Fluid Cognition Among Individuals With Systemic Lupus Erythematosus.

OBJECTIVE: We sought to describe fluid cognition and its correlates among individuals with systemic lupus erythematosus (SLE). METHODS: Participants (n = 199) were recruited from a population-based cohort for a single study visit (October 2019 to May 2022). Fluid cognition was measured via the National Institutes of Health Toolbox Fluid Cognition Battery (including episodic memory, working memory, attention and inhibitory control, processing speed, and cognitive flexibility domains) and expressed as age-corrected standard scores (mean 100, SD 15). Potential impairment was defined as a standard score >1.5 SD below the mean. Descriptive statistics were calculated and associations of various participant characteristics with the potential fluid cognition impairment were assessed with multivariable logistic regression. RESULTS: Participants' mean age was 46.1 years; most were female (87.4%), Black (86.4%), and non-Hispanic (95.0%). The mean overall fluid cognition score was 87.2; of the individual domains, the participants' mean score was lowest on attention and inhibitory control (82.0). Working status (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.14-0.64) and higher self-reported physical functioning (OR 0.46, 95% CI 0.28-0.75) and physical performance (OR 0.72, 95% CI 0.59-0.87) were associated with lower odds of fluid cognition impairment; lower educational attainment was associated with higher odds (OR 3.82, 95% CI 1.67-8.75). Self-reported forgetfulness, neuropsychiatric damage, and depressive symptoms were not statistically significantly associated with potential impairment. CONCLUSION: Fluid cognition and, particularly, attention and inhibitory control were low in those with SLE relative to the general US population. Working status, higher physical functioning and performance, and higher educational attainment were associated with lower prevalence of potential impairment. Future work is needed to develop and implement interventions to help support cognition in individuals with SLE.

Acute psychological stress-induced progenitor cell mobilization and cardiovascular events.

OBJECTIVE: Certain brain activation responses to psychological stress are associated with worse outcomes in CVD patients. We hypothesized that elevated acute psychological stress, manifesting as greater activity within neural centers for emotional regulation, mobilizes CPC from the bone marrow to the peripheral blood and predicts future cardiovascular events. METHODS: In 427 patients with stable CAD undergoing a laboratory-based mental stress (MS) test, CPCs were enumerated using flow cytometry as CD34-expressing mononuclear cells (CD34+) before and 45 min after stress. Changes in brain regional blood flow with MS were measured using high resolution-positron emission tomography (HR-PET). Association between the change in CPC with MS and the risk of cardiovascular death or myocardial infarction (MI) during a 5-year follow-up period was analyzed. RESULTS: MS increased CPC counts by a mean of 150 [630] cells/mL (15%), P < 0.001. Greater limbic lobe activity, indicative of activation of emotion-regulating centers, was associated with greater CPC mobilization (P < 0.005). Using Fine and Gray models after adjustment for demographioc, clinical risk factors and medications use, greater CPC mobilization was associated with a higher adjusted risk of adverse events; a rise of 1000 cells/mL was associated with a 50% higher risk of cardiovascular death/MI [hazards ratio, 1.5, 95% confidence interval, 1.1-2.2). CONCLUSION: Greater limbic lobe activity, brain areas involved in emotional regulation, is associated with MS-induced CPC mobilization. This mobilization isindependently associated with cardiovascular events. These findings provide novel insights into mechanisms through which psychological stressors modulate cardiovascular risk.

Physical Performance in a Diverse, Population-Based Cohort of Individuals With Systemic Lupus Erythematosus.

