Prevalence of Complex Post-Traumatic Stress Disorder in Serving Military and Veteran Populations: A Systematic Review.

Serving military personnel and veterans are known to be at elevated risk of post-traumatic stress disorder (PTSD), and some veterans have been shown to respond poorly to current standard treatments. Evidence so far suggests that according to the 11th edition of the International Classification of Diseases and Related Health Problems guidelines, complex PTSD (CPTSD) may be of higher prevalence in the general population than PTSD. The aim of the study was to investigate the prevalence of CPTSD compared to PTSD in serving and ex-serving military populations. A systematic review was conducted with the search criteria set to peer-reviewed English language journal articles, focusing on serving military or veteran populations, reporting on the prevalence of CPTSD, not restricted by year. Four comprehensive databases (Psycinfo, Pubmed, CINAHL, and Embase) were searched. Of the 297 identified articles, 16 primary studies were eligible for inclusion. The review was registered in the PROSPERO database (CRD42023416458), and results were reported based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of the 16 studies, 13 demonstrated higher prevalence of CPTSD than PTSD. Studies were predominantly veteran focused. Prevalence of CPTSD ranged from 5% to 80.63%, while prevalence of PTSD ranged from 3.8% to 42.37%. There was high heterogeneity in study populations, preventing meta-analysis. This is the first systematic review to assess the prevalence of CPTSD in serving military and veteran populations, with the findings demonstrating a higher rate of CPTSD compared to PTSD. It is hoped that the review will assist clinicians and military and veteran health services with appropriate assessment, diagnosis, and intervention for those affected by CPTSD, as well as PTSD.

Polypharmacy in Australian Veterans with Post-traumatic Stress Disorder upon Admission to a Mental Health Facility: A Retrospective Chart Review.

OBJECTIVE: Polypharmacy increases the risk of adverse drug events and drug-drug interactions, and contributes to falls, hospital admissions, morbidity and mortality. Veterans with post-traumatic stress disorder often have psychological and physical comorbidities, increasing the likelihood of general and psychotropic polypharmacy. This study investigates the prevalence of general and psychotropic polypharmacy in inpatient veterans with post-traumatic stress disorder, and illustrates potential risks associated with polypharmacy in this population. METHODS: Medical records of 219 veterans admitted to a mental health facility for post-traumatic stress disorder management were retrospectively reviewed. Medication lists on admission were extracted and coded according to Anatomical Therapeutic Chemical Classification classes. The prevalence of general (five or more total medications), psychotropic (two or more N-code medications), and sedative (two or more medications with sedating effects) polypharmacy and Drug Burden Index were calculated. Class combinations were reported, and associations between demographic characteristics and polypharmacy were determined. RESULTS: Mean age was 62.5 (± 14.6) years. In addition to post-traumatic stress disorder, 90.9% had a diagnosis of at least one other psychiatric condition, and 96.8% had a diagnosis of at least one non-psychiatric medical condition. The prevalence of general polypharmacy was 76.7%, psychotropic polypharmacy was 79.9% and sedative polypharmacy was 75.3%. Drug Burden Index scores ranged from 0 to 8.2, with 66.2% of participants scoring ≥ 1. CONCLUSIONS: This cohort of inpatient veterans with post-traumatic stress disorder had a high prevalence of general, psychotropic and sedative polypharmacy, and were at high risk for drug-related adverse events. This highlights the importance of increasing awareness of polypharmacy and potentially inappropriate drug combinations, and the need for improved medication review by prescribers.

Keeping military in mind: The Royal Australian & New Zealand College of Psychiatrists' Military and Veterans' Mental Health Network.

OBJECTIVE: The objective of this study is to introduce The Royal Australian & New Zealand College of Psychiatrists (RANZCP) Military and Veterans' Mental Health Network (The Network) and profile its inaugural members. METHODS: We implemented an online survey of demographic, professional and practice characteristics of network members; self-rated knowledge of military and veterans' mental health; reasons for joining The Network; and suggestions as to how The Network could best support members' needs. Quantitative survey responses were analysed descriptively. Qualitative responses were analysed thematically. RESULTS: Thirty-two out of 60 network members returned the survey. The membership was predominately male and 50 years of age or older. One-half had completed their fellowship or specialty 20 or more years ago. A high level of self-rated knowledge with respect to the assessment and management of current and ex-serving military personnel was reported. Knowledge of the assessment and management of current and ex-serving emergency services personnel was lower. CONCLUSION: There are RANZCP members with an active interest, expertise and knowledge in the field of military, veterans' and emergency services personnel mental health; this affirms the significant role the RANZCP can play in this area. There is a need to expand, diversify and ensure sustainability of the workforce.

Increased risk of attempted suicide in Australian veterans is associated with total and permanent incapacitation, unemployment and posttraumatic stress disorder severity.

