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Stephen P Myers,1 Ann M Mulder,1 Don G Baker,1 Shelley R Robinson,1 Margaret I Rolfe,2 Lyndon Brooks,1 J Helen Fitton,3 1NatMed-Research Unit, Southern Cross University, 2University Centre for Rural Health, Sydney School of Public Health, The University of Sydney, Lismore, NSW, 3Marinova Pty Ltd, Cambridge, TAS, Australia Purpose: Preliminary investigation of a fucoidan with demonstrated reduction in the symptoms of osteoarthritis (OA) of the hip and knee. Patients and methods: A double-blind randomized controlled trial was carried out to determine the safety and efficacy of a 300 mg dose of a Fucus vesiculosus extract (85% fucoidan) over a 12-week period in a population (n=122) with mild-to-moderate OA of the hip and knee as measured by the validated instrument "Comprehensive Osteoarthritis Test." Safety was measured by assessing cholesterol, liver function, renal function, and hematopoietic function, and closely monitoring adverse events. Result: Ninety-six participants completed the study. The reduction in symptoms of OA was not significantly different from the placebo response. There were no changes in the blood measurements that were of any clinical significance during the course of the study. Conclusion: The F. vesiculosus fucoidan extract was safe and well tolerated. At a dose of 300 mg, the extract showed no difference in reduction of OA symptoms from the placebo. Keywords: joint pain, clinical trial, seaweed, polysaccharide

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

Background: Pervasive use of improvised explosive devices (IEDs), rocket-propelled grenades, and land mines in the recent conflicts in Iraq and Afghanistan has brought traumatic brain injury (TBI) and its impact on health outcomes into public awareness. Blast injuries have been deemed signature wounds of these wars. War-related TBI is not new, having become prevalent during WWI and remaining medically relevant in WWII and beyond. Medicine's past attempts to accurately diagnose and disentangle the pathophysiology of war-related TBI parallels current lines of inquiry and highlights limitations in methodology and attribution of symptom etiology, be it organic, psychological, or behavioral. New approaches and biomarkers are needed. Preclinical: Serological biomarkers and biomarkers of injury obtained with imaging techniques represent cornerstones in the translation between experimental data and clinical observations. Experimental models for blast related TBI and PTSD can generate critical data on injury threshold, for example for white matter injury from acceleration. Carefully verified and validated models can be evaluated with gene expression arrays and proteomics to identify new candidates for serological biomarkers. Such models can also be analyzed with diffusion MRI and microscopy in order to identify criteria for detection of diffuse white matter injuries, such as DAI (diffuse axonal injury). The experimental models can also be analyzed with focus on injury outcome in brain stem regions, such as locus coeruleus or nucleus raphe magnus that can be involved in response to anxiety changes. Clinical: Mild (and some moderate) TBI can be difficult to diagnose because the injuries are often not detectable on conventional MRI or CT. There is accumulating evidence that injured brain tissues in TBI patients generate abnormal low-frequency magnetic activity (ALFMA, peaked at 1-4 Hz) that can be measured and localized by magnetoencephalography (MEG). MEG imaging detects TBI abnormalities at the rates of 87% for the mild TBI, group (blast-induced plus non-blast causes) and 100% for the moderate group. Among the mild TBI patients, the rates of abnormalities are 96% and 77% for the blast and non-blast TBI groups, respectively. There is emerging evidence based on fMRI and MEG studies showing hyper-activity in the amygdala and hypo-activity in pre-frontal cortex in individuals with PTSD. MEG signal may serve as a sensitive imaging marker for mTBI, distinguishable from abnormalities generated in association with PTSD. More work is needed to fully describe physiological mechanisms of post-concussive symptoms.

The molecular factors involved in the development of Post-Traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD.