OBJECTIVE: To report the burden and correlates of poor physical performance in a diverse cohort of individuals with systemic lupus erythematosus (SLE). METHODS: In this single-visit study of 446 individuals with SLE from a population-based metropolitan Atlanta cohort, we measured physical performance via the Short Physical Performance Battery (score range 0-12; intermediate-low [<10] vs high [≥10]). We also collected demographic, clinical, and psychosocial variables and examined the associations (adjusted odds ratios [aORs]) of intermediate-low versus high physical performance with these characteristics via multivariable logistic regression. RESULTS: We found that more than half (59.6%) of our participants had poorer (intermediate-low) overall physical performance. Only 7% of the cohort received the maximum score on the lower body strength task versus 90% and 76% receiving the maximum scores on balance and gait speed tasks. Current employment status (aOR 0.69, 95% confidence interval [CI] 0.45-1.05) and higher cognitive functioning (aOR 0.57, 95% CI 0.42-0.77) were strongly associated with lower odds of intermediate-low physical performance. Higher body mass index (aOR 1.25, 95% CI 1.01-1.56), disease activity (aOR 1.59, 95% CI 1.27-1.98), and disease burden (aOR 1.38, 95% CI 1.08-1.77) were associated with poorer performance, as were higher depressive symptoms, perceived stress scores, and lower educational attainment (not statistically significant). CONCLUSION: In our population-based, primarily Black cohort, we found that individuals with SLE commonly had poor physical performance. We identified both SLE- and non-SLE-specific factors that could help clinicians identify those most at risk for poor physical performance and intervene to improve, maintain, and support physical performance among those with SLE.

Transcutaneous vagal nerve stimulation modulates stress-induced plasma ghrelin levels: A double-blind, randomized, sham-controlled trial.

BACKGROUND: Transcutaneous cervical vagus nerve stimulation (tcVNS) has emerged as a potential treatment strategy for patients with stress-related psychiatric disorders. Ghrelin is a hormone that has been postulated to be a biomarker of stress. While the mechanisms of action of tcVNS are unclear, we hypothesized that tcVNS reduces the levels of ghrelin in response to stress. METHODS: Using a randomized double-blind approach, we studied the effects of tcVNS on ghrelin levels in individuals with a history of exposure to traumatic stress. Participants received either sham (n = 29) or active tcVNS (n = 26) after exposure to acute personalized traumatic script stress and mental stress challenges (public speech, mental arithmetic) over a three day period. RESULTS: There were no significant differences in the levels of ghrelin between the tcVNS and sham stimulation groups at either baseline or in the absence of trauma scripts. However, tcVNS in conjunction with personalized traumatic scripts resulted in lower ghrelin levels compared to the sham stimulation group (265.2 ± 143.6 pg/ml vs 478.7 ± 349.2 pg/ml, P = 0.01). Additionally, after completing the public speaking and mental arithmetic tests, ghrelin levels were found to be lower in the group receiving tcVNS compared to the sham group (293.3 ± 102.4 pg/ml vs 540.3 ± 203.9 pg/ml, P = 0.009). LIMITATIONS: Timing of ghrelin measurements, and stimulation of only left vagus nerve. CONCLUSION: tcVNS decreases ghrelin levels in response to various stressful stimuli. These findings are consistent with a growing literature that tcVNS modulates hormonal and autonomic responses to stress.

Association of infection with Toxoplasma gondii and Toxocara on cognitive function among US adults aged 60 and over, NHANES 2011-2014.

BACKGROUND: Toxoplasma gondii and Toxocara are common parasites that infect humans globally. Our aim was to examine the relationship between T. gondii and Toxocara infection and cognition. METHODS: Multivariate logistic regression was used to test the association of T. gondii and Toxocara seropositivity on indices of cognitive function (a word list learning trial with delayed recall from the Consortium to Establish a Registry for Alzheimer's Disease, an animal fluency test (AFT) and a digit symbol substitution test (DSST)) among 2643 adults aged 60 years and older in the 2011-2014 National Health and Nutrition Examination Survey. RESULTS: Seropositivity to T. gondii or Toxocara were both associated with lower scores in all three cognitive function measures examined in univariate analyses. Except for the DSST, these associations were not significant after adjustment for age, gender, race and Hispanic origin, poverty level, education, US birth status, depression and hypertension. On stratification to account for significant interactions, Toxocara seropositivity was associated with worse scores on the AFT among those born outside the USA, worse scores on the DSST among those aged 60-69 years, female, Hispanic and with a high school diploma or less. Lower DSST scores with Toxocara infection was greater for adults living below compared with at or above the poverty level. CONCLUSIONS: Seropositivity to these parasites, particularly to Toxocara, may be associated with diminished cognitive performance in certain subgroups of older adults.

