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Despite the frequency that refugees suffer bereavement, there is a dearth of research into the prevalence and predictors of problematic grief reactions in refugees. To address this gap, this study reports a nationally representative population-based study of refugees to determine the prevalence of probable prolonged grief disorder (PGD) and its associated problems.
This study recruited participants from the Building a New Life in Australia (BNLA) prospective cohort study of refugees admitted to Australia between October 2013 and February 2014. The current data were collected in 2015–2016, and comprised 1767 adults, as well as 411 children of the adult respondents. Adult refugees were assessed for trauma history, post-migration difficulties, probable PGD, post-traumatic stress disorder (PTSD) and mental illness. Children were administered the Strengths and Difficulties Questionnaire.
In this cohort, 38.1% of refugees reported bereavement, of whom 15.8% reported probable PGD; this represents 6.0% of the entire cohort. Probable PGD was associated with a greater likelihood of mental illness, probable PTSD, severe mental illness, currently unemployed and reported disability. Children of refugees with probable PGD reported more psychological difficulties than those whose parents did not have probable PGD. Probable PGD was also associated with the history of imprisonment, torture and separation from family. Only 56.3% of refugees with probable PGD had received psychological assistance.
Bereavement and probable PGD appear highly prevalent in refugees, and PGD seems to be associated with disability in the refugees and psychological problems in their children. The low rate of access to mental health assistance for these refugees highlights that there is a need to address this issue in refugee populations.
The mental health and social functioning of millions of forcibly displaced individuals worldwide represents a key public health priority for host governments. This is the first longitudinal study with a representative sample to examine the impact of interpersonal trust and psychological symptoms on community engagement in refugees.
Participants were 1894 resettled refugees, assessed within 6 months of receiving a permanent visa in Australia, and again 2–3 years later. Variables measured included post-traumatic stress disorder symptoms, depression/anxiety symptoms, interpersonal trust and engagement with refugees’ own and other communities.
A multilevel path analysis was conducted, with the final model evidencing good fit (Comparative Fit Index = 0.97, Tucker–Lewis Index = 0.89, Root Mean Square Error of Approximation = 0.05, Standardized Root-Mean-Square-Residual = 0.05). Findings revealed that high levels of depression symptoms were associated with lower subsequent engagement with refugees’ own communities. In contrast, low levels of interpersonal trust were associated with lower engagement with the host community over the same timeframe.
Findings point to differential pathways to social engagement in the medium-term post-resettlement. Results indicate that depression symptoms are linked to reduced engagement with one's own community, while interpersonal trust is implicated in engagement with the broader community in the host country. These findings have potentially important implications for policy and clinical practice, suggesting that clinical and support services should target psychological symptoms and interpersonal processes when fostering positive adaptation in resettled refugees.
The mental health outcomes of military personnel deployed on peacekeeping
missions have been relatively neglected in the military mental health
To assess the mental health impacts of peacekeeping deployments.
In total, 1025 Australian peacekeepers were assessed for current and
lifetime psychiatric diagnoses, service history and exposure to
potentially traumatic events (PTEs). A matched Australian community
sample was used as a comparator. Univariate and regression analyses were
conducted to explore predictors of psychiatric diagnosis.
Peacekeepers had significantly higher 12-month prevalence of
post-traumatic stress disorder (16.8%), major depressive episode (7%),
generalised anxiety disorder (4.7%), alcohol misuse (12%), alcohol
dependence (11.3%) and suicidal ideation (10.7%) when compared with the
civilian comparator. The presence of these psychiatric disorders was most
strongly and consistently associated with exposure to PTEs.
Veteran peacekeepers had significant levels of psychiatric morbidity.
Their needs, alongside those of combat veterans, should be recognised
within military mental health initiatives.
Prolonged separation from parental support is a risk factor for psychopathology. This study assessed the impact of brief separation from parents during childhood trauma on adult attachment tendencies and post-traumatic stress.
Children (n = 806) exposed to a major Australian bushfire disaster in 1983 and matched controls (n = 725) were assessed in the aftermath of the fires (mean age 7–8 years) via parent reports of trauma exposure and separation from parents during the fires. Participants (n = 500) were subsequently assessed 28 years after initial assessment on the Experiences in Close Relationships scale to assess attachment security, and post-traumatic stress disorder (PTSD) was assessed using the PTSD checklist.
