Changes in guilt cognitions mediate the effect of trauma-informed guilt reduction therapy on PTSD and depression outcomes.

OBJECTIVE: Trauma-informed guilt reduction therapy (TrIGR), a six-session cognitive behavioral therapy targeting trauma-related guilt and distress, reduces guilt and symptoms of posttraumatic stress disorder (PTSD) and depression, yet little is known regarding how and why TrIGR may be effective. METHOD: This study examined treatment-related changes in avoidant coping and trauma-related guilt cognitions as possible mediators of treatment effects on PTSD and depression outcomes at 3- and 6-month follow-up. Data were from a randomized controlled trial for treatment of trauma-related guilt comparing TrIGR and supportive care therapy among 145 post-9/11 US veterans (Mage = 39.2 [8.1], 93.8% male). RESULTS: At pretreatment, most (86%) met PTSD criteria. Intent to treat analyses using parallel mediation models indicated changes in guilt cognitions, but not avoidant coping, mediated the effect of TrIGR on reducing PTSD severity at 3-month (a × b = -0.15, p < 0.01, 95% CI: [-0.24 to -0.06], p = 0.001) and 6-month (a × b = -0.17, 95% CI: [-0.26 to -0.07], p = 0.001) follow-up. Similarly, changes in guilt cognitions, but not avoidant coping, mediated the effect of TrIGR on reducing depression severity at 3-month (a × b = -0.10, 95% CI: [-0.18 to -0.02], p = 0.02) and 6-month (a × b = -0.11, 95% CI: [-0.20 to -0.03], p = 0.01) follow-up. CONCLUSIONS: Compared to guilt cognitions, changes in avoidant coping were less integral to downstream PTSD and depression symptom reduction. Guilt cognition change may be a salient active ingredient of PTSD and depression treatment for those with trauma-related guilt and a key therapy element to which providers should be attuned.

Prostaglandin E2 Inhibits the Ability of Neutrophils to Kill Listeria monocytogenes.

PGE2 is a lipid-signaling molecule with complex roles in both homeostasis and inflammation. Depending on the cellular context, PGE2 may also suppress certain immune responses. In this study, we tested whether PGE2 could inhibit bacterial killing by polymorphonuclear neutrophils (PMN) using a mouse model of foodborne listeriosis. We found that PGE2 pretreatment decreased the ability of PMN harvested from the bone marrow of either BALB/cByJ or C57BL/6J mice to kill Listeria monocytogenes in vitro. PGE2 treatment slowed the migration of PMN toward the chemoattractant leukotriene B4, decreased uptake of L. monocytogenes by PMN, and inhibited the respiratory burst of PMN compared with vehicle-treated cells. When immune cells were isolated from the livers of infected mice and tested directly ex vivo for the presence of PGE2, BALB/cByJ cells produced significantly more than C57BL/6J cells. Together, these data suggest that robust PGE2 production can suppress PMN effector functions, leading to decreased bacterial killing, which may contribute to the innate susceptibility of BALB/cByJ mice to infection with the facultative intracellular bacterial pathogen L. monocytogenes.

Relationship between General and Sport-Related Drinking Motives and Athlete Alcohol Use and Problems.

OBJECTIVE: Alcohol use (and adverse consequences due to alcohol use) among college student-athletes is a common occurrence and consequently garners attention as a health concern within athletic departments and the NCAA. One of the strongest predictors of alcohol use in athletes is motivation to drink. However, not much is known about the influence of alcohol use motivations on drinking in collegiate athletes. Therefore, this study examined the influence of sport-related and general drinking motives on alcohol use and alcohol-related problems. METHOD: Participants were female collegiate softball players (N = 721) from 62 NCAA teams. Athletes completed the Athlete Drinking Scale (Martens et al., 2005), the Drinking Motives Questionnaire, revised (Cooper, 1994; Cooper et al., 1992), alcohol consumption measures, and the Rutgers Alcohol Problems Index (White & Labouvie, 1989). Multilevel modeling was used to analyze the data. RESULTS: Higher scores on Positive Reinforcement motives were associated with greater alcohol consumption, heavy episodic drinking, and alcohol-related problems. Enhancement motives were positively associated with heavy episodic drinking and alcohol-related problems, while Coping motives were positively associated with alcohol-related problems. Lower scores on Conformity motives were related to higher alcohol consumption, whereas higher scores were related to more alcohol-related problems. CONCLUSIONS: These results assist in understanding salient drinking motives among athletes while accounting for nesting effects of athletes within teams. Results demonstrate alcohol use as a perceived means of reward for hard work or good athletic performance, thus attempts to control alcohol use in college athletics should emphasize alternative methods to positively reinforce efforts or celebrate victories.