Child Maltreatment and Inflammatory Response to Mental Stress Among Adults Who Have Survived a Myocardial Infarction.

OBJECTIVE: Experiences of child maltreatment are associated with cardiovascular risk and disease in adulthood; however, the mechanisms underlying these associations are poorly understood. METHODS: We examined associations between retrospectively self-reported exposure to child maltreatment (Early Trauma Inventory Self-Report Short Form) and inflammatory responses to mental stress among adults (mean age = 50 years) who recently had a myocardial infarction ( n = 227). Inflammation was assessed as blood interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), and monocyte chemoattractant protein-1 concentrations, measured before and after a standardized public speaking stress task. We used mixed linear regression models adjusting for cardiovascular disease severity, medication usage, and psychosocial, demographic, and life-style factors. RESULTS: In women, increases in IL-6 levels and MMP-9 levels with stress were smaller in those exposed to sexual abuse, relative to those unexposed (IL-6 geometric mean increases = 1.6 [95% confidence interval {CI} = 1.4-1.9] pg/ml versus 2.1 [95% CI = 1.8-2.4] pg/ml; MMP-9 geometric mean increases = 1.0 [95% CI = 0.9-1.2] ng/ml versus 1.2 [95% CI = 1.1-1.4] ng/ml). No differences were noted for emotional or physical abuse. By contrast in men, individuals exposed to sexual abuse had larger IL-6 responses than those not exposed to abuse. CONCLUSIONS: These findings suggest sex differences in stress response among survivors of a myocardial infarction exposed to abuse early in life. They also underscore the importance of examining sex as an effect modifier of relationships between exposure to early life adversity and inflammatory responses to mental stressors in midlife.

Dietary emulsifier consumption alters gene expression in the amygdala and paraventricular nucleus of the hypothalamus in mice.

Dietary emulsifier consumption promotes systemic low-grade inflammation, metabolic deregulation, and possibly an anxiety-like phenotype. The latter finding suggests that dietary emulsifiers impact brain areas that modulate stress responses. The goal of the current study was to test whether emulsifier consumption is associated with changes in gene expression in the amygdala and the paraventricular nucleus of the hypothalamus (PVN), two brain areas that are involved in behavioral and neuroendocrine responses to stress. Using RNA-Seq, we compared groups consuming either carboxymethylcellulose or polysorbate 80 for 12-weeks. A total of 243 genes were differentially expressed in the amygdala and PVN of emulsifier-treated mice compared to controls. There was minimal overlap of differentially expressed genes in CMC- and P80-treated animals, suggesting that each emulsifier acts via distinct molecular mechanisms to produce an anxiety-like phenotype. Furthermore, gene ontology and pathway analysis revealed that various stress, metabolic, and immune terms and pathways were altered by emulsifiers. These findings are the first to demonstrate that emulsifier consumption changes gene expression in brain regions that are critical for stress responding, providing possible molecular mechanisms that may underly the previously observed anxiety-like phenotype.

Early life stress and autonomic response to acute mental stress in individuals with coronary heart disease.

Early life stress (ELS) has been associated with an increased risk of cardiovascular disease. We examined whether ELS was associated with autonomic function and stress reactivity among individuals with coronary heart disease (CHD). We included patients with stable CHD from two parallel studies, the Mental Stress Ischemia Prognosis Study (MIPS) and the Myocardial Infarction and Mental Stress Study 2 (MIMS2), and assessed ELS using the Early Trauma Inventory-Self-Report-Short Form. Participants underwent a laboratory-based mental stress task while undergoing ambulatory electrocardiographic monitoring. We used multivariate linear regression models to estimate the associations between ELS and heart rate variability (HRV; low frequency [LF], high frequency [HF], and LF and HF [LH] ratio). The analytic sample included 405 MIPS and 284 MIMS2 participants. Most participants endorsed at least one experience of ELS (92.2%). Although we did not observe associations between ELS and HRV outcomes in the overall sample, ELS was associated with lower LH ratio HRV during recovery in the posttraumatic stress disorder (PTSD) subgroup, ELS x PTSD interaction, p = .041. In the MIMS2 subgroup, ELS was associated with lower resting period LF HRV, B ̂ $ \widehat{B} $  = -0.16 ln ms2 ; 95% CI [-0.31, -0.02]. Exposure to physical trauma was associated with decreased HF HRV overall reactivity only among participants with high to moderate depressive symptoms, B ̂ $ \widehat{B} $  = -0.52 ln ms2 vs. B ̂ $ \widehat{B} $  = 0.01 ln ms2 , p = .013. Overall, heterogeneous associations between ELS and HRV emerged, suggesting the need for additional research regarding longer-term ambulatory HRV.