Being separated from parents was significantly related to having an avoidant attachment style as an adult (B = −3.69, s.e. = 1.48, β = −0.23, p = 0.013). Avoidant attachment was associated with re-experiencing (B = 0.03, s.e. = 0.01, β = 0.31, p = 0.045), avoidance (B = 0.03, s.e. = 0.01, β = 0.30, p = 0.001) and numbing (B = 0.03, s.e. = 0.01, β = 0.30, p < 0.001) symptoms. Anxious attachment was associated with re-experiencing (B = 0.03, s.e. = 0.01, β = 0.18, p = 0.001), numbing (B = 0.03, β = 0.30, s.e. = 0.01, p < 0.001) and arousal (B = 0.04, s.e. = 0.01, β = 0.43, p < 0.001) symptoms.
These findings demonstrate that brief separation from attachments during childhood trauma can have long-lasting effects on one's attachment security, and that this can be associated with adult post-traumatic psychopathology.
Glioblastoma (GBM) is an aggressive brain tumor that is resistant to conventional radiation and cytotoxic chemotherapies. We hypothesize that brain tumor initiating cells (BTICs), a subpopulation of treatment-resistant cells with stem cell properties cause tumor relapse and a subset of neural stem cell genes regulate BTIC self-renewal, driving GBM recurrence. We adapted the existing treatment protocol for adults with primary GBM for in vivo treatment of immunocompromised mice engrafted with GBMs. Post-chemoradiotherapy, the recovered GFP+GBMs were profiled for self-renewal and expression of critical stem cell genes. Using invitro and invivo gain-of-function/loss-of-function experiments, we investigated the regulatory functions of Bmi1 in primary neural stem & progenitor cells (NSPCs) and GBM tumor formation. Finally, global RNA-Seq profiling was performed to understand the consequences of Bmi1 dysregulation on target gene expression. GBM cells showed an increase in Bmi1 levels post-chemoradiotherapy, suggesting the presence of a treatment-refractory BTICs. GFP+cells extracted from treated xenografts had higher self-renewal and BTIC marker expression. Although treated mice responded to therapy, we observed tumor relapse with increased Bmi1 expression. Knockdown of Bmi1 diminished self-renewal and proliferation of GBM cells and delayed tumorigenesis, highlighting a critical role for Bmi1 in tumor maintenance. Conversely, over-expressing Bmi1 in NSPCs failed to initiate tumor formation in vivo. Using high-throughput sequencing data, we generated a map of signaling pathways dysregulated in GBM that may lead to tumor recurrence. Our data confirms the existence of a rare treatment-refractory BTIC population with enhanced self-renewal capacity that escapes therapy and drives tumor relapse.
Medulloblastoma (MB) is the most common malignant pediatric brain tumour, and is categorized into four molecular subgroups, with Group 3 MB having the worst prognosis due to the highest rate of metastatic dissemination and relapse. In this work, we describe the epigenetic regulator Bmi1 as a novel therapeutic target for treatment of recurrent Group 3 MB. Through comparative profiling of primary and recurrent MB, we show that Bmi1 defines a treatment-refractory cell population that is uniquely targetable by a novel class of small molecule inhibitors. We have optimized an in vivo mouse-adapted therapy model that has the advantage of generating recurrent, human, treatment-refractory MBs. Our preliminary studies showed that although chemoradiotherapy administered to mice engrafted with human MB showed reduction in tumour size, Bmi1 expression was enriched in the post-treatment residual tumour. Furthermore, we found that knockdown of Bmi1 in human recurrent MB cells decreases proliferation and self-renewing capacities of MB cells in vitro as well as both tumour size and extent of spinal leptomeningeal metastases in vivo. Oral administration of a potent Bmi1 inhibitor, PTC 028, resulted in a marked reduction in tumour burden and an increased survival in treatment cohort. Bmi1 inhibitors showed high specificity for MB cells and spared normal human neural stem cells, when treated with doses relevant for MB cells. As Group 3 medulloblastoma is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious agent such as Bmi1 inhibitor could be rapidly transitioned to clinical trials.
