Trauma Exposure and Transdiagnostic Distress: Examining Shared and PTSD-Specific Associations

Dimensional models of psychopathology suggest that the causes and consequences of psychopathology are attributable to a combination of syndrome specific and transdiagnostic features. There is considerable evidence that trauma exposure confers risk for a wide range of psychiatric conditions, yet no previous work has specifically examined the higher-order effects of trauma exposure within a structural model. We examined transdiagnostic and PTSD-specific associations with multiple forms of trauma exposure within a nation-wide sample (N = 1,649; 50% female) of military Veterans over-selected for posttraumatic stress disorder (PTSD). A higher-order Distress variable was estimated using PTSD, major depressive disorder (MDD), and generalized anxiety disorder (GAD) symptoms as indicators. A structural equation model spanning three measurement time points over an average of 3.85 years was then used to examine the unique roles of higher-order Distress and PTSD residual variance in accounting for the relations between trauma exposure and psychosocial impairment. Results suggest that the association between trauma exposure and PTSD symptoms is primarily mediated by higher-order Distress, but that PTSD severity does have a significant association with trauma exposure independent of Distress. Both higher-order Distress and PTSD-specific variance were necessary to account for the association between trauma exposure and future functional impairment. This work suggests there may be shared etiology linking cumulative trauma exposure and a range of internalizing symptoms. Continued application of higher-order dimensional models is needed to provide a more comprehensive understanding of the consequences of trauma exposure

Mediation of smoking-associated postoperative mortality by perioperative complications in veterans undergoing elective surgery: data from Veterans Affairs Surgical Quality Improvement Program (VASQIP)--a cohort study

OBJECTIVE: To assess the mediation of smoking-associated postoperative mortality by postoperative complications. DESIGN: Observational cohort study. SETTING: Using data from the Veterans Affairs (VA) Surgical Quality Improvement Programme, a quality assurance programme for major surgical procedures in the VA healthcare system, we assessed the association of current smoking at the time of the surgery with 6-month and 1-year mortality. PRIMARY AND SECONDARY OUTCOME MEASURES: Using mediation analyses, we calculated the relative contribution of each smoking-associated complication to smoking-associated postoperative mortality, both unadjusted and adjusted for age, race/ethnicity, work relative value unit of the operation, surgeon specialty, American Society of Anesthesiologists class and year of surgery. Smoking-associated complications included surgical site infection (SSI), cardiovascular complications (myocardial infarction, cardiac arrest and/or stroke) and pulmonary complications (pneumonia, failure to wean and/or reintubation). RESULTS: There were 186 632 never smokers and 135 741 current smokers. The association of smoking and mortality was mediated by smoking-related complications with varying effects. In unadjusted analyses, the proportions of mediation of smoking to 6-month mortality explained by the complications were as follows: SSIs 22%, cardiovascular complications 12% and pulmonary complications 89%. In adjusted analyses, the per cents mediated by each complication were as follows: SSIs 2%, cardiovascular complications 4% and pulmonary complications 22%. In adjusted analyses for 1-year mortality, respective per cents mediated were 2%, 3% and 16%. CONCLUSIONS: Pulmonary complications, followed by cardiovascular complications and SSIs were mediators of smoking-associated 6-month and 1-year mortality. Interventions targeting smoking cessation and prevention and early treatment of pulmonary complications has the likelihood of reducing postoperative mortality after elective surgery

PTSD and Alcohol Use Disorders Predict the Pace of Cellular Aging

Advanced epigenetic age is associated with psychopathology and may help to explain the link between psychopathology and physical health morbidity and mortality. Using a longitudinal sample of 171 trauma-exposed Veterans, we modeled the rate of change in epigenetic age across two time points (averaging 5.58 years apart) using two epigenetic age algorithms (GrimAge and Horvath) and tested associations with posttraumatic stress disorder (PTSD), alcohol use disorder (AUD), and depression. Results showed that PTSD (β = .199) and AUD (β = .186) were associated with a quickened pace of epigenetic aging over time (ps \u3c .021). Results replicate and extend prior work and offer foundational support for identifying interventions that slow the pace of biological aging among those with psychopathology

For Whom the Bell Tolls: Psychopathological and Neurobiological Correlates of the DNA Methylation Index of Time-To-Death