Transcutaneous Cervical Vagal Nerve Stimulation in Patients with Posttraumatic Stress Disorder (PTSD): A Pilot Study of Effects on PTSD Symptoms and Interleukin-6 Response to Stress.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a highly disabling condition associated with alterations in multiple neurobiological systems, including increases in inflammatory and sympathetic function, responsible for maintenance of symptoms. Treatment options including medications and psychotherapies have limitations. We previously showed that transcutaneous Vagus Nerve Stimulation (tcVNS) blocks inflammatory (interleukin (IL)-6) responses to stress in PTSD. The purpose of this study was to assess the effects of tcVNS on PTSD symptoms and inflammatory responses to stress. METHODS: Twenty patients with PTSD were randomized to double blind active tcVNS (N=9) or sham (N=11) stimulation in conjunction with exposure to personalized traumatic scripts immediately followed by active or sham tcVNS and measurement of IL-6 and other biomarkers of inflammation. Patients then self administered active or sham tcVNS twice daily for three months. PTSD symptoms were measured with the PTSD Checklist (PCL) and the Clinician Administered PTSD Scale (CAPS), clinical improvement with the Clinical Global Index (CGI) and anxiety with the Hamilton Anxiety Scale (Ham-A) at baseline and one-month intervals followed by a repeat of measurement of biomarkers with traumatic scripts. After three months patients self treated with twice daily open label active tcVNS for another three months followed by assessment with the CGI. RESULTS: Traumatic scripts increased IL-6 in PTSD patients, an effect that was blocked by tcVNS (p<.05). Active tcVNS treatment for three months resulted in a 31% greater reduction in PTSD symptoms compared to sham treatment as measured by the PCL (p=0.013) as well as hyperarousal symptoms and somatic anxiety measured with the Ham-A p<0.05). IL-6 increased from baseline in sham but not tcVNS. Open label tcVNS resulted in improvements measured with the CGI compared to the sham treatment period p<0.05). CONCLUSIONS: These preliminary results suggest that tcVNS reduces inflammatory responses to stress, which may in part underlie beneficial effects on PTSD symptoms.

Noninvasive Cervical Vagal Nerve Stimulation Alters Brain Activity During Traumatic Stress in Individuals With Posttraumatic Stress Disorder.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a disabling condition affecting a large segment of the population; however, current treatment options have limitations. New interventions that target the neurobiological alterations underlying symptoms of PTSD could be highly beneficial. Transcutaneous cervical (neck) vagal nerve stimulation (tcVNS) has the potential to represent such an intervention. The goal of this study was to determine the effects of tcVNS on neural responses to reminders of traumatic stress in PTSD. METHODS: Twenty-two participants were randomized to receive either sham (n = 11) or active (n = 11) tcVNS stimulation in conjunction with exposure to neutral and personalized traumatic stress scripts with high-resolution positron emission tomography scanning with radiolabeled water for brain blood flow measurements. RESULTS: Compared with sham, tcVNS increased brain activations during trauma scripts (p < .005) within the bilateral frontal and temporal lobes, left hippocampus, posterior cingulate, and anterior cingulate (dorsal and pregenual), and right postcentral gyrus. Greater deactivations (p < .005) with tcVNS were observed within the bilateral frontal and parietal lobes and left thalamus. Compared with tcVNS, sham elicited greater activations (p < .005) in the bilateral frontal lobe, left precentral gyrus, precuneus, and thalamus, and right temporal and parietal lobes, hippocampus, insula, and posterior cingulate. Greater (p < .005) deactivations were observed with sham in the right temporal lobe, posterior cingulate, hippocampus, left anterior cingulate, and bilateral cerebellum. CONCLUSIONS: tcVNS increased anterior cingulate and hippocampus activation during trauma scripts, potentially indicating a reversal of neurobiological changes with PTSD consistent with improved autonomic control.Trial Registration: No. NCT02992899.

