p53 Gain-of-Function Mutation Induces Metastasis via BRD4-Dependent CSF-1 Expression.

TP53 mutations are frequent in esophageal squamous cell carcinoma (ESCC) and other SCCs and are associated with a proclivity for metastasis. Here, we report that colony-stimulating factor-1 (CSF-1) expression is upregulated significantly in a p53-R172H-dependent manner in metastatic lung lesions of ESCC. The p53-R172H-dependent CSF-1 signaling, through its cognate receptor CSF-1R, increases tumor cell invasion and lung metastasis, which in turn is mediated in part through Stat3 phosphorylation and epithelial-to-mesenchymal transition (EMT). In Trp53R172H tumor cells, p53 occupies the Csf-1 promoter. The Csf-1 locus is enriched with histone 3 lysine 27 acetylation (H3K27ac), which is likely permissive for fostering an interaction between bromodomain-containing domain 4 (BRD4) and p53-R172H to regulate Csf-1 transcription. Inhibition of BRD4 not only reduces tumor invasion and lung metastasis but also reduces circulating CSF-1 levels. Overall, our results establish a novel p53-R172H-dependent BRD4-CSF-1 axis that promotes ESCC lung metastasis and suggest avenues for therapeutic strategies for this difficult-to-treat disease. SIGNIFICANCE: The invasion-metastasis cascade is a recalcitrant barrier to effective cancer therapy. We establish that the p53-R172H-dependent BRD4-CSF-1 axis is a mediator of prometastatic properties, correlates with patient survival and tumor stages, and its inhibition significantly reduces tumor cell invasion and lung metastasis. This axis can be exploited for therapeutic advantage. This article is featured in Selected Articles from This Issue, p. 2489.

Occupational posttraumatic stress disorder and workplace violence in workers' compensation claims.

Acts of violence are the fifth leading cause of nonfatal occupational injuries in the United States. Experiencing a traumatic event at work can have serious mental health consequences, including the development of posttraumatic stress disorder (PTSD). This study aimed to quantify the prevalence of PTSD caused by workplace violence (WPV) in a statewide workers' compensation system and compare the outcomes and treatment of WPV cases versus those caused by other traumatic events. Using a retrospective cohort study design, workers who reported PTSD as the primary reason for a workers' compensation claim and had no coexisting physical injuries were found in California during 2009-2018. A total of 3,772 PTSD cases were identified, 48.9% of which were attributed to WPV. Demographic risk factors associated with WPV PTSD included lower income, younger age, female gender, and employment in retail or finance, p < .001-p = .007. For individuals who returned to work, claims due to WPV resulted in longer medically approved time away from work than non-WPV causes (Mdn = 132.5 days vs. Mdn = 91 days, respectively), p < .001. Three of the top 10 most frequently prescribed medications were administered against evidence-based guidelines. This study found that many treatments prescribed to PTSD patients are based on insufficient evidence, and the provision of existing empirically supported treatments is needed, particularly in generalized populations. The findings support the need for additional recognition of the cause of workplace PTSD to facilitate appropriate referrals to WPV or PTSD specialists to support return-to-work efforts.

Platelet-Coated Circulating Tumor Cells Are a Predictive Biomarker in Patients with Metastatic Castrate-Resistant Prostate Cancer.