Despite aggressive multimodal therapy, human glioblastoma (hGBM), a highly malignant grade IV astrocytic tumour, remains incurable and inevitably relapses. Recent data has implicated intratumoral heterogeneity as the driver of therapy resistance and tumour relapse in hGBM. Thus models that capture the evolving hGBM biology in response to chemoradiotherapy will allow for the identification of cellular pathways that govern GBM therapy failure. In this study, we have developed a novel model to profile the clonal evolution of treatment naïve brain tumour initiating cell (BTIC) enriched hGBMs through chemoradiotherapy using: stem cell assays, BTIC marker expression and transcriptome analysis, immunohistochemistry, and cellular DNA barcoding technology. We report that treatment of hGBM BTICs leads to increased self-renewal capacity and higher transcript expression of stem cell genes Bmi1 and Sox2. Based on global transcriptome analysis of the in vitro treated hGBM, we also identify a hyper-aggressive form of glioma. Using our therapy-adapted hGBM-mouse xenograft model, we discover that despite tumour regression and increased mouse survival post-therapy, tumour relapse remains inevitable. The treatment-refractory cells again have increased self-renewal capacity and higher expression of Bmi1 and Sox2. Furthermore, by combining cellular DNA barcoding technology, which barcodes hGBM at single cell resolution, with our novel in vitro and in vivo therapy models, we are able to determine whether a pre-existing or a therapy driven subpopulation(s) seeds hGBM tumour relapse. Profiling the dynamic nature of heterogeneous hGBM subpopulations through disease progression and treatment may lead to the identification of novel therapeutic targets for the treatment of recurrent hGBM.
Medulloblastoma (MB), the most common malignant pediatric brain tumor, is categorized into four molecular subgroups. Given the high rate of metastatic dissemination at diagnosis and recurrence in Group 3 MBs, these patients have the worst clinical outcome with a 5-year survivorship of approximately 50%. By adapting the existing COG (Children’s Oncology Group) Protocol for children with newly diagnosed high-risk MB, for treatment of immuno-deficient mice intracranially engrafted with human MB brain tumour initiating cells we aim to identify and characterize the treatment-refractory cell population in Group 3 MBs. Mice were sacrificed at multiple time points during the course of tumor development and therapy: (i) at engraftment; (ii) post-radiation; (iii) post-radiation and chemotherapy; and (iv) at MB recurrence. MB cell populations recovered separately from brains and spines were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy. We report a higher expression of CD133, Sox2 and Bmi1 in addition to increased self-renewal capacity following chemoradiotherapy treatment. The enrichment map constructed from global gene expression analysis showed an increase in pathways regulating self-renewal, DNA repair and chemoresistance post-therapy despite the apparent decrease in tumour size and vascularity. Additionally, from gene expression at MB recurrence, we identified a list of genes that negatively correlate with survival in patients diagnosed with Group 3 MB. A differential genomic profile of the “treatment-responsive” tumors against those that fail therapy may contribute to discovery of novel therapeutic approaches for the most aggressive subgroup of MB.
Brain Metastases (BM) represent a leading cause of cancer mortality. While metastatic lesions contain subclones derived from their primary lesion, their functional characterization has been limited by a paucity of preclinical models accurately recapitulating the stages of metastasis. This work describes the isolation of a unique subset of metastatic stem-like cells from primary human patient samples of BM, termed brain metastasis initiating cells (BMICs). Utilizing these BMICs we have established a novel patient-derived xenograft (PDX) model of BM that recapitulates the entire metastatic cascade, from primary tumor initiation to micro-metastasis and macro-metastasis formation in the brain. We then comprehensively interrogated human BM to identify genetic regulators of BMICs using in vitro and in vivo RNA interference screens, and validated hits using both our novel PDX model as well as primary clinical BM specimens. We identified SPOCK1 and TWIST2 as novel BMIC regulators, where in our model SPOCK1 regulated BMIC self-renewal and tumor initiation, and TWIST2 specifically regulated cell migration from lung to brain. A prospective cohort of primary lung cancer specimens was used to establish that SPOCK1 and TWIST2 were only expressed in patients who ultimately developed BM, thus establishing both clinical and functional utility for these gene products. This work offers the first comprehensive preclinical model of human brain metastasis for further characterization of therapeutic targets, identification of predictive biomarkers, and subsequent prophylactic treatment of patients most likely to develop BM. By blocking this process, metastatic lung cancer would effectively become a localized, more manageable disease.
