Stigmatization Is Associated With Increased PTSD Risk After Traumatic Stress and Diminished Likelihood of Spontaneous Remission–A Study With East-African Conflict Survivors

Studies in conflict population have repeatedly documented that the number of traumatic event types experienced (trauma load) increases the risk to develop posttraumatic stress disorder (PTSD) in a dose-dependent manner. Misconceptions about survivors' experiences and actions during the war, as well as mental health symptoms frequently lead to stigmatization by their own families and the community, which might render them even more vulnerable for PTSD development and prevent successful recovery. We therefore investigated whether stigmatization affects trauma-related psychopathology beyond the well-known effect of trauma load. The study sample comprised N = 1131 survivors of the rebel war led by the Lord's Resistance Army (LRA) in Northern Uganda, including a large proportion of formerly abducted individuals and child soldiers. We investigated how the experience of stigmatization affects PTSD risk and the likelihood of spontaneous remission, taking trauma load into account. Further, the association of stigmatization with treatment outcome was determined in a subsample of N = 284 individuals with PTSD who received trauma-focused psychotherapy. More than one third of the total sample, and almost two-thirds of the therapy subsample, reported experiences of stigmatization. The main reasons for stigmatization were related to an association with a rebel group (e.g., being called a rebel), followed by mental health problems/PTSD symptoms and HIV/AIDS. Stigmatization was strongly associated with a higher prevalence of lifetime and current PTSD, a diminished probability of spontaneous remission and higher PTSD symptoms before and after trauma-focused psychotherapy, beyond the effect of trauma load. In sum, our results support the assumption that stigmatization aggravates trauma-related psychopathology and impede symptom improvement. In post-conflict regions, community and family interventions which aim at reducing stigmatization and discrimination might therefore complement individual psychotherapy in order to allow survivors to recover and reintegrate into society

The Challenge of Living On: Psychopathology and Its Mediating Influence on the Readjustment of Former Child Soldiers

Ertl V, Pfeiffer A, Schauer-Kaiser E, Elbert T, Neuner F. The Challenge of Living On: Psychopathology and Its Mediating Influence on the Readjustment of Former Child Soldiers. PLoS ONE. 2014;9(7): e102786.Current civil wars are characterized by the increasing involvement of civilian populations and the systematic employment of child soldiers. An example of such wars was the conflict in Northern Uganda, where the war-affected population is still challenged by the reintegration of formerly abducted children and youths. A cross-sectional, population-based survey, using a multistage cluster sampling approach of 1,113 Northern Ugandans aged between 12 and 25 in camps for internally displaced persons and locally validated instruments was conducted to assess symptoms and diagnoses of Posttraumatic Stress Disorder (PTSD) and probable Depression in war-affected, as well as formerly abducted individuals. Further objectives were to determine predictors of psychopathology and to relate indicators of maladjustment (i.e., impairments in daily and community functioning, somatic complaints, suicidality, aggressiveness and discrimination) to abduction, level of exposure to violence and psychopathology. 43% of the sample reported abduction by the rebel army. Exposure to violence among this group was higher than for non-abducted youths (t = 28.05; p<.001). PTSD point prevalence rates were 25% among former child soldiers and 7% among the comparison group. High suicidal ideation was present in 16% and 6% respectively. A higher amount of experienced and witnessed event-types (β = . 32. p<.001), loss of first-degree relatives (β = .13. p<.001) and the number of event-types involving forced perpetration (β = .23. p<.001) were identified as risk factors of PTSD symptoms in former child soldiers. The associations between abductee-status and indicators of maladjustment were fully mediated by level of trauma exposure and psychopathology. Results show that child soldiering and its psychological sequelae affect a substantial proportion of children and youths. After release or flight, their readjustment depends at least partly on their level of mental traumatization

Cell-cell adhesion regulates Merlin/NF2 interaction with the PAF complex

The PAF complex (PAFC) coordinates transcription elongation and mRNA processing and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions both at the cell cortex and nucleus and is a key mediator of contact inhibition but the molecular mechanisms remain unclear. In this study we have used affinity proteomics to identify novel Merlin interacting proteins and show that Merlin forms a complex with multiple proteins involved in RNA processing including the PAFC and the CHD1 chromatin remodeller. Tumour-derived inactivating mutations in both Merlin and the CDC73 PAFC subunit mutually disrupt their interaction and growth suppression by Merlin requires CDC73. Merlin interacts with the PAFC in a cell density-dependent manner and we identify a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, Merlin is part of a tumour suppressor network regulated by cell-cell adhesion which coordinates post-initiation steps of the transcription cycle of genes mediating contact inhibition

PTSD, depression and anxiety among former abductees in Northern Uganda

<p>Abstract</p> <p>Background</p> <p>The population in Northern Uganda has been exposed to extreme levels of traumatic stress and thousands abducted forcibly became rebel combatants.</p> <p>Methods</p> <p>Using structured interviews, the prevalence and severity of posttraumatic stress disorder (PTSD), depression and anxiety was assessed in 72 former abducted adults, 62 of them being former child soldiers.</p> <p>Results</p> <p>As retrospective reports of exposure to traumatic stress increased, anxiety and PTSD occurrence increased (r = .45). 49% of respondents were diagnosed with PTSD, 70% presented with symptoms of depression, and 59% with those of anxiety. In a multiple linear regression analysis four factors could best explain the development of PTSD symptoms: male respondents (sex) living in an IDP-Camp (location) with a kinship murdered in the war (family members killed in the war) and having experienced a high number of traumatic events (number of traumatic events) were more likely to develop symptoms of PTSD than others. In disagreement to a simple dose-response-effect though, we also observed a negative correlation between the time spent with the rebels and the PTSD symptom level.</p> <p>Conclusions</p> <p>Former abductees continue to suffer from severe mental ill-health. Adaptation to the living condition of rebels, however, may lower trauma-related mental suffering.</p

CD8 Receptor-Targeted Lentiviral Vectors – an Approach for the in vivo Generation of Chimeric Antigen Receptor (CAR) T Cells

Gene therapeutic applications have gained substantial significance in modern medicine, especially for the treatment of cancer diseases. Genetically engineered T cells that express a chimeric antigen receptor (CAR) have been shown to mediate impressive anti tumoral efficacy in patients suffering from B cell malignancies. In 2017, the first CAR T cell product was approved in the United States (U.S.). However, cell selective gene delivery still represents a big hurdle, making ex vivo gene delivery indispensable that is accompanied by complex efforts and high costs due to the personalized treatment. Receptor-targeted lentiviral vectors mediate selective gene delivery into a certain cell type and represent a powerful tool for the in vivo gene transfer. This thesis investigates the in vivo generation of CAR T cells in small animal models using a CD8-targeted lentiviral vector (CD8-LV). CD8-LV has been generated before by pseudotyping lentiviral vectors with modified Nipah virus glycoproteins displaying an anti-human CD8-targeting domain. In this thesis, selective in vivo reporter gene delivery into CD8+ lymphocytes was demonstrated upon systemic administration of CD8-LV into mice engrafted with human peripheral blood mononuclear cells (PBMC). Thereby, reporter gene expression exclusively within the CD8+ cells proved the highly selective targeting of CD8-LV. In vitro generation of CAR T cells upon transduction of PBMC with CD8-LV transferring a CD19 specific chimeric antigen receptor was shown, and functionality of these generated CAR T cells was demonstrated. They selectively expanded upon antigen stimulus and specifically killed CD19+ target tumor cells in vitro. CD8-LV(CAR) administration into mice resulted in the in vivo generation of CAR T cells with remarkably high frequencies of CAR positive cells. Higher frequencies of transgene-positive and CD8-positive cells compared to reporter gene transfer indicated selective CAR T cell expansion in vivo. Importantly, functionality of in vivo generated CAR T cells was demonstrated when CD19+ target cells had been eliminated. Moreover, CD19+ cells were identified as antigen stimulus triggering antigen-specific CAR T cell proliferation. Phenotype analysis of CAR T cells by surface marker analysis revealed the presence of diversely differentiated CAR T cells, which is highly preferable in terms of generating a pool of CAR T cells with various effector functions and proliferative capabilities. Furthermore, anti-tumoral efficacy was evaluated in xenograft mice engrafted with human tumor cells. Although tumor outgrowth was not prevented, these CAR T cells demonstrated killing activities against CD19+ B cells and emigrated to various organs. Showing organ-specific subset distribution of diversely differentiated CAR T cells, highest levels of effector CAR T cells were observed at the tumor site. This thesis highlights the potential of CD8-LV to genetically engineer CD8 T cells in vivo. Selective gene transfer and functionality of in vivo generated human CAR T cells represent encouraging data to build on for further investigations in translational research. Pursuing receptor-targeted LVs for clinical application as an alternative approach of CAR T cell generation opens up an attractive possibility to tremendously simplifying CAR T cell therapy. In conclusion, CD8-LV represents a promising tool for the in vivo CAR T cell generation with the potential to transform personalized CAR T cell therapy into a broad applicable treatment option

CD8 Receptor-Targeted Lentiviral Vectors – an Approach for the in vivo Generation of Chimeric Antigen Receptor (CAR) T Cells

Gene therapeutic applications have gained substantial significance in modern medicine, especially for the treatment of cancer diseases. Genetically engineered T cells that express a chimeric antigen receptor (CAR) have been shown to mediate impressive anti tumoral efficacy in patients suffering from B cell malignancies. In 2017, the first CAR T cell product was approved in the United States (U.S.). However, cell selective gene delivery still represents a big hurdle, making ex vivo gene delivery indispensable that is accompanied by complex efforts and high costs due to the personalized treatment. Receptor-targeted lentiviral vectors mediate selective gene delivery into a certain cell type and represent a powerful tool for the in vivo gene transfer. This thesis investigates the in vivo generation of CAR T cells in small animal models using a CD8-targeted lentiviral vector (CD8-LV). CD8-LV has been generated before by pseudotyping lentiviral vectors with modified Nipah virus glycoproteins displaying an anti-human CD8-targeting domain. In this thesis, selective in vivo reporter gene delivery into CD8+ lymphocytes was demonstrated upon systemic administration of CD8-LV into mice engrafted with human peripheral blood mononuclear cells (PBMC). Thereby, reporter gene expression exclusively within the CD8+ cells proved the highly selective targeting of CD8-LV. In vitro generation of CAR T cells upon transduction of PBMC with CD8-LV transferring a CD19 specific chimeric antigen receptor was shown, and functionality of these generated CAR T cells was demonstrated. They selectively expanded upon antigen stimulus and specifically killed CD19+ target tumor cells in vitro. CD8-LV(CAR) administration into mice resulted in the in vivo generation of CAR T cells with remarkably high frequencies of CAR positive cells. Higher frequencies of transgene-positive and CD8-positive cells compared to reporter gene transfer indicated selective CAR T cell expansion in vivo. Importantly, functionality of in vivo generated CAR T cells was demonstrated when CD19+ target cells had been eliminated. Moreover, CD19+ cells were identified as antigen stimulus triggering antigen-specific CAR T cell proliferation. Phenotype analysis of CAR T cells by surface marker analysis revealed the presence of diversely differentiated CAR T cells, which is highly preferable in terms of generating a pool of CAR T cells with various effector functions and proliferative capabilities. Furthermore, anti-tumoral efficacy was evaluated in xenograft mice engrafted with human tumor cells. Although tumor outgrowth was not prevented, these CAR T cells demonstrated killing activities against CD19+ B cells and emigrated to various organs. Showing organ-specific subset distribution of diversely differentiated CAR T cells, highest levels of effector CAR T cells were observed at the tumor site. This thesis highlights the potential of CD8-LV to genetically engineer CD8 T cells in vivo. Selective gene transfer and functionality of in vivo generated human CAR T cells represent encouraging data to build