Metastatic castration-resistant prostate cancer (mCRPC) includes a subset of patients with particularly unfavorable prognosis characterized by combined defects in at least two of three tumor suppressor genes: PTEN, RB1, and TP53 as aggressive variant prostate cancer molecular signature (AVPC-MS). We aimed to identify circulating tumor cells (CTC) signatures that could inform treatment decisions of patients with mCRPC with cabazitaxel-carboplatin combination therapy versus cabazitaxel alone. Liquid biopsy samples were collected prospectively from 79 patients for retrospective analysis. CTCs were detected, classified, enumerated through a computational pipeline followed by manual curation, and subjected to single-cell genome-wide copy-number profiling for AVPC-MS detection. On the basis of immunofluorescence intensities, detected rare cells were classified into 8 rare-cell groups. Further morphologic characterization categorized CTC subtypes from 4 cytokeratin-positive rare-cell groups, utilizing presence of mesenchymal features and platelet attachment. Of 79 cases, 77 (97.5%) had CTCs, 24 (30.4%) were positive for platelet-coated CTCs (pc.CTCs) and 25 (38.5%) of 65 sequenced patients exhibited AVPC-MS in CTCs. Survival analysis indicated that the presence of pc.CTCs identified the subset of patients who were AVPC-MS-positive with the worst prognosis and minimal benefit from combination therapy. In AVPC-MS-negative patients, its presence showed significant survival improvement from combination therapy. Our findings suggest the presence of pc.CTCs as a predictive biomarker to further stratify AVPC subsets with the worst prognosis and the most significant benefit of additional platinum therapy. IMPLICATIONS: HDSCA3.0 can be performed with rare cell detection, categorization, and genomic characterization for pc.CTC identification and AVPC-MS detection as a potential predictive biomarker of mCRPC.

Nonsuicidal Self-Injury Disorder, Borderline Personality Disorder, and Lifetime History of Suicide Attempts among Male and Female Veterans with Mental Health Disorders.

BACKGROUND: Expanding on research that has identified nonsuicidal self-injury (NSSI) as a strong predictor of suicide risk, the present study examined NSSI disorder (NSSID) and borderline personality disorder (BPD) as unique contributors to lifetime suicide attempts. To our knowledge, the present study represents the first exploration of these associations among veterans. METHODS: Participants included 124 male (74%) and female (26%) veterans diagnosed with at least one mental health disorder. Posttraumatic stress disorder (93%) and major depression (86%) were the most common mental health diagnoses. Large proportions of the sample met criteria for NSSID (48%) and BPD (40%). Suicide attempts were reported by 28% of the sample. Chi-square tests determined the bivariate associations among NSSID, BPD, history of suicide attempts, and other variables. Significant diagnostic (i.e., MDD, BPD, and NSSID) and demographic (i.e., age) characteristics were included as covariates in a logistic regression model examining the associations of BPD and NSSID with suicide attempts. RESULTS: BPD, Χ2=11.1, p<0.001, and NSSID, Χ2=13.9, p<0.001, were uniquely associated with suicide attempts. When all significant predictors were included in the final model, only NSSID emerged as a significant contributor to suicide attempts, OR = 4.9, p < 0.001. LIMITATIONS: Causality cannot be determined from cross-sectional analyses. CONCLUSION: These findings highlight NSSID as a powerful and unique correlate of suicide attempts among veterans, beyond the associations of established diagnostic risk factors. Improving our understanding of the relationship between NSSID and suicide risk has the potential to inform suicide prevention efforts and improve clinical outcomes among veterans.

Quantification of Opioid Prescription Practice Changes Due to Hydrocodone Combination Product Rescheduling in an Academic Pain Clinic.

PURPOSE: To determine the effect of rescheduling on prescription practices in a large academic hospital-based multidisciplinary practice comprising anesthesiologist-trained pain physicians. PATIENTS AND METHODS: We examined the number of HCP prescriptions written and quantity of tablets prescribed during a 6-month period prior to rescheduling and compared this with a 6-month period 1 year after rescheduling. We also examined the changes in prescription of tramadol and acetaminophen with codeine from one period to the next. RESULTS: Our pain clinic conducted 3,320 office visits during the 6-month period prior to HCP rescheduling and 6,003 office visits in the 6-month period 1 year after rescheduling. The charted data from each of these visits were used for our analysis. The mean number of tablets of HCPs prescribed per patient decreased from 318.48 in the pre-period to 242.27 tablets in the post-period, while the mean number of HCP prescriptions per patient decreased from 2.24 to 1.84. The mean number of acetaminophen with codeine tablets prescribed per patient increased from 3.46 to 15.27 in the pre- and post-period. Similarly, the mean number of tramadol tablets per patient increased from 47.33 to 61.97 in the pre- and post-period. The mean number of acetaminophen with codeine and tramadol prescriptions per patient increased from 0.02 to 0.15 and 0.38 to 0.51 in the pre- and post-period, respectively. In the 6-month post-period, fewer new patients were started on opioids compared to the 6-month pre-period, 16% and 27%, respectively. CONCLUSION: Our study showed a significant decrease in the mean number of HCP prescriptions written per patient, as well as a decrease in the mean number of HCP tablets prescribed. Pain physicians in our clinic increased the number of prescriptions for the non-HCPs. The number of acetaminophen with codeine and tramadol tablets prescribed significantly increased. Therefore, the rescheduling of HCPs has profoundly impacted practices within this academic pain clinic.