Although perceived social support is thought to be a strong predictor of psychological outcomes following trauma exposure, the temporal relationship between perceived positive and negative social support and post-traumatic stress disorder (PTSD) symptoms has not been empirically established. This study investigated the temporal sequencing of perceived positive social support, perceived negative social support, and PTSD symptoms in the 6 years following trauma exposure among survivors of traumatic injury.
Participants were 1132 trauma survivors initially assessed upon admission to one of four Level 1 trauma hospitals in Australia after experiencing a traumatic injury. Participants were followed up at 3 months, 12 months, 24 months, and 6 years after the traumatic event.
Latent difference score analyses revealed that greater severity of PTSD symptoms predicted subsequent increases in perceived negative social support at each time-point. Greater severity of PTSD symptoms predicted subsequent decreases in perceived positive social support between 3 and 12 months. High levels of perceived positive or negative social support did not predict subsequent changes in PTSD symptoms at any time-point.
Results highlight the impact of PTSD symptoms on subsequent perceived social support, regardless of the type of support provided. The finding that perceived social support does not influence subsequent PTSD symptoms is novel, and indicates that the relationship between PTSD and perceived social support may be unidirectional.
Traumatic injuries affect millions of patients each year, and resulting post-traumatic stress disorder (PTSD) significantly contributes to subsequent impairment.
To map the distinctive long-term trajectories of PTSD responses over 6 years by using latent growth mixture modelling.
Randomly selected injury patients (n = 1084) admitted to four hospitals around Australia were assessed in hospital, and at 3, 12, 24 and 72 months. Lifetime psychiatric history and current PTSD severity and functioning were assessed.
Five trajectories of PTSD response were noted across the 6 years: (a) chronic (4%), (b) recovery (6%), (c) worsening/recovery (8%), (d) worsening (10%) and (e) resilient (73%). A poorer trajectory was predicted by female gender, recent life stressors, presence of mild traumatic brain injury and admission to intensive care unit.
These findings demonstrate the long-term PTSD effects that can occur following traumatic injury. The different trajectories highlight that monitoring a subset of patients over time is probably a more accurate means of identifying PTSD rather than relying on factors that can be assessed during hospital admission.
The latent structure of the proposed ICD-11 post-traumatic stress
disorder (PTSD) symptoms has not been explored.
To investigate the latent structure of the proposed ICD-11 PTSD
Confirmatory factor analyses using data from structured clinical
interviews administered to injury patients (n = 613) 6
years post-trauma. Measures of disability and psychological quality of
life (QoL) were also administered.
Although the three-factor model implied by the ICD-11 diagnostic criteria
fit the data well, a two-factor model provided equivalent, if not
superior, fit. Whereas diagnostic criteria based on this two-factor model
resulted in an increase in PTSD point prevalence (5.1%
v. 3.4%; z = 2.32,
P<0.05), they identified individuals with similar
levels of disability (P = 0.933) and QoL
(P = 0.591) to those identified by the ICD-11
Consistent with theorised reciprocal relationships between
re-experiencing and avoidance in PTSD, these findings support an
alternative diagnostic algorithm requiring at least two of any of the
four re-experiencing/avoidance symptoms and at least one of the two
There have been changes to the criteria for diagnosing post-traumatic
stress disorder (PTSD) in DSM-5 and changes are proposed for ICD-11.
To investigate the impact of the changes to diagnostic criteria for PTSD
in DSM-5 and the proposed changes in ICD-11 using a large multisite
trauma-exposed sample and structured clinical interviews.
Randomly selected injury patients admitted to four hospitals were
assessed 72 months post trauma (n = 510). Structured
clinical interviews for PTSD and major depressive episode, as well as
self-report measures of disability and quality of life were
Current prevalence of PTSD under DSM-5 scoring was not significantly
different from DSM-IV (6.7% v. 5.9%, z
= 0.53, P = 0.59). However, the ICD-11 prevalence was
significantly lower than ICD-10 (3.3% v. 9.0%,
z =–3.8, P<0.001). The PTSD
current prevalence was significantly higher for DSM-5 than ICD-11 (6.7%
v. 3.3%, z = 2.5, P
= 0.01). Using ICD-11 tended to show lower rates of comorbidity with
depression and a slightly lower association with disability.