Psychopathology is a risk factor for accelerated biological aging and early mortality. We examined associations between broad underlying dimensions of psychopathology (reflecting internalizing and externalizing psychiatric symptoms), PTSD, and age-adjusted GrimAge (“GrimAge residuals”), a DNA methylation biomarker of mortality risk relative to age. We also examined neurobiological correlates of GrimAge residuals, including neurocognitive functioning, blood-based biomarkers (of inflammation, neuropathology, metabolic disease), and cortical thickness. Data from two independent trauma-exposed military cohorts (n = 647 [62.9% male, Mage = 52], n = 434 [90% male, Mage = 32]) were evaluated using linear regression models to test associations between GrimAge residuals, psychopathology, and health correlates. Externalizing psychopathology significantly predicted GrimAge residuals in both cohorts (ps \u3c 0.028). PTSD predicted GrimAge residuals in the younger (p = 0.001) but not the older cohort. GrimAge residuals were associated with several neurobiological variables available in the younger cohort, including cognitive disinhibition (padj = 0.021), poorer memory recall (padj = 0.023), cardiometabolic pathology (padj \u3c 0.001), oxidative stress (padj = 0.003), astrocyte damage (padj = 0.021), inflammation (C-reactive protein: padj \u3c 0.001; IL-6: padj \u3c 0.001), and immune functioning (padj \u3c 0.001). A subset of inflammatory and neuropathology analytes were available in the older cohort and showed associations with GrimAge residuals (IL-6: padj \u3c 0.001; TNF-α: padj \u3c 0.001). GrimAge residuals were also associated with reduced cortical thickness in right lateral orbitofrontal cortex (padj = 0.018) and left fusiform gyrus (padj = 0.030), which are related to emotion regulation and facial recognition, respectively. Psychopathology may be a common risk factor for elevated mortality risk. GrimAge could help identify those at risk for adverse health outcomes and allow for early disease identification and treatment

A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease

Although Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens, the influence of polymorphisms in this gene family on human susceptibility to infection is poorly understood. We demonstrated recently that TLR5 recognizes flagellin, a potent inflammatory stimulus present in the flagellar structure of many bacteria. Here, we show that a common stop codon polymorphism in the ligand-binding domain of TLR5 (TLR5392STOP) is unable to mediate flagellin signaling, acts in a dominant fashion, and is associated with susceptibility to pneumonia caused by Legionella pneumophila, a flagellated bacterium. We also show that flagellin is a principal stimulant of proinflammatory cytokine production in lung epithelial cells. Together, these observations suggest that TLR5392STOP increases human susceptibility to infection through an unusual dominant mechanism that compromises TLR5's essential role as a regulator of the lung epithelial innate immune response

Targeting deficiencies in the TLR5 mediated vaginal response to treat female recurrent urinary tract infection

Abstract The identification of the host defence peptides as target effectors in the innate defence of the uro-genital tract creates new translational possibilities for immunomodulatory therapies, specifically vaginal therapies to treat women suffering from rUTI, particularly those carrying the TLR5_C1174T SNP. Urinary tract infections (UTIs) are a microbial disease reported worldwide. Women are particularly susceptible with many suffering debilitating recurrent (r) infections. Treatment is by antibiotics, but such therapy is linked to antibiotic resistance and re-infection. This study explored the innate protective mechanisms of the urogenital tract with the aim of boosting such defences therapeutically. Modelling UTIs in vitro, human vaginal and bladder epithelial cells were challenged with uropathogenic Escherichia coli (CFT073) and microbial PAMPs including flagellin, LPS and peptidoglycan. Flagellin functioning via the TLR5/NFκB pathway was identified as the key UPEC virulence factor causing a significant increase (P < 0.05) in the production of the host-defence peptide (HDP), BD2. BD2-depleted urine samples from bladder infected mice supported increased UPEC growth, strengthening the significance of the HDPs in protecting the urogenital tissues from infection. Clinically, vaginal-douche BD2 concentrations were reduced (p < 0.05) in women suffering rUTIs, compared to age-matched healthy controls with concentrations further decreased (p < 0.05) in a TLR5392Stop SNP rUTI subgroup. Topical vaginal estrogen treatment increased (p < 0.001) BD2 concentrations in all women, including those carrying the SNP. These data identify therapeutic and antibiotic sparing roles for vaginal immunomodulatory agents that specifically target HDP induction, facilitate bacterial killing and disrupt the UPEC infection cycle

Ethnic Variation in Inflammatory Profile in Tuberculosis

PMCID: PMC3701709This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Genetic variation in TLR genes in Ugandan and South African populations and comparison with HapMap data

Genetic epidemiological studies of complex diseases often rely on data from the International HapMap Consortium for identification of single nucleotide polymorphisms (SNPs), particularly those that tag haplotypes. However, little is known about the relevance of the African populations used to collect HapMap data for study populations conducted elsewhere in Africa. Toll-like receptor (TLR) genes play a key role in susceptibility to various infectious diseases, including tuberculosis. We conducted full-exon sequencing in samples obtained from Uganda (n = 48) and South Africa (n = 48), in four genes in the TLR pathway: TLR2, TLR4, TLR6, and TIRAP. We identified one novel TIRAP SNP (with minor allele frequency [MAF] 3.2%) and a novel TLR6 SNP (MAF 8%) in the Ugandan population, and a TLR6 SNP that is unique to the South African population (MAF 14%). These SNPs were also not present in the 1000 Genomes data. Genotype and haplotype frequencies and linkage disequilibrium patterns in Uganda and South Africa were similar to African populations in the HapMap datasets. Multidimensional scaling analysis of polymorphisms in all four genes suggested broad overlap of all of the examined African populations. Based on these data, we propose that there is enough similarity among African populations represented in the HapMap database to justify initial SNP selection for genetic epidemiological studies in Uganda and South Africa. We also discovered three novel polymorphisms that appear to be population-specific and would only be detected by sequencing efforts