Xenogeneic cross-circulation for extracorporeal recovery of injured human lungs.

Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplantation, including a lung that failed to recover on EVLP, can be recovered by cross-circulation of whole blood between explanted human lungs and a Yorkshire swine. This xenogeneic platform provided explanted human lungs a supportive, physiologic milieu and systemic regulation that resulted in functional and histological recovery after 24 h of normothermic support. Our findings suggest that cross-circulation can serve as a complementary approach to clinical EVLP to recover injured donor lungs that could not otherwise be utilized for transplantation, as well as a translational research platform for immunomodulation and advanced organ bioengineering.

Multiday maintenance of extracorporeal lungs using cross-circulation with conscious swine.

OBJECTIVES: Lung remains the least-utilized solid organ for transplantation. Efforts to recover donor lungs with reversible injuries using ex vivo perfusion systems are limited to <24 hours of support. Here, we demonstrate the feasibility of extending normothermic extracorporeal lung support to 4 days using cross-circulation with conscious swine. METHODS: A swine behavioral training program and custom enclosure were developed to enable multiday cross-circulation between extracorporeal lungs and recipient swine. Lungs were ventilated and perfused in a normothermic chamber for 4 days. Longitudinal analyses of extracorporeal lungs (ie, functional assessments, multiscale imaging, cytokine quantification, and cellular assays) and recipient swine (eg, vital signs and blood and tissue analyses) were performed. RESULTS: Throughout 4 days of normothermic support, extracorporeal lung function was maintained (arterial oxygen tension/inspired oxygen fraction >400 mm Hg; compliance >20 mL/cm H2O), and recipient swine were hemodynamically stable (lactate <3 mmol/L; pH, 7.42 ± 0.05). Radiography revealed well-aerated lower lobes and consolidation in upper lobes of extracorporeal lungs, and bronchoscopy showed healthy airways without edema or secretions. In bronchoalveolar lavage fluid, granulocyte-macrophage colony-stimulating factor, interleukin (IL) 4, IL-6, and IL-10 levels increased less than 6-fold, whereas interferon gamma, IL-1α, IL-1ß, IL-1ra, IL-2, IL-8, IL-12, IL-18, and tumor necrosis factor alpha levels decreased from baseline to day 4. Histologic evaluations confirmed an intact blood-gas barrier and outstanding preservation of airway and alveolar architecture. Cellular viability and metabolism in extracorporeal lungs were confirmed after 4 days. CONCLUSIONS: We demonstrate feasibility of normothermic maintenance of extracorporeal lungs for 4 days by cross-circulation with conscious swine. Cross-circulation approaches could support the recovery of damaged lungs and enable organ bioengineering to improve transplant outcomes.

Intraoperative Unfractionated Heparin Unresponsiveness during Endovascular Repair of a Ruptured Abdominal Aortic Aneurysm following Administration of Andexanet Alfa for the Reversal of Rivaroxaban.