The diagnostic systems performed in different ways in terms of current
prevalence rates and levels of comorbidity with depression, but on other
broad key indicators they were relatively similar. There was overlap
between those with PTSD diagnosed by ICD-11 and DSM-5 but a substantial
portion met one but not the other set of criteria. This represents a
challenge for research because the phenotype that is studied may be
markedly different according to the diagnostic system used.
Few studies have focused on post-traumatic stress disorder (PTSD) remission in the population, none have modelled remission beyond age 54 years and none have explored in detail the correlates of remission from PTSD. This study examined trauma experience, symptom severity, co-morbidity, service use and time to PTSD remission in a large population sample.
Data came from respondents (n=8841) of the 2007 Australian National Survey of Mental Health and Wellbeing (NSMHWB). A modified version of the World Health Organization's World Mental Health Composite International Diagnostic Interview (WMH-CIDI) was used to determine the presence and age of onset of DSM-IV PTSD and other mental and substance use disorders, type, age, and number of lifetime traumas, severity of re-experiencing, avoidance and hypervigilance symptoms and presence and timing of service use.
Projected lifetime remission rate was 92% and median time to remission was 14 years. Those who experienced childhood trauma, interpersonal violence, severe symptoms or a secondary anxiety or affective disorder were less likely to remit from PTSD and reported longer median times to remission compared to those with other trauma experiences, less severe symptoms or no co-morbidity.
Although most people in the population with PTSD eventually remit, a significant minority report symptoms decades after onset. Those who experience childhood trauma or interpersonal violence should be a high priority for intervention.
Fear circuitry disorders purportedly include post-traumatic stress disorder (PTSD), panic disorder, agoraphobia, social phobia and specific phobia. It is proposed that these disorders represent a cluster of anxiety disorders triggered by stressful events and lead to fear conditioning. Elevated heart rate (HR) at the time of an aversive event may reflect strength of the unconditioned response, which may contribute to fear circuitry disorders.
This prospective cohort study assessed HR within 48 h of hospital admission in 602 traumatically injured patients, who were assessed during hospital admission and within 1 month of trauma exposure for lifetime psychiatric diagnosis. At 3 months after the initial assessment, 526 patients (87%) were reassessed for PTSD, major depressive disorder, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and generalized anxiety disorder.
At the 3-month assessment there were 77 (15%) new cases of fear circuitry disorder and 87 new cases of non-fear circuitry disorder (17%). After controlling for gender, age, type of injury and injury severity, patients with elevated HR (defined as ⩾96 beats per min) at the time of injury were more likely to develop PTSD [odds ratio (OR) 5.78, 95% confidence interval (CI) 2.32–14.43], panic disorder (OR 3.46, 95% CI 1.16–10.34), agoraphobia (OR 3.90, 95% CI 1.76–8.61) and social phobia (OR 3.98, 95% CI 1.42–11.14). Elevated HR also predicted new fear circuitry disorders that were not co-morbid with a non-fear circuitry disorder (OR 7.28, 95% CI 2.14–24.79).
These data provide tentative evidence of a common mechanism underpinning the onset of fear circuitry disorders.
Recent explorations in Cueva Charles Brewer, a large cave in a sandstone tepui, SE Venezuela, have revealed silica biospeleothems of unprecedented size and diversity. Study of one — a sub-spherical mass of opaline silica — reveals a complex, laminated internal structure consisting of three narrow dark bands alternating with two wider light bands. Uranium–thorium dating has produced 3 stratigraphically correct dates on the light bands from 298 ± 6 (MIS 9) to 390 ± 33 ka (MIS 11). U concentration is only 30–110 ppb. Initial 234U/238U ratios are high and increase over time from 1.8 to 5.3. Growth rate is very low, the fastest, at 0.37 ± 0.23 mm/ka, in MIS 9. Trace element and heavy metal content of the dark bands is distinctly higher than that of the light bands. It is hypothesized that the dark and light bands correlate with drier/glacial and wetter/interglacial periods, respectively, and that this sample probably began to grow in MIS 13. The cave is in a region that straddles a regionally important ecotone: the speleothem isotopic and trace element variations may preserve a useful paleoclimatic signal. This is the first published suite of U–Th dates from a single silica speleothem and the longest Quaternary record for this region.