BackgroundPosttraumatic Stress Disorder (PTSD) is a major public health concern, especially given the recent wars in Iraq and Afghanistan. Nevertheless, despite a sharp increase in the incidence of psychiatric disorders in returning veterans, empirically based prevention strategies are still lacking. To develop effective prevention and treatment strategies, it is necessary to understand the underlying biological mechanisms contributing to PTSD and other trauma related symptoms.MethodsThe "Marine Resiliency Study II" (MRS-II; October 2011-October 2013) Neurocognition project is an investigation of neurocognitive performance in Marines about to be deployed to Afghanistan. As part of this investigation, 1195 Marines and Navy corpsmen underwent a fear conditioning and extinction paradigm and psychiatric symptom assessment prior to deployment. The current study assesses (1) the effectiveness of the fear potentiated startle paradigm in producing fear learning and extinction and (2) the association of performance in the paradigm with baseline psychiatric symptom classes (healthy: n=923, PTSD symptoms: n=42, anxiety symptoms: n=37, and depression symptoms: n=12).ResultsResults suggest that the task was effective in producing differential fear learning and fear extinction in this cohort. Further, distinct patterns emerged differentiating the PTSD and anxiety symptom classes from both healthy and depression classes. During fear acquisition, the PTSD symptom group was the only group to show deficient discrimination between the conditioned stimulus (CS+) and safety cue (CS-), exhibiting larger startle responses during the safety cue compared to the healthy group. During extinction learning, the PTSD symptom group showed significantly less reduction in their CS+ responding over time compared to the healthy group, as well as reduced extinction of self-reported anxiety to the CS+ by the end of the extinction session. Conversely, the anxiety symptom group showed normal safety signal discrimination and extinction of conditioned fear, but exhibited increased baseline startle reactivity and potentiated startle to CS+, as well as higher self-reported anxiety to both cues. The depression symptom group showed similar physiological and self-report measures as the healthy group.DiscussionThese data are consistent with the idea that safety signal discrimination is a relatively specific marker of PTSD symptoms compared to general anxiety and depression symptoms. Further research is needed to determine if deficits in fear inhibition vs. exaggerated fear responding are separate biological "domains" across anxiety disorders that may predict differential biological mechanisms and possibly treatment needs. Future longitudinal analyses will examine whether poor learning of safety signals provides a marker of vulnerability to develop PTSD or is specific to symptom state.

Leptin (OB protein) is an important signal in the regulation of energy balance. Leptin levels correlate with adiposity, but also decrease acutely with caloric restriction and increase with refeeding. The brain is an established critical site of leptin function, yet little is known about leptin concentrations in the central nervous system relative to plasma levels, psychiatric diagnoses, and other endocrine parameters. Therefore, using a novel ultrasensitive leptin assay, we explored relationships of human plasma and cerebrospinal fluid (CSF) leptin levels to body mass index, smoking, posttraumatic stress disorder diagnosis, and levels of dopamine, monoamine metabolites, beta-lipotropin, glucocorticoid, and thyroid and cytokine hormones. A strong linear relation between CSF and plasma leptin levels in the am (r = 0.63; P < 0.002) and afternoon (r = 0.90; P < 0.0001) was revealed. CSF and plasma leptin concentrations decreased during a 12- to 20-h period of fasting. A strong association was found between plasma leptin and CSF dopamine levels (r = 0.74; P < 0.01) as well as between CSF leptin levels and urinary free cortisol (r = 0.73; P < 0.01). Both of these parameters covaried with leptin independently of adiposity, as estimated by body mass index. Implications for leptin transport, regulation, and its potential role in therapeutic strategies for obesity and diabetes are discussed.

To date, little study has been performed to determine the importance of upper-body strength-endurance (S-E) to success in rugby league football. Furthermore, debate exists as to which type of S-E testing, absolute resistance or relative percent S-E testing, where performance is gauged with an absolute resistance in kilograms or with a set percentage of 1 repetition maximum (1RM), respectively, would garner more informative results. To this end, 3 different methods of assessing S-E (1 relative and 2 absolute S-E) were investigated to determine their effectiveness and validity for distinguishing between rugby league players of different ranking. In study 1, 26 players of similar strength, but different playing ranking, performed a bench press test with a resistance of 60% of their 1RM to determine if any differences existed between the groups in how many repetitions could be completed with the same relative percentage resistance. The fact that no significant difference existed between the groups in repetitions performed indicated that this test of relative S-E did not differentiate playing rank in rugby league. In study 2, 38 subjects performed tests with absolute resistances of 60 and 102.5 kg (bench press repetitions-to-fatigue (BP RTF) 60 and 102.5, respectively) in an effort to determine the merits of absolute S-E testing. Both tests significantly differentiated playing rank, but on the basis of how many repetitions were performed, only the BP RTF 60 could be considered a valid test of S-E. Absolute S-E testing with a moderate resistance of 60 kg appears to be a valid and effective test for discriminating playing rank in rugby league players. [ABSTRACT FROM AUTHOR]