The authors describe a case of unfractionated heparin (UFH) unresponsiveness in the operating room secondary to reversal of rivaroxaban with coagulation factor Xa (recombinant) inactivated-zhzo (andexanet alfa). A 70-year-old man with a known 4.5- to 5.0-cm abdominal aortic aneurysm and atrial fibrillation managed with rivaroxaban presented with severe right-sided flank pain radiating to the left side of his abdomen. Computed tomography-angiography on arrival demonstrated a left retroperitoneal hematoma and a suspected ruptured abdominal aortic aneurysm. He received andexanet alfa to reverse rivaroxaban prior to an emergent endovascular aneurysm repair. During surgery, he received a total of 14,000 units (167 units/kg) of UFH with minimal changes in activated clotting time (132-144 sec; baseline 135 sec [reference range 74-137 sec]). This case highlights the potential complications of using UFH anticoagulation following reversal of factor Xa inhibitors with andexanet alfa and underscores the importance of peri-procedural anticoagulation planning. For patients who require intra-operative anticoagulation, providers should consider anticoagulation reversal with prothrombin complex concentrate instead of andexanet alfa or administration of a parenteral direct thrombin inhibitor, such as argatroban or bivalirudin during the surgical procedure.

Regeneration of severely damaged lungs using an interventional cross-circulation platform.

The number of available donor organs limits lung transplantation, the only lifesaving therapy for the increasing population of patients with end-stage lung disease. A prevalent etiology of injury that renders lungs unacceptable for transplantation is gastric aspiration, a deleterious insult to the pulmonary epithelium. Currently, severely damaged donor lungs cannot be salvaged with existing devices or methods. Here we report the regeneration of severely damaged lungs repaired to meet transplantation criteria by utilizing an interventional cross-circulation platform in a clinically relevant swine model of gastric aspiration injury. Enabled by cross-circulation with a living swine, prolonged extracorporeal support of damaged lungs results in significant improvements in lung function, cellular regeneration, and the development of diagnostic tools for non-invasive organ evaluation and repair. We therefore propose that the use of an interventional cross-circulation platform could enable recovery of otherwise unsalvageable lungs and thus expand the donor organ pool.

Nonsuicidal Self-Injury and Borderline Personality Features as Risk Factors for Suicidal Ideation Among Male Veterans With Posttraumatic Stress Disorder.

U.S. veterans are at increased risk for suicide compared to their civilian counterparts and account for approximately 20% of all deaths by suicide. Posttraumatic stress disorder (PTSD) and borderline personality features (BPF) have each been associated with increased suicide risk. Additionally, emerging research suggests that nonsuicidal self-injury (NSSI) may be a unique risk factor for suicidal behavior. Archival data from 728 male veterans with a PTSD diagnosis who were receiving care through an outpatient Veterans Health Administration (VHA) specialty PTSD clinic were analyzed. Diagnosis of PTSD was based on a structured clinical interview administered by trained clinicians. A subscale of the Personality Assessment Inventory was used to assess BPF, and NSSI and suicidal ideation (SI) were assessed by self-report. Findings revealed that NSSI (58.8%) and BPF (23.5%) were both relatively common in this sample of male veterans with PTSD. As expected, each condition was associated with significantly increased odds of experiencing SI compared to PTSD alone, odds ratios (ORs) = 1.2-2.6. Moreover, co-occurring PTSD, NSSI, and BPF were associated with significantly increased odds of experiencing SI compared with PTSD, OR = 5.68; comorbid PTSD and NSSI, OR = 2.57; and comorbid PTSD and BPF, OR = 2.13. The present findings provide new insight into the rates of NSSI and BPF among male veterans with PTSD and highlight the potential importance of these factors in suicide risk.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) Autoagresiones no suicidas y características del Trastorno de Personalidad Limítrofe como Factores de Riesgo para Ideación Suicida entre Veteranos varones con Trastorno de Estrés Postraumático ALNS, TPL E IS ENTRE VETERANOS VARONES CON TEPT Los veteranos estadounidenses tienen un riesgo de suicidio mayor que su contraparte civil, dando cuenta de aproximadamente el 20% de las muertes por suicidio. El Trastorno de Estrés Postraumático (TEPT) y los síntomas del Trastorno de Personalidad Limítrofe (TPL) han sido asociados individualmente con un aumento del riesgo suicida. Adicionalmente, la investigación emergente sugiere que las autolesiones no suicidas (ALNS) pueden ser un factor de riesgo único para la conducta suicida. Se analizaron datos de archivo de 728 veteranos varones con diagnóstico de TEPT que estaban recibiendo atención a través de una clínica ambulatoria especializada en TEPT de la Administración de Salud de Veteranos (VHA, por sus siglas en inglés). El diagnóstico de TEPT se basó en una entrevista clínica estructurada administrada por clínicos entrenados. Se usó una subescala del Inventario de Evaluación de la Personalidad para evaluar TPL, y las ALNS e Ideación Suicida (IS) fueron evaluadas por auto-reporte. Los hallazgos revelaron que las ALNS (58.8%) y las características de TPL (23.5%) fueron ambas relativamente comunes en esta muestra de varones veteranos con TEPT. Como era esperado, cada condición se asoció con una probabilidad significativamente aumentada de experimentar IS comparado al TEPT solo, odds ratio (ORs) = 1.2-2.6. Más aún, la co-ocurrencia de TEPT, ALNS y TPL se asoció a una probabilidad significativamente mayor de experimentar IS comparado con TEPT, OR = 5.68; TEPT y ALNS comórbidos, OR=2.57; y TEPT comórbido con TPL, OR=2.13. Los presentes hallazgos proveen una nueva visión en las tasas de ALNS y características de TPL entre los varones veteranos con TEPT y destacan la potencial importancia de estos factores en el riesgo de suicidio.