A randomized trial of race-related stress among African Americans with chronic kidney disease.

OBJECTIVE: African Americans progress from early to late-stage chronic kidney disease (CKD) at a rate that is three times that of Whites. Given research that implicates social stress in poor kidney outcomes, there is a need to examine whether race-related stress contributes to these disparities. Through experimental manipulation, this study sought to determine whether acute race-related stress was associated with autonomic arousal and an inflammatory marker, which are well-established pathways to poor kidney outcomes. Further we tested the hypothesis that expectations of racism may moderate this relationship. METHOD: Fifty-two African American patients along the CKD continuum were randomized to recall a general or race-related stressful experience. Before, during, and after the recall, patients' blood pressure and Interleukin-6 (IL-6) were monitored. Prior to the experimental manipulation, participants completed self-reported measures of expectations of racism. RESULTS: Across both study conditions, change in self-reported distress from baseline to stress was associated with both systolic and diastolic reactivity (both ps <.01), but not change in IL-6 responses (all ps > 0.05). A significant interaction revealed that those who were randomized to recall a race-related stressor demonstrated less diastolic blood pressure reactivity (F=4.80, p<.05) if they scored lower in expectations of racism as compared to those who scored high. Moreover, those who were randomized to the race-related stressor demonstrated greater increase in IL-6 from 45 to 90 min post-recall than those who recalled a general stressor (F=6.35, p<.05). CONCLUSIONS: Acute race-related stress may be associated with autonomic arousal and inflammatory response among African American patients along the CKD continuum, suggesting the need to further understand its role in racial disparities in CKD progression.

Vaginal Microbiome Composition in Early Pregnancy and Risk of Spontaneous Preterm and Early Term Birth Among African American Women.

Objective: To evaluate the association between the early pregnancy vaginal microbiome and spontaneous preterm birth (sPTB) and early term birth (sETB) among African American women. Methods: Vaginal samples collected in early pregnancy (8-14 weeks' gestation) from 436 women enrolled in the Emory University African American Vaginal, Oral, and Gut Microbiome in Pregnancy Study underwent 16S rRNA gene sequencing of the V3-V4 region, taxonomic classification, and community state type (CST) assignment. We compared vaginal CST and abundance of taxa for women whose pregnancy ended in sPTB (N = 44) or sETB (N= 84) to those who delivered full term (N = 231). Results: Nearly half of the women had a vaginal microbiome classified as CST IV (Diverse CST), while one-third had CST III (L. iners dominated) and just 16% had CST I, II, or V (non-iners Lactobacillus dominated). Compared to vaginal CST I, II, or V (non-iners Lactobacillus dominated), both CST III (L. iners dominated) and CST IV (Diverse) were associated with sPTB with an adjusted odds ratio (95% confidence interval) of 4.1 (1.1, infinity) and 7.7 (2.2, infinity), respectively, in multivariate logistic regression. In contrast, no vaginal CST was associated with sETB. The linear decomposition model (LDM) based on amplicon sequence variant (ASV) relative abundance found a significant overall effect of the vaginal microbiome on sPTB (p=0.034) but not sETB (p=0.320), whereas the LDM based on presence/absence of ASV found no overall effect on sPTB (p=0.328) but a significant effect on sETB (p=0.030). In testing for ASV-specific effects, the LDM found that no ASV was significantly associated with sPTB considering either relative abundance or presence/absence data after controlling for multiple comparisons (FDR 10%), although in marginal analysis the relative abundance of Gardnerella vaginalis (p=0.011), non-iners Lactobacillus (p=0.016), and Mobiluncus curtisii (p=0.035) and the presence of Atopobium vaginae (p=0.049), BVAB2 (p=0.024), Dialister microaerophilis (p=0.011), and Prevotella amnii (p=0.044) were associated with sPTB. The LDM identified the higher abundance of 7 ASVs and the presence of 13 ASVs, all commonly residents of the gut, as associated with sETB at FDR < 10%. Conclusions: In this cohort of African American women, an early pregnancy vaginal CST III or IV was associated with an increased risk of sPTB but not sETB. The relative abundance and presence of distinct taxa within the early pregnancy vaginal microbiome was associated with either sPTB or sETB.

Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1.

While the discovery of immune checkpoint inhibitors has led to robust, durable responses in a range of cancers, many patients do not respond to currently available therapeutics. Therefore, an urgent need exists to identify alternative mechanisms to augment the immune-mediated clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a serine-threonine kinase that acts as a negative regulator of T-cell receptor (TCR) signaling, to dampen the immune response. Herein we describe the structure-based discovery of isofuranones as inhibitors of HPK1. Optimization of the chemotype led to improvements in potency, selectivity, plasma protein binding, and metabolic stability, culminating in the identification of compound 24. Oral administration of 24, in combination with an anti-PD1 antibody, demonstrated robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal cancer.

Using yeast surface display to engineer a soluble and crystallizable construct of hematopoietic progenitor kinase 1 (HPK1).

Hematopoietic progenitor kinase 1 (HPK1) is an intracellular kinase that plays an important role in modulating tumor immune response and thus is an attractive target for drug discovery. Crystallization of the wild-type HPK1 kinase domain has been hampered by poor expression in recombinant systems and poor solubility. In this study, yeast surface display was applied to a library of HPK1 kinase-domain variants in order to select variants with an improved expression level and solubility. The HPK1 variant with the most improved properties contained two mutations, crystallized readily in complex with several small-molecule inhibitors and provided valuable insight to guide structure-based drug design. This work exemplifies the benefit of yeast surface display towards engineering crystallizable proteins and thus enabling structure-based drug discovery.

Transcutaneous cervical vagal nerve stimulation reduces sympathetic responses to stress in posttraumatic stress disorder: A double-blind, randomized, sham controlled trial.

OBJECTIVE: Exacerbated autonomic responses to acute stress are prevalent in posttraumatic stress disorder (PTSD). The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to acute stress in patients with PTSD. The authors hypothesized tcVNS would reduce the sympathetic response to stress compared to a sham device. METHODS: Using a randomized double-blind approach, we studied the effects of tcVNS on physiological responses to stress in patients with PTSD (n = 25) using noninvasive sensing modalities. Participants received either sham (n = 12) or active tcVNS (n = 13) after exposure to acute personalized traumatic script stress and mental stress (public speech, mental arithmetic) over a three-day protocol. Physiological parameters related to sympathetic responses to stress were investigated. RESULTS: Relative to sham, tcVNS paired to traumatic script stress decreased sympathetic function as measured by: decreased heart rate (adjusted ß = -5.7%; 95% CI: ±3.6%, effect size d = 0.43, p < 0.01), increased photoplethysmogram amplitude (peripheral vasodilation) (30.8%; ±28%, 0.29, p < 0.05), and increased pulse arrival time (vascular function) (6.3%; ±1.9%, 0.57, p < 0.0001). Similar (p < 0.05) autonomic, cardiovascular, and vascular effects were observed when tcVNS was applied after mental stress or without acute stress. CONCLUSION: tcVNS attenuates sympathetic arousal associated with stress related to traumatic memories as well as mental stress in patients with PTSD, with effects persisting throughout multiple traumatic stress and stimulation testing days. These findings show that tcVNS has beneficial effects on the underlying neurophysiology of PTSD. Such autonomic metrics may also be evaluated in daily life settings in tandem with tcVNS therapy to provide closed-loop delivery and measure efficacy.ClinicalTrials.gov Registration # NCT02992899.

Toxoplasma gondii Effects on the Relationship of Kynurenine Pathway Metabolites to Acoustic Startle Latency in Schizophrenia vs. Control Subjects.