BACKGROUND: Military veterans have higher rates of suicidality and completed suicides compared to the general population. Previous research has demonstrated suicidal behaviour is higher in US combat veterans who are younger, suffer from posttraumatic stress disorder, depression and anxiety and score lower on measures of health. However, research on predictors of suicide for Australian veterans is limited. The aim of this study was to identify significant demographic and psychological differences between veterans with posttraumatic stress disorder who had attempted suicide and those with posttraumatic stress disorder who had not, as well as determine predictors of suicide attempts within an Australian cohort. METHODS: A retrospective analysis was conducted on 229 ex-service personnel diagnosed with posttraumatic stress disorder who had attended a Military Service Trauma Recovery Day Program as outpatients at Toowong Private Hospital from 2007 to 2014. Patients completed a battery of mental health self-report questionnaires assessing symptoms of posttraumatic stress disorder, alcohol use, anger, depression, anxiety and quality of life. Demographic information and self-reported history of suicide attempts were also recorded. RESULTS: Results indicated the average age was significantly lower, and the rates of posttraumatic stress disorder, anger, anxiety and depression symptoms were significantly higher in those veterans with history of a suicide attempt. Multivariate logistic regression analyses indicated posttraumatic stress disorder symptom severity, unemployment or total and permanent incapacity pension status significantly predicted suicide attempt history. CONCLUSION: Among a cohort of Australian veterans with posttraumatic stress disorder, psychopathology severity, unemployment and total and permanent incapacity status are significantly associated with suicidality. This study highlights the importance of early identification of posttraumatic stress disorder and psychopathology, therapeutic and social engagement, and prioritisation of tangible employment options or meaningful and goal-directed activities for veterans deemed unable to work.

Regulation of the ubiquitylation and deubiquitylation of CREB-binding protein modulates histone acetylation and lung inflammation.

Cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-binding protein (CBP) is a histone acetyltransferase that plays a pivotal role in the control of histone modification and the expression of cytokine-encoding genes in inflammatory diseases, including sepsis and lung injury. We found that the E3 ubiquitin ligase subunit FBXL19 targeted CBP for site-specific ubiquitylation and proteasomal degradation. The ubiquitylation-dependent degradation of CBP reduced the extent of lipopolysaccharide (LPS)-dependent histone acetylation and cytokine release in mouse lung epithelial cells and in a mouse model of sepsis. Furthermore, we demonstrated that the deubiquitylating enzyme USP14 (ubiquitin-specific peptidase 14) stabilized CBP by reducing its ubiquitylation. LPS increased the stability of CBP by reducing the association between CBP and FBXL19 and by activating USP14. Inhibition of USP14 reduced CBP protein abundance and attenuated LPS-stimulated histone acetylation and cytokine release. Together, our findings delineate the molecular mechanisms through which CBP stability is regulated by FBXL19 and USP14, which results in the modulation of chromatin remodeling and the expression of cytokine-encoding genes.

Serum starvation regulates E-cadherin upregulation via activation of c-Src in non-small-cell lung cancer A549 cells.

E-cadherin is essential for the integrity of adherens junctions between lung epithelial cells, and the loss of E-cadherin allows cell motility and is thought to promote lung cancer metastasis. While the downregulation of E-cadherin expression has been well characterized and is seen with transforming growth factor-ß1 (TGF-ß1) exposure, few studies have focused on E-cadherin upregulation. Here, we show that serum starvation causes increased E-cadherin expression via the activation of c-Src kinase in non-small-cell lung cancer A549 cells. Serum starvation increased E-cadherin protein levels in a time- and dose-dependent manner. E-cadherin mRNA transcripts were unchanged with starvation, while protein translation inhibition with cycloheximide attenuated E-cadherin protein induction by starvation, suggesting that E-cadherin is regulated at the translational level by serum starvation. c-Src is a nonreceptor tyrosine kinase known to regulate protein translation machinery; serum starvation caused early and sustained activation of c-Src in A549 cells followed by E-cadherin upregulation. Furthermore, overexpression of a dominant negative c-Src attenuated the induction of E-cadherin by serum deprivation. Finally, we observed that TGF-ß1 treatment attenuated the serum activation of c-Src as well as E-cadherin expression when cells were deprived of serum. In conclusion, our data demonstrate that the c-Src kinase is activated by serum starvation to increase E-cadherin expression in A549 cells, and these phenomena are antagonized by TGF-ß1. These novel observations implicate the c-Src kinase as an upstream inducer of E-cadherin protein translation with serum starvation and TGF-ß1 diametrically regulating c-Src kinase activity and thus E-cadherin abundance in A549 cells.

F-box protein complex FBXL19 regulates TGFß1-induced E-cadherin down-regulation by mediating Rac3 ubiquitination and degradation.

