posttraumatic stress disorder (PTSD). Participants completed the Brief Traumatic Brain Injury Screen (BTBIS), Neurobehavioral Symptom Inventory (NSI), PTSD Checklist-Stressor Version (PCL-S), Beck Depression Inventory-II (BDI-II). Significant differences in NSI total score between individuals with and without history of TBI were not found. A series of regression analyses demonstrated that Depression and PTSD were significant predictors of NSI score even after removal of NSI symptoms that overlap with PTSD or depression. TBI status was also a significant predictor of PCS in most models, but its relative contribution was much smaller than that of depression and PTSD. Within PTSD symptoms, hyperarousal cluster was a significant predictor of NSI scores. Findings demonstrate that depression and PTSD are related to PCS beyond similarities in construct. Further, within a primarily PTSD treatment-seeking population, these psychiatric symptoms appear to be a stronger contributor than TBI., (Copyright © 2018. Published by Elsevier Ltd.)

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

The glucocorticoid hormone cortisol is known to have wide-ranging effects on a variety of physiological systems, including the morphology and physiology of the amygdala and hippocampus. Disruptions of cortisol regulation and signaling are also linked with psychiatric disorders involving emotional disturbances. Although there is much evidence to suggest a relationship between cortisol signaling and the brain physiology underlying emotion, few studies have attempted to test for direct effects of cortisol on the neurophysiology of emotion. We administered exogenous synthetic cortisol (hydrocortisone, HCT) using two different dosing regimens (25 mg/day over 4 days, 100 mg single dose), in a double-blind placebo-controlled functional magnetic resonance imaging (fMRI) study. During fMRI scanning, healthy subjects viewed images designed to induce happy, sad, and neutral emotional states. Subjective emotional reactions were collected for each experimental stimulus after fMRI scanning. Mood ratings were also collected throughout the 4 days of the study. Both dose regimens of HCT resulted in decreased subgenual cingulate activation during sadness conditions. The 25 mg/day regimen also resulted in higher arousal ratings of sad stimuli. No effects of HCT were observed on any mood ratings. Few reliable effects of HCT were observed on brain activity patterns or subjective emotional responses to stimuli that were not sad. The inhibitory effects of cortisol on sadness-induced subgenual cingulate activity may have critical relevance to the pathophysiology of major depression, as both subgenual hyperactivity and decreased sensitivity to cortisol signaling have been documented in patients with depression.