Neutrophils from Both Susceptible and Resistant Mice Efficiently Kill Opsonized Listeria monocytogenes.

Inbred mouse strains differ in their susceptibility to infection with the facultative intracellular bacterium Listeria monocytogenes, largely due to delayed or deficient innate immune responses. Previous antibody depletion studies suggested that neutrophils (polymorphonuclear leukocytes [PMN]) were particularly important for clearance in the liver, but the ability of PMN from susceptible and resistant mice to directly kill L. monocytogenes has not been examined. In this study, we showed that PMN infiltrated the livers of BALB/c/By/J (BALB/c) and C57BL/6 (B6) mice in similar numbers and that both cell types readily migrated toward leukotriene B4 in an in vitro chemotaxis assay. However, CFU burdens in the liver were significantly higher in BALB/c mice than in other strains, suggesting that PMN in the BALB/c liver might not be able to clear L. monocytogenes as efficiently as B6 PMN. Unprimed PMN harvested from either BALB/c or B6 bone marrow killed L. monocytogenes directly ex vivo, and pretreatment with autologous serum significantly enhanced killing efficiency for both. L. monocytogenes were internalized within 10 min and rapidly triggered intracellular production of reactive oxygen species in a dose-dependent manner. However, PMN from gp91phox-deficient mice also readily killed L. monocytogenes, which suggested that nonoxidative killing mechanisms may be sufficient for bacterial clearance. Together, these results indicate that there is not an intrinsic defect in the ability of PMN from susceptible BALB/c mice to kill L. monocytogenes and further suggest that if PMN function is impaired in BALB/c mice, it is likely due to locally produced modulating factors present in the liver during infection.

Type I IFN Does Not Promote Susceptibility to Foodborne Listeria monocytogenes.

Type I IFN (IFN-α/ß) is thought to enhance growth of the foodborne intracellular pathogen Listeria monocytogenes by promoting mechanisms that dampen innate immunity to infection. However, the type I IFN response has been studied primarily using methods that bypass the stomach and, therefore, fail to replicate the natural course of L. monocytogenes infection. In this study, we compared i.v. and foodborne transmission of L. monocytogenes in mice lacking the common type I IFN receptor (IFNAR1(-/-)). Contrary to what was observed using i.v. infection, IFNAR1(-/-) and wild-type mice had similar bacterial burdens in the liver and spleen following foodborne infection. Splenocytes from wild-type mice infected i.v. produced significantly more IFN-ß than did those infected by the foodborne route. Consequently, the immunosuppressive effects of type I IFN signaling, which included T cell death, increased IL-10 secretion, and repression of neutrophil recruitment to the spleen, were all observed following i.v. but not foodborne transmission of L. monocytogenes. Type I IFN was also previously shown to cause a loss of responsiveness to IFN-γ through downregulation of the IFN-γ receptor α-chain on macrophages and dendritic cells. However, we detected a decrease in surface expression of IFN-γ receptor α-chain even in the absence of IFN-α/ß signaling, suggesting that in vivo, this infection-induced phenotype is not type I IFN-dependent. These results highlight the importance of using the natural route of infection for studies of host-pathogen interactions and suggest that the detrimental effects of IFN-α/ß signaling on the innate immune response to L. monocytogenes may be an artifact of the i.v. infection model.

Adherence to extended release naltrexone: Patient and treatment characteristics.