Significant mental health symptoms are reported in troops deployed to Iraq and Afghanistan (OEF/OIF). Symptomatic troops are more likely to be discharged and become eligible for Department of Veterans Affairs (DVA) care. Prevalence and predictors of mental health symptoms were assessed in 339 OEF/OIF veterans and reservists registering at the San Diego DVA. Participants completed self-report questionnaires assessing combat exposure, posttraumatic stress disorder (PTSD) symptom frequency and severity, depression, and substance and alcohol abuse. A minority of participants (36%) did not screen positive for mental health symptoms; the remainder met threshold for caseness of PTSD, depression, or substance and alcohol abuse. Using a hierarchical logistic regression model, gender, age, race, and rank were not significantly related to PTSD caseness, whereas most recent branch of service and report of injury during combat were. Follow-up analyses revealed that trauma history and combat exposure varied by branch of service. Knowledge of base rates and vulnerability factors can aid in rapid detection of "at risk" individuals. [ABSTRACT FROM AUTHOR]

Success in rugby league football seems heavily reliant on players possessing an adequate degree of various physical fitness qualities, such as strength, power, speed, agility, and endurance, as well as the individual skills and team tactical abilities. The purpose of this study was to describe and compare the lower body strength, power, acceleration, maximal speed, agility, and sprint momentum of elite first-division national rugby league (NRL) players (n = 20) to second-division state league (SRL) players (n = 20) players from the same club. Strength and maximal power were the best discriminators of which players were in the NRL or SRL squads. None of the sprinting tests, such as acceleration (10-m sprint), maximal speed (40-m sprint), or a unique 40-m agility test, could distinguish between the NRL or SRL squads. However, sprint momentum, which was a product of 10-m velocity and body mass, was better for discriminating between NRL and SRL players as heavier, faster players would possess better drive forward and conversely be better able to repel their opponents' drive forward. Strength and conditioning specialists should therefore pay particular attention to increasing lower body strength and power and total body mass through appropriate resistance training while maintaining or improving 10-m sprint speed to provide their players with the underlying performance characteristics of play at the elite level in rugby leagues. [ABSTRACT FROM AUTHOR]

Objective: The authors tested the hypothesis that concentrations of the pain-transmitting neuropeptide substance P are elevated in the CSF of patients with major depression or posttraumatic stress disorder (PTSD), which have overlapping symptoms. The authors also sought to determine if CNS substance P concentrations change on provocation of symptoms in PTSD patients.Method: The authors measured CSF substance P concentrations in medication-free patients with either major depression or PTSD and in healthy comparison subjects. Next, using a within-subject, crossover design, the authors sampled CSF for 6 hours through an indwelling subarachnoid catheter in PTSD patients before, during, and after exposure to a 60-minute traumatic or neutral videotape stimulus.Results: Both depressed and PTSD patients had significantly elevated basal CSF substance P concentrations. In the challenge study, marked increases in CSF substance P concentrations were found only after precipitation of PTSD symptoms. CSF substance P concentrations increased by 169% and 90.6% of baseline levels at 10 and 70 minutes, respectively, after the start of the traumatic videotape but changed by only 1.1% and -8.1% of baseline levels 10 and 70 minutes after the start of the neutral videotape.Conclusions: These results suggest that elevated CNS substance P concentrations are involved in both major depression and PTSD. The marked increase in CSF substance P concentrations during and after the symptom-provoking stimulus, but not after the neutral stimulus, implicates CNS release of substance P in the mechanism of acute PTSD symptoms. These data also reveal that CNS substance P responds acutely to psychological stress in humans. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) negatively impacts sexuality, yet few studies have evaluated which component of PTSD contributes to this known association. The present study examined which of four PTSD clusters (numbing, avoidance, intrusiveness, and hyperarousal) was most closely linked to sexual problems in a sample of 197 veterans from the Iraq or Afghanistan wars. Newly registered veterans completed a packet of questionnaires including standardized measures of PTSD and questions regarding sexual functioning. A stepwise logistic regression was performed to examine the relationship between symptom cluster and sexual functioning. As predicted, only the numbing cluster was retained in the regression model. The numbing cluster appears to be intimately tied to sexual functioning, assessment of which should be part of a comprehensive evaluation during the postdeployment readjustment phase. Those exhibiting numbing symptoms should be thoroughly assessed for sexual functioning problems and referred for treatment as necessary. [ABSTRACT FROM AUTHOR]

Limited research exists on the relationship between physical injury and PTSD within military populations. The present study assessed postinjury rates of PTSD and other psychological correlates among battle and non-battle injuries. A total of 1,968 men (831 battle injuries and 1,137 nonbattle injuries) injured between September 2004 and February 2005 during Operation Iraqi Freedom (OIF) composed the study sample. Patients were followed through November 2006 for mental health diagnosis (ICD-9 290-319). Compared with nonbattle injuries, those with battle injuries had a greater risk of PTSD and other mental health diagnosis, and there was a positive association with injury severity. Self-reported mental health symptoms were significantly higher for both minor and moderate-severe battle injury in comparison to nonbattle injury and previous population estimates from an earlier OIF period. More research is needed to further define this relationship by examining potential mechanisms and addressing the possible contributing effect of combat exposure. [ABSTRACT FROM AUTHOR]

Background: Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not., Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts., Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD., Conclusion: The inclusion of exposure variables adds to the predictive power of MRS. Classification-based MRS may be useful in predicting risk of future PTSD in populations with anticipated trauma exposure. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting PTSD and, relatedly, improve their performance in independent cohorts., (© 2024. The Author(s).)