Roles of Guilt Cognitions in Trauma-Related Sleep Disturbance in Military Veterans With Posttraumatic Stress Disorder.

Objective/Background: Despite a well-established role of guilt cognitions in the maintenance and treatment of posttraumatic stress disorder (PTSD), relationships of guilt cognitions to nightmares are not well understood. This study investigated the ways in which guilt cognitions, related to traumatic events, influenced the relationship between combat exposure and trauma-related sleep disturbance in military Veterans with PTSD. Participants: We recruited a sample of 50 Veterans with PTSD who completed study measures at a screening session. Methods: Participants completed self-report measures of exposure to potentially traumatic events, trauma-related guilt (hindsight bias, wrongdoing, and lack of justification) and trauma-related sleep disturbance as measured by a self-report scale and clinician ratings of nightmare severity. Results: Bivariate regression analyses established a relationship of combat exposure to wrongdoing (ß = .31, p = .031), and a relationship of wrongdoing with self-reported trauma-related sleep disturbance (ß = .27, p = .049) and clinician-rated nightmare severity (ß = .36, p = .009). Bootstrapping analysis that included years of education as a covariate found a significant overall indirect effect of combat exposure on clinician-rated nightmare severity exerted through wrongdoing (ß = .10, 95% CI [.004, .246]). Conclusions: Results suggest the association of combat exposure with trauma-related sleep disturbance is significantly influenced by perceived wrongdoing related to a traumatic event. Targeting cognitions related to wrongdoing and moral injury during a traumatic event in PTSD treatment may help ameliorate trauma-related sleep disturbance.

Shame as a mediator between posttraumatic stress disorder symptoms and suicidal ideation among veterans.

BACKGROUND: Suicidal ideation is a problem that disproportionately affects veterans. Moreover, veterans with posttraumatic stress disorder (PTSD) appear to be at particularly high risk for suicide. OBJECTIVE: The purpose of the present research was to examine whether shame mediates the association between PTSD and suicidal ideation. METHODS: Secondary analyses were conducted in a sample of 201 veterans with PTSD seeking care through an outpatient Veterans Affairs specialty PTSD clinic. RESULTS: Path analysis revealed that shame fully accounted for the effects of PTSD on suicidal ideation, suggesting that shame may represent a key link between PTSD and suicidal ideation among veterans. LIMITATIONS: Although the reverse mediation effect was also examined, the present sample was cross-sectional and predominantly male. CONCLUSIONS: The present findings suggest that shame may be an effective point of treatment intervention to reduce suicidal ideation among veterans with PTSD; however, additional prospective research is still needed to delineate the precise nature of these associations over time.