BACKGROUND AND OBJECTIVES: Despite the promise of extended release naltrexone in the treatment of the opioid and alcohol use disorders, challenges with initiation and subsequent adherence have limited its potential. The purpose of this study is to identify the patient and treatment characteristics associated with adherence to extended release naltrexone. METHODS: Retrospective cohort study of 155 veterans who initiated the medication in FY 2014 and FY2015. Medical records were abstracted for patient and treatment data including preferred drug and utilization of substance use treatment in the year before and after medication initiation. RESULTS: Sample characteristics include 94% male, 70% domiciled, 60% without current legal problems, 30% employed, and preferred drug being opioids for 55% and alcohol for 45%. The mean of five extended release naltrexone injections did not differ by preferred drug. Treatment variables associated with medication adherence included concurrent substance use residential, individual, group, and psychiatric therapies (all p < .05) with inpatient detoxification admissions halved afterward (p < .0001) . DISCUSSION AND CONCLUSIONS: Whereas most studies of extended release naltrexone have focused on patients with either alcohol or opioid use disorders for 6 months, this study allowed for a direct comparison of adherence in both groups over a year. The average treatment persistence in this veteran sample is greater than described in other public sector studies and may illustrate the importance of concurrent psychosocial therapies. SCIENTIFIC SIGNIFICANCE: Results extend the findings of other studies and add to an emerging appreciation of the factors associated with treatment retention for extended release naltrexone. (Am J Addict 2018;27:524-530).

In vivo assessment of triazine lipid nanoparticles as transfection agents for plasmid DNA.

Non-viral vectors for in vivo delivery of plasmid DNA rely on optimized formulations to achieve robust transgene expression. Several cationic lipids have been developed to deliver nucleic acids, but most recent literature has focused on mRNA due to its increased expression profile and excluded plasmid DNA, which may have the advantage of being less immunogenic. In this study, we describe the in vivo evaluation of cationic triazine based lipids, previously prepared by our group. We identify one lipid with limited in vivo toxicity for studies to optimize the lipid formulations, which include an evaluation of the influence of PEG and helper lipids on transgene expression. We then demonstrate that lipoplexes, but not lipid nanoparticles, formed from triazine lipids achieve similar transgene expression levels as AAV vectors and offer enhanced expression as compared to a commercially available cationic lipid, DOTAP. Importantly, the lipid nanoparticles and lipoplexes induce minimal antibody profiles toward the expressed protein, while serving as a platform to induce robust antibody responses when directly delivering the protein. Collectively, these data demonstrate the potential for triazine based lipids as non-viral vectors for gene delivery, and highlights the need to optimize each formulation based on the exact contents to achieve enhanced transgene expression with plasmid DNA constructs.

Subgroups of comorbid PTSD and AUD in U.S. military veterans predict differential responsiveness to two integrated treatments: A latent class analysis.

Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) frequently co-occur. Integrated treatments are effective, but not all patients respond and predicting outcome remains difficult. In this study, latent class analysis (LCA) identified symptom-based subgroups of comorbid PTSD/AUD among 119 veterans with PTSD/AUD from a randomized controlled trial of integrated exposure therapy (I-PE) versus integrated coping skills therapy (I-CS). Multilevel models compared subgroups on PTSD severity and percentage of heavy drinking days at post-treatment and 3- and 6-month follow-up. LCA revealed three subgroups best fit the data: Moderate PTSD/Low AUD Impairment (21%), High PTSD/High AUD Impairment (48%), and Low PTSD/High AUD Impairment (31%). There was a three-way interaction between time, treatment condition, and subgroup in predicting PTSD outcomes (p < .05). For the Moderate PTSD/Low AUD Impairment class, outcomes at post-treatment and 3-months were similar (ds = 0.17, 0.55), however I-PE showed greater reductions at 6-months (d = 1.36). For the High PTSD/High AUD Impairment class, I-PE demonstrated better post-treatment (d = 0.83) but comparable follow-up (ds = -0.18, 0.49) outcomes. For the Low PTSD/High AUD Impairment class, I-PE demonstrated stronger outcomes at every timepoint (ds = 0.82-1.15). Heavy drinking days declined significantly through follow-up, with an effect of subgroup, but not treatment, on timing of response. This was the first study modeling how PTSD and AUD symptoms might cluster together in a treatment sample of veterans with PTSD/AUD. Symptom-based subgroups show promise in helping understand variability in treatment response among patients with PTSD/AUD and deserve further study.

Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19.

The rapid advancement of the COVID-19 pandemic has prompted an accelerated pursuit to identify effective therapeutics. Stages of the disease course have been defined by viral burden, lung pathology, and progression through phases of the immune response. Immunological factors including inflammatory cell infiltration and cytokine storm have been associated with severe disease and death. Many immunomodulatory therapies for COVID-19 are currently being investigated, and preliminary results support the premise of targeting the immune response. However, because suppressing immune mechanisms could also impact the clearance of the virus in the early stages of infection, therapeutic success is likely to depend on timing with respect to the disease course. Azithromycin is an immunomodulatory drug that has been shown to have antiviral effects and potential benefit in patients with COVID-19. Multiple immunomodulatory effects have been defined for azithromycin which could provide efficacy during the late stages of the disease, including inhibition of pro-inflammatory cytokine production, inhibition of neutrophil influx, induction of regulatory functions of macrophages, and alterations in autophagy. Here we review the published evidence of these mechanisms along with the current clinical use of azithromycin as an immunomodulatory therapeutic. We then discuss the potential impact of azithromycin on the immune response to COVID-19, as well as caution against immunosuppressive and off-target effects including cardiotoxicity in these patients. While azithromycin has the potential to contribute efficacy, its impact on the COVID-19 immune response requires additional characterization so as to better define its role in individualized therapy.

Enrichment of Neutrophils and Monocytes From the Liver Following Either Oral or Intravenous Listeria monocytogenes Infection.

Listeria monocytogenes is a foodborne pathogen that causes serious, often deadly, systemic disease in susceptible individuals such as neonates and the elderly. These facultative intracellular bacteria have been an invaluable tool in immunology research for more than three decades. Intravenous (i.v.) injection is the most commonly used transmission route in mice, but oral models of infection have also been developed in recent years, and these may be more appropriate for many studies. This article includes detailed instructions for use of either foodborne or i.v. inoculation of mice and discusses the rationale for choosing either model. Additionally, a protocol is provided for enrichment of neutrophils and monocytes from the infected liver in a manner that allows for determination of bacterial burden while still providing sufficient cells for use in flow cytometric analysis or in vitro assays. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Foodborne L. monocytogenes infection Support Protocol 1: Preparing L. monocytogenes for foodborne infection Basic Protocol 2: Intravenous L. monocytogenes infection Support Protocol 2: Preparing L. monocytogenes for intravenous infection Basic Protocol 3: Enrichment of non-parenchymal cells from the infected liver.

Autoantibody Responses to Apolipoprotein A-I Are Not Diet- or Sex-Linked in C57BL/6 Mice.

Atherosclerosis is responsible for a large percentage of all-cause mortality worldwide, but it is only now beginning to be understood as a complex disease process involving metabolic insult, chronic inflammation, and multiple immune mechanisms. Abs targeting apolipoprotein A-I (ApoA-I) have been found in patients with cardiovascular disease, autoimmune conditions, as well as those with no documented history of either. However, relatively little is known about how these Abs are generated and their relationship to diet and sex. In the current study, we modeled this aspect of autoimmunity using anti-ApoA-I immunization of male and female C57BL/6 mice. Unexpectedly, we found that autoantibodies directed against a single, previously unknown, epitope within the ApoA-I protein developed irrespective of immunization status or dyslipidemia in mice. When total IgG subclasses were analyzed over the course of time, we observed that rather than driving an increase in inflammatory IgG subclasses, consumption of Western diet suppressed age-dependent increases in IgG2b and IgG2c in male mice only. The lack of change observed in female mice suggested that diet and sex might play a combined role in Th1/Th2 balance and, ultimately, in immunity to pathogen challenge. This report demonstrates the need for inclusion of both sexes in studies pertaining to diet and aging and suggests that further study of immunogenic epitopes present in ApoA-I is warranted.

Everything Is Science: A Free City-Wide Science Festival.

A week-long, city-wide science festival called Everything is Science (EiS) was developed to educate the community in an informal manner. The festival serves as a platform for presenters from diverse professions to give engaging talks (without PowerPoint slides) to the public, free of charge, in restaurants and bars around town. Over 350 people attended the events over 5 days with 33 presenters. Surveys completed by attendees and session coordinators indicate strong support for this festival. Altogether, the EiS festival serves as a no-cost method to engage with the community and improve science literacy with potential for adoption in other cities.