BACKGROUND: Rac3 is a small GTPase multifunctional protein that regulates cell adhesion, migration, and differentiation. It has been considered as an oncogene in breast cancer; however, its role in esophageal cancer and the regulation of its stability have not been studied. F-box proteins are major subunits within the Skp1-Cullin-1-F-box (SCF) E3 ubiquitin ligases that recognize particular substrates for ubiquitination and proteasomal degradation. Recently, we have shown that SCFFBXL19 targets Rac1 and RhoA, thus regulating Rac1 and RhoA ubiquitination and degradation. Here, we demonstrate the role of FBXL19 in the regulation of Rac3 site-specific ubiquitination and stability. Expression of TGFß1 is associated with poor prognosis of esophageal cancer. TGFß1 reduces tumor suppressor, E-cadherin, expression in various epithelial-derived cancers. Here we investigate the role of FBXL19-mediated Rac3 degradation in TGFß1-induced E-cadherin down-regulation in esophageal cancer cells. METHODS: FBXL19-regulated endogenous and over-expressed Rac3 stability were determined by immunoblotting and co-immunoprecipitation. Esophageal cancer cells (OE19 and OE33) were used to investigate TGFß1-induced E-cadherin down-regulation by Immunoblotting and Immunostaining. RESULTS: Overexpression of FBXL19 decreased endogenous and over-expressed Rac3 expression by interacting and polyubiquitinating Rac3, while down-regulation of FBXL19 suppressed Rac3 degradation. Lysine166 within Rac3 was identified as an ubiquitination acceptor site. The FBXL19 variant with truncation at the N-terminus resulted in an increase in Rac3 degradation; however, the FBXL19 variant with truncation at the C-terminus lost its ability to interact with Rac3 and ubiquitinate Rac3 protein. Further, we found that Rac3 plays a critical role in TGFß1-induced E-cadherin down-regulation in esophageal cancer cells. Over-expression of FBXL19 attenuated TGFß1-induced E-cadherin down-regulation and esophageal cancer cells elongation phenotype. CONCLUSIONS: Collectively these data unveil that FBXL19 functions as an antagonist of Rac3 by regulating its stability and regulates the TGFß1-induced E-cadherin down-regulation. This study will provide a new potential therapeutic strategy to regulate TGFß1 signaling, thus suppressing esophageal tumorigenesis.

A new mechanism of RhoA ubiquitination and degradation: roles of SCF(FBXL19) E3 ligase and Erk2.

RhoA is a small GTPase multifunctional protein that regulates cell proliferation and cytoskeletal reorganization. Regulation of its protein stability plays an important role in its biological functions. We have shown that a Skp1-Cul1-F-box (SCF) FBXL19 E3 ubiquitin ligase targets Rac1, a related member of the Rho family for ubiquitination and degradation. Here, SCF(FBXL19) mediates RhoA ubiquitination and proteasomal degradation in lung epithelial cells. Ectopically expressed FBXL19 decreased RhoA wild type, active, and inactive forms. Cellular depletion of FBXL19 increased RhoA protein levels and extended its half-life. FBXL19 bound the small GTPase in the cytoplasm leading to RhoA ubiquitination at Lys(135). A RhoA(K135R) mutant protein was resistant to SCF(FBXL19)-mediated ubiquitination and degradation and exhibited a longer lifespan. Protein kinase Erk2-mediated phosphorylation of RhoA was both sufficient and required for SCF(FBXL19)-mediated RhoA ubiquitination and degradation. Thus, SCF(FBXL19) targets RhoA for its disposal, a process regulated by Erk2. Ectopically expressed FBXL19 reduced phosphorylation of p27 and cell proliferation, a process mediated by RhoA. Further, FBXL19 cellular expression diminished lysophosphatidic acid (LPA)-induced phosphorylation of myosin light chain (MLC) and stress fiber formation. Hence, SCF(FBXL19) functions as a RhoA antagonist during cell proliferation and cytoskeleton rearrangement. These results provide the first evidence of an F-box protein targeting RhoA thereby modulating its cellular lifespan that impacts cell proliferation and cytoskeleton rearrangement.

Group cognitive behaviour therapy for military service-related post-traumatic stress disorder: effectiveness, sustainability and repeatability.

OBJECTIVE: The aim of this study was to assess 12 month outcomes of Australian combat veterans with post-traumatic stress disorder (PTSD) who participated in a 6 week group-based CBT programme at the Toowong Private Hospital. The study population included 496 consecutive admissions to the programme between 1999 and 2008. METHOD: Self-report measures of PTSD, depression, anxiety, anger, alcohol use, relationship satisfaction and quality of life parameters were collected at intake and 3, 6 and 12 months post intake. RESULTS: Statistically significant and sustained improvements were noted in 12 month outcome measures for PTSD, depression, anxiety, alcohol use, anger, and quality of life. PTSD symptom reduction occurred consistently each year for 9 years and exhibited an aggregated effect size of 0.68. CONCLUSIONS: This naturalistic research demonstrates that treatment administered under clinical conditions produces equivocal magnitudes of positive change in terms of PTSD symptoms when compared with existing efficacy data in individual and group treatments. Further, these symptomatic gains are sustainable and consistently reproducible. The benefits noted from group therapy were seen as independent of whether or not individual treatment was in place.