Cannabis Use Disorder and Post-Deployment Suicide Attempts in Iraq/Afghanistan-Era Veterans.

The objective of the present study was to use retrospective data to test the hypothesis that cannabis dependence would be associated with an increased rate of post-deployment suicide attempts. Participants included 319 veterans who had deployed to either Iraq or Afghanistan. Study procedures involved completion of a structured clinical interview and a battery of self-report questionnaires. As expected, lifetime cannabis dependence was significantly associated with post-deployment suicide attempts, AOR = 7.963, p = .014, even after controlling for the effects of pre-deployment suicide attempts, posttraumatic stress disorder, depression, pain, non-cannabis substance use disorder, and gender. Although preliminary, our findings provide the first evidence to date that heavy cannabis use may be a unique risk factor for post-deployment suicide attempts among veterans.

Does Deployment-Related Military Sexual Assault Interact with Combat Exposure to Predict Posttraumatic Stress Disorder in Female Veterans?

The objective of the present research was to expand upon previous findings indicating that military sexual trauma interacts with combat exposure to predict PTSD among female Iraq/Afghanistan-era veterans. Three hundred and thirty female veterans completed self-report measures of combat experiences, military sexual assault (MSA) experiences, and PTSD symptoms as well as structured diagnostic interviews for PTSD. A significant strength of the present research was the use of PTSD diagnosis as an outcome measure. Consistent with prior research, both combat exposure and MSA were significant predictors of PTSD symptoms (linear regression) and PTSD diagnoses (logistic regression). Specifically, participants who experienced deployment-related MSA had approximately six times the odds of developing PTSD compared to those who had not experienced deployment-related MSA, over and above the effects of combat exposure. Contrary to expectations, the hypothesized interaction between MSA and combat exposure was not significant in any of the models. The low base rate of MSA may have limited power to find a significant interaction; however, these findings are also consistent with other recent studies that have failed to find support for the hypothesized interaction. Thus, whereas the majority of available evidence indicates that MSA increases risk for PTSD among veterans over and above the effects of combat, there is presently only limited support for the hypothesized MSA x combat interaction. These findings highlight the continued need for prevention and treatment of MSA in order to improve veterans' long-term mental health and well-being.

Examination of the indirect effects of combat exposure on suicidal behavior in veterans.

BACKGROUND: Researchers have theorized that increased rates of suicide in the military are associated with combat exposure; however, this hypothesis has received inconsistent support in the literature, potentially because combat exposure may be indirectly related to suicide risk through its influence on posttraumatic stress disorder (PTSD) and depressive symptoms. The current study tested the hypothesis that combat exposure has a significant indirect effect on suicidal behavior among Iraq/Afghanistan-era veterans through its effects on PTSD-depressive symptomatology. METHODS: Iraq/Afghanistan-era veterans (N = 3,238) participated in a cross-sectional, multi-site study of post-deployment mental health consisting of clinical interviews and self-report questionnaires. Structural equation modeling (SEM) was used to examine direct and indirect relationships between three latent variables: combat exposure, PTSD-depression, and suicidal behavior (past attempts and current ideation, intent, and preparation). RESULTS: A partial mediation model was the best-fitting model for the data. Combat exposure was significantly associated with PTSD-depression (ß = 0.50, p < .001), which was in turn associated with suicidal behavior (ß = 0.62, p < .001). As expected, the indirect effect between combat exposure and suicidal behavior was statistically significant, ß = 0.31, p < .001. LIMITATIONS: Data were cross-sectional, and suicidal behavior was measured via self-report. CONCLUSIONS: Results indicated that combat exposure was indirectly related to suicidal behavior via PTSD-depressive symptomatology. Findings lend support for a higher-order combined PTSD-depression latent factor and suggest that Iraq/Afghanistan-era veterans with high levels of PTSD-depressive symptoms are at increased risk for suicidal behavior.