Aims: Most lifetime mental health disorders begin by age 25 years, and the prevalence among young people has been increasing over recent years. We sought to understand what impact, if any, social determinants have had on this increase through the analysis of an Australian longitudinal dataset (with data from 2007 to 2021)., Methods: The analysis focused on five social determinants: loneliness and lack of social support, family relationships, participation in education and employment, receipt of government benefits and relative socio-economic status. We analysed cross-sectional changes in self-reported psychological distress between 2007 and 2021 (using the Kessler-10 item; K10 scores) and examined the effects of these five social determinants on psychological distress using weighted linear regression models., Results: We identified a significant increase in psychological distress among Australians from 2007 to 2021, with the sharpest rise among those aged 15 to 25 years, who saw more than doubling in the percentage of high and very high K10. This period also saw an increase in the prevalence of social determinants such as loneliness and lack of social support, as well as poor family relationships, particularly in 2021 post COVID-19 pandemic. Regression models suggest loneliness and lack of social support had the most pronounced and increasing impact on psychological distress, followed by poor family relationships., Discussion: The observed significant and steady increases in psychological distress and related social determinant factors, particularly loneliness and lack of social support among young people, highlight the urgent need for comprehensive actions. Coordinated research and community-based initiatives are needed to deliver intrapersonal, interpersonal and socially-focused interventions with a holistic approach to support psychosocial wellbeing. Policymakers must adopt a comprehensive shift in political commitment and a whole-of-government approach to address these challenges., Competing Interests: Conflict of interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: rygen is funded by the Australian Government Department of Health and Aged Care to provide technical advice and policy direction on a number of youth mental health topics, including social determinants. This is relevant for DB, RM and VB.

We are developing an economic model to explore multiple topics in Australian youth mental health policy. To help make that model more readily transferable to other jurisdictions, we developed a software framework for authoring modular computational health economic models (CHEMs) (the software files that implement health economic models). We specified framework user requirements for: a simple programming syntax; a template CHEM module; tools for authoring new CHEM modules; search tools for finding existing CHEM modules; tools for supplying CHEM modules with data; reproducible analysis and reporting tools; and tools to help maintain a CHEM project website. We implemented the framework as six development version code libraries in the programming language R that integrate with online services for software development and research data archiving. We used the framework to author five development version R libraries of CHEM modules focussed on utility mapping in youth mental health. These modules provide tools for variable validation, dataset description, multi-attribute instrument scoring, construction of mapping models, reporting of mapping studies and making out of sample predictions. We assessed these CHEM module libraries as mostly meeting transparency, reusability and updatability criteria that we have previously developed, but requiring more detailed documentation and unit testing of individual modules. Our software framework has potential value as a prototype for future tools to support the development of transferable CHEMs.Code: Visit https://www.ready4-dev.com for more information about how to find, install and apply the prototype software framework., (© 2024. The Author(s).)

CD4 + T cells recognising citrullinated self-epitopes presented by HLA-DRB1 bearing the shared susceptibility epitope (SE) are implicated in rheumatoid arthritis (RA). However, the underlying T cell receptor (TCR) determinants of epitope specificity towards distinct citrullinated peptide antigens, including vimentin-64cit 59-71 and α-enolase-15cit 10-22 remain unclear. Using HLA-DR4-tetramers, we examine the T cell repertoire in HLA-DR4 transgenic mice and observe biased TRAV6 TCR gene usage across these two citrullinated epitopes which matches with TCR bias previously observed towards the fibrinogen β-74cit 69-81 epitope. Moreover, shared TRAV26-1 gene usage is evident in four α-enolase-15cit 10-22 reactive T cells in three human samples. Crystal structures of mouse TRAV6 + and human TRAV26-1 + TCR-HLA-DR4 complexes presenting vimentin-64cit 59-71 and α-enolase-15cit 10-22 , respectively, show three-way interactions between the TCR, SE, citrulline, and the basis for the biased selection of TRAV genes. Position 2 of the citrullinated epitope is a key determinant underpinning TCR specificity. Accordingly, we provide a molecular basis of TCR specificity towards citrullinated epitopes., (© 2024. The Author(s).)