Background: Chronic infection with Toxoplasma gondii (TOXO) results in microcysts in the brain that are controlled by inflammatory activation and subsequent changes in the kynurenine pathway. TOXO seropositivity is associated with a heightened risk of schizophrenia (SCZ) and with cognitive impairments. Latency of the acoustic startle response, a putative index of neural processing speed, is slower in SCZ. SCZ subjects who are TOXO seropositive have slower latency than SCZ subjects who are TOXO seronegative. We assessed the relationship between kynurenine pathway metabolites and startle latency as a potential route by which chronic TOXO infection can lead to cognitive slowing in SCZ. Methods: Fourty-seven SCZ subjects and 30 controls (CON) were tested on a standard acoustic startle paradigm. Kynurenine pathway metabolites were measured using liquid chromatography-tandem mass spectrometry were kynurenine (KYN), tryptophan (TRYP), 3-hydroxyanthranilic acid (3-OHAA), anthranilic acid (AA), and kynurenic acid (KYNA). TOXO status was determined by IgG ELISA. Results: In univariate ANCOVAs on onset and peak latency with age and log transformed startle magnitude as covariates, both onset latency [F(1,61) = 5.76; p = 0.019] and peak latency [F(1,61) = 4.34; p = 0.041] were slower in SCZ than CON subjects. In stepwise backward linear regressions after stratification by Diagnosis, slower onset latency in SCZ subjects was predicted by higher TRYP (B = 0.42; p = 0.008) and 3-OHAA:AA (B = 3.68; p = 0.007), and lower KYN:TRYP (B = -185.42; p = 0.034). In regressions with peak latency as the dependent variable, slower peak latency was predicted by higher TRYP (B = 0.47; p = 0.013) and 3-OHAA:AA ratio (B = 4.35; p = 0.010), and by lower KYNA (B = -6.67; p = 0.036). In CON subjects neither onset nor peak latency was predicted by any KYN metabolites. In regressions stratified by TOXO status, in TOXO positive subjects, slower peak latency was predicted by lower concentrations of KYN (B = -8.08; p = 0.008), KYNA (B = -10.64; p = 0.003), and lower KYN:TRYP ratios (B = -347.01; p = 0.03). In TOXO negative subjects neither onset nor peak latency was predicted by any KYN metabolites. Conclusions: KYN pathway markers predict slowing of startle latency in SCZ subjects and in those with chronic TOXO infection, but this is not seen in CON subjects nor TOXO seronegative subjects. These findings coupled with prior work indicating a relationship of slower latency with SCZ and TOXO infection suggest that alterations in KYN pathway markers may be a mechanism by which neural processing speed, as indexed by startle latency, is affected in these subjects.

Association of Early-Life Trauma and Risk of Adverse Cardiovascular Outcomes in Young and Middle-aged Individuals With a History of Myocardial Infarction.

IMPORTANCE: Compared with older patients, young adults with a history of myocardial infarction (MI) tend to have a higher burden of psychosocial adversity. Exposure to early-life stressors may contribute to the risk of adverse outcomes in this patient population, potentially through inflammatory pathways. OBJECTIVE: To investigate the association of early-life trauma with adverse events and examine whether inflammation plays a role. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included patients aged 18 to 60 years with a verified history of MI in the past 8 months from a university-affiliated hospital network. Baseline data were collected from June 2011 to March 2016, and follow-up data were obtained through July 2019. Analysis began September 2019. EXPOSURES: Early-life trauma was assessed using the Early Trauma Inventory-Self Report short form (ETI-SR-SF), both as a continuous and as a binary variable at the threshold of a score of 7 or higher. Inflammatory biomarkers, interleukin 6, and C-reactive protein were obtained at baseline. MAIN OUTCOMES AND MEASURES: A composite end point of recurrent MI, stroke, heart failure hospitalization, and cardiovascular death over a median 3-year follow-up. RESULTS: Of 300 patients, the mean (SD) age was 51 (7) years, 198 (66%) were African American, and 150 (50%) were women. Compared with participants with MI with an ETI-SR-SF score less than 7, those with a score of 7 or higher had higher levels of interleukin 6 and C-reactive protein at baseline. Compared with participants with an ETI-SR-SF score less than 7, those with a score of 7 or higher were at a greater risk for adverse outcomes, with a hazards ratio of 2.3 (95% CI, 1.3-3.9). Results remained consistent in multivariable analysis. Further adjustment for C-reactive protein rendered the results no longer statistically significant. Early-life trauma displayed a dose-dependent response when analyzed as a continuous variable and by quartiles. CONCLUSIONS AND RELEVANCE: Early-life trauma is an independent risk factor for adverse outcomes in young and middle-aged individuals with a history of MI. Neurobiological mechanisms leading to lifetime activation of systemic inflammatory cascades may be implicated.