A relative weights comparison of trauma-related shame and guilt as predictors of DSM-5 posttraumatic stress disorder symptom severity among US veterans and military members.

OBJECTIVES: Veterans and military service members have increased risk for post-traumatic stress disorder (PTSD) and consequent problems with health, psychosocial functioning, and quality of life. In this population and others, shame and guilt have emerged as contributors to PTSD, but there is a considerable need for research that precisely demonstrates how shame and guilt are associated with PTSD. This study examined whether a) trauma-related shame predicts PTSD severity beyond the effects of trauma-related guilt and b) shame accounts for a greater proportion of variance in PTSD symptoms than guilt. DESIGN: We collected cross-sectional self-report data on measures of PTSD symptom severity based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, trauma-related shame, and trauma-related guilt via online survey. METHOD: Participants included 61 US veterans and active duty service members. Hierarchical multiple regression and relative weights analysis were used to test hypotheses. RESULTS: In step 1 of regression analysis, guilt was significantly associated with PTSD. However, when shame was added to the model, the effect of guilt became non-significant, and only shame significant predicted PTSD. Results from relative weights analysis indicated that both shame and guilt predicted PTSD, jointly accounting for 46% of the variance in PTSD. Compared to guilt, trauma-related shame accounted for significantly more explained variance in PTSD. CONCLUSIONS: This study provided evidence that among US veterans and service members, trauma-related shame and guilt differ in their association with PTSD and that trauma-related shame, in particular, is associated with the severity of PTSD. PRACTITIONER POINTS: Trauma-related shame and guilt explained almost half of the observed variance in PTSD symptom severity among this sample of US military veterans and service members. Trauma-related shame and guilt each made a unique contribution to PTSD severity after accounting for the similarity between these two emotions; however, shame was particularly associated with increased PTSD severity. These results highlight the importance of assessing and addressing trauma-related shame and guilt in PTSD treatment among military populations. We suggest that emotion- and compassion-focused techniques may be particularly relevant for addressing trauma-related shame and guilt. Limitations of the study Cross-sectional data does not allow for determination of causal relationships. Although sufficiently powered, the sample size is small. The present sample self-selected to participate in a study about stress and emotions.

The association of alcohol consumption patterns with self-rated physical health and psychiatric distress among Afghanistan- and Iraq-era U.S. veterans.

Alcohol misuse is associated with negative mental and physical health outcomes, which presents a public health concern in veterans. However, less is known regarding outcomes among veterans with low to moderate alcohol consumption. This study included veterans with military service in Iraq and/or Afghanistan (N = 1083) who resided in the VA Mid-Atlantic region catchment area (North Carolina, Virginia, and parts of West Virginia). Participants completed a mailed survey that inquired about demographics, past-year alcohol consumption, self-rated physical health, and psychiatric symptoms. Logistic regression was used to evaluate associations between alcohol consumption and posttraumatic stress disorder (PTSD), depression, and self-rated physical health. In both bivariate results and adjusted models, non-drinkers and hazardous drinkers were more likely to endorse clinically significant PTSD and depression symptoms than moderate drinkers. Moderate drinkers were also less likely to report fair/poor health, after adjusting for demographics and psychiatric symptoms. Results overall showed a U-shaped curve, such that moderate alcohol use was associated with lower rates of mental health problems and fair/poor health. While the VA routinely screens for alcohol misuse, current results suggest that non-drinkers are also at risk for poor mental and physical health.

Functional vascularized lung grafts for lung bioengineering.