Purpose in Life and Conscientiousness Protect Against the Development of Suicidal Ideation in U.S. Military Veterans With PTSD and MDD: Results From the National Health and Resilience in Veterans Study.

BACKGROUND: Although several studies have examined risk factors for suicidal ideation among veterans, little is known about risk and protective factors for suicidal ideation in high-risk veteran samples. Thus, this study examined a broad range of risk and protective factors associated with the development of suicidal ideation in a high-risk sample of U.S. veterans who screened positive for current posttraumatic stress disorder (PTSD) and/or major depressive disorder (MDD). METHODS: Data were analyzed from the National Health and Resilience in Veterans Study, a nationally representative, prospective cohort study of U.S. veterans. Veterans completed self-report measures to screen for PTSD and MDD and to assess for risk and protective factors. The sample included 222 veterans with PTSD and/or MDD who did not endorse suicidal ideation at baseline and completed at least one assessment over a seven-year follow-up period. A multivariable binary logistic regression analysis was conducted to examine baseline factors associated with incident suicidal ideation. RESULTS: Nearly one in three (27.1%) of veterans with PTSD and/or MDD developed suicidal ideation over the seven-year follow-up period. Non-Caucasian race and lower scores on measures of purpose in life, conscientiousness, and frequency of religious service attendance were independently associated with incident suicidal ideation. Lower purpose in life (52.3%) and conscientiousness (33.2%) explained the vast majority of variance in incident suicidal ideation. CONCLUSION: Nearly 30% of veterans with PTSD and/or MDD who did not endorse suicidal ideation at baseline developed suicidal ideation over a seven-year period. Prevention and treatment efforts designed to bolster purpose in life and conscientiousness may help mitigate risk for suicidal ideation in this high-risk population.

A Comparison of Oral and Intravenous Mouse Models of Listeriosis.

Listeria monocytogenes is one of several enteric microbes that is acquired orally, invades the gastric mucosa, and then disseminates to peripheral tissues to cause systemic disease in humans. Intravenous (i.v.) inoculation of mice with L. monocytogenes has been the most widely-used small animal model of listeriosis over the past few decades. The infection is highly reproducible and has been invaluable in deciphering mechanisms of adaptive immunity in vivo, particularly CD8⁺ T cell responses to intracellular pathogens. However, the i.v. model completely bypasses the gut phase of the infection. Recent advances in generating both humanized mice and murinized bacteria, as well as the development of a foodborne route of transmission has reignited interest in studying oral models of listeriosis. In this review, we analyze previously published reports to highlight both the similarities and differences in tissue colonization and host response to infection using either oral or i.v. inoculation.

Development and initial psychometric examination of the Home Safety and Beautification Assessment in mothers referred to treatment by child welfare agents.

Unintentional injury is the leading cause of death among children, with approximately 45% of injuries occurring in and around the home. Rates of home injury are particularly high in the homes of caregivers who are referred for intervention services by child welfare agents. However, there are few validated methods of home safety assessment available. The Home Safety and Beautification Assessment (HSBA) was developed to assist intervention planning specific to home safety and appearance in a sample of 77 mothers who were referred to treatment by Child Welfare Services. Exploratory factor analysis of HSBA items indicated that safety and appearance factors emerged across rooms in the home, and internal consistencies were good. For each room, the sums of assessors' safety and appearance intervention priority item scores were correlated with the assessors' global safety and appearance ratings of the entire home, respectively. The participants' overall room attractiveness scores were correlated with the assessors' overall room appearance intervention priority scores, whereas the participants' ratings of overall room safety were not correlated with the assessors' overall room safety intervention priority scores. Participants' scores on the Abuse subscale of the Child Abuse Potential Inventory, personal income, and education level were not associated with the assessors' home safety and appearance intervention priority ratings, suggesting the HSBA is assessing constructs that are distinct from child abuse potential and socioeconomic status. The results support the HSBA in a sample referred to treatment by child welfare agents. (PsycINFO Database Record