Exploring the Determinants of Color Perception Using #Thedress and Its Variants: The Role of Spatio-Chromatic Context, Chromatic Illumination, and Material-Light Interaction.

The colors that people see depend not only on the surface properties of objects but also on how these properties interact with light as well as on how light reflected from objects interacts with an individual's visual system. Because individual visual systems vary, the same visual stimulus may elicit different perceptions from different individuals. #thedress phenomenon drove home this point: different individuals viewed the same image and reported it to be widely different colors: blue and black versus white and gold. This phenomenon inspired a collection of demonstrations presented at the Vision Sciences Society 2015 Meeting which showed how spatial and temporal manipulations of light spectra affect people's perceptions of material colors and illustrated the variability in individual color perception. The demonstrations also explored the effects of temporal alterations in metameric lights, including Maxwell's Spot, an entoptic phenomenon. Crucially, the demonstrations established that #thedress phenomenon occurs not only for images of the dress but also for the real dress under real light sources of different spectral composition and spatial configurations.

Application of Noninvasive Vagal Nerve Stimulation to Stress-Related Psychiatric Disorders.

BACKGROUND: Vagal Nerve Stimulation (VNS) has been shown to be efficacious for the treatment of depression, but to date, VNS devices have required surgical implantation, which has limited widespread implementation. METHODS: New noninvasive VNS (nVNS) devices have been developed which allow external stimulation of the vagus nerve, and their effects on physiology in patients with stress-related psychiatric disorders can be measured with brain imaging, blood biomarkers, and wearable sensing devices. Advantages in terms of cost and convenience may lead to more widespread implementation in psychiatry, as well as facilitate research of the physiology of the vagus nerve in humans. nVNS has effects on autonomic tone, cardiovascular function, inflammatory responses, and central brain areas involved in modulation of emotion, all of which make it particularly applicable to patients with stress-related psychiatric disorders, including posttraumatic stress disorder (PTSD) and depression, since dysregulation of these circuits and systems underlies the symptomatology of these disorders. RESULTS: This paper reviewed the physiology of the vagus nerve and its relevance to modulating the stress response in the context of application of nVNS to stress-related psychiatric disorders. CONCLUSIONS: nVNS has a favorable effect on stress physiology that is measurable using brain imaging, blood biomarkers of inflammation, and wearable sensing devices, and shows promise in the prevention and treatment of stress-related psychiatric disorders.

Diet, Stress and Mental Health.

INTRODUCTION: There has long been an interest in the effects of diet on mental health, and the interaction of the two with stress; however, the nature of these relationships is not well understood. Although associations between diet, obesity and the related metabolic syndrome (MetS), stress, and mental disorders exist, causal pathways have not been established. METHODS: We reviewed the literature on the relationship between diet, stress, obesity and psychiatric disorders related to stress. RESULTS: Diet and obesity can affect mood through direct effects, or stress-related mental disorders could lead to changes in diet habits that affect weight. Alternatively, common factors such as stress or predisposition could lead to both obesity and stress-related mental disorders, such as depression and posttraumatic stress disorder (PTSD). Specific aspects of diet can lead to acute changes in mood as well as stimulate inflammation, which has led to efforts to assess polyunsaturated fats (PUFA) as a treatment for depression. Bidirectional relationships between these different factors are also likely. Finally, there has been increased attention recently on the relationship between the gut and the brain, with the realization that the gut microbiome has an influence on brain function and probably also mood and behavior, introducing another way diet can influence mental health and disorders. Brain areas and neurotransmitters and neuropeptides that are involved in both mood and appetite likely play a role in mediating this relationship. CONCLUSIONS: Understanding the relationship between diet, stress and mood and behavior could have important implications for the treatment of both stress-related mental disorders and obesity.