End-stage lung disease is the third leading cause of death worldwide, accounting for 400,000 deaths per year in the United States alone. To reduce the morbidity and mortality associated with lung disease, new therapeutic strategies aimed at promoting lung repair and increasing the number of donor lungs available for transplantation are being explored. Because of the extreme complexity of this organ, previous attempts at bioengineering functional lungs from fully decellularized or synthetic scaffolds lacking functional vasculature have been largely unsuccessful. An intact vascular network is critical not only for maintaining the blood-gas barrier and allowing for proper graft function but also for supporting the regenerative cells. We therefore developed an airway-specific approach to removing the pulmonary epithelium, while maintaining the viability and function of the vascular endothelium, using a rat model. The resulting vascularized lung grafts supported the attachment and growth of human adult pulmonary cells and stem cell-derived lung-specified epithelial cells. We propose that de-epithelialization of the lung with preservation of intact vasculature could facilitate cell therapy of pulmonary epithelium and enable bioengineering of functional lungs for transplantation.

Phenotypic, chemical and functional characterization of cyclic nucleotide phosphodiesterase 4 (PDE4) as a potential anthelmintic drug target.

BACKGROUND: Reliance on just one drug to treat the prevalent tropical disease, schistosomiasis, spurs the search for new drugs and drug targets. Inhibitors of human cyclic nucleotide phosphodiesterases (huPDEs), including PDE4, are under development as novel drugs to treat a range of chronic indications including asthma, chronic obstructive pulmonary disease and Alzheimer's disease. One class of huPDE4 inhibitors that has yielded marketed drugs is the benzoxaboroles (Anacor Pharmaceuticals). METHODOLOGY/PRINCIPAL FINDINGS: A phenotypic screen involving Schistosoma mansoni and 1,085 benzoxaboroles identified a subset of huPDE4 inhibitors that induced parasite hypermotility and degeneration. To uncover the putative schistosome PDE4 target, we characterized four PDE4 sequences (SmPDE4A-D) in the parasite's genome and transcriptome, and cloned and recombinantly expressed the catalytic domain of SmPDE4A. Among a set of benzoxaboroles and catechol inhibitors that differentially inhibit huPDE4, a relationship between the inhibition of SmPDE4A, and parasite hypermotility and degeneration, was measured. To validate SmPDE4A as the benzoxaborole molecular target, we first generated Caenorhabditis elegans lines that express a cDNA for smpde4a on a pde4(ce268) mutant (hypermotile) background: the smpde4a transgene restored mutant worm motility to that of the wild type. We then showed that benzoxaborole inhibitors of SmPDE4A that induce hypermotility in the schistosome also elicit a hypermotile response in the C. elegans lines that express the smpde4a transgene, thereby confirming SmPDE4A as the relevant target. CONCLUSIONS/SIGNIFICANCE: The orthogonal chemical, biological and genetic strategies employed identify SmPDE4A's contribution to parasite motility and degeneration, and its potential as a drug target. Transgenic C. elegans is highlighted as a potential screening tool to optimize small molecule chemistries to flatworm molecular drug targets.

A model comparison approach to trauma-related guilt as a mediator of the relationship between PTSD symptoms and suicidal ideation among veterans.

BACKGROUND: Suicidal ideation (SI) is a serious issue affecting U.S. veterans, and those with posttraumatic stress disorder (PTSD) are at an especially high risk of SI. Guilt has been associated with both PTSD and SI and may therefore be an important link between these constructs. METHODS: The present study compared models of trauma-related guilt and used path analysis to examine the direct and indirect effects of PTSD and trauma-related guilt on SI among a sample of 988 veterans receiving outpatient PTSD treatment at a Veterans Affairs (VA) specialty clinic. RESULTS: Results showed that a model of trauma-related guilt including guilt-cognitions and global guilt (but not distress) provided the best model fit for the data. PTSD and trauma-related guilt had direct effects on SI, and PTSD exhibited indirect effects on SI via trauma-related guilt. LIMITATIONS: The use of cross-sectional data limits the ability to make causal inferences. A treatment-seeking sample composed primarily of Vietnam veterans limits generalizability to other populations. CONCLUSIONS: Trauma-related guilt, particularly guilt cognitions, may be an effective point of intervention to help reduce SI among veterans with PTSD. This is an important area of inquiry, and suggestions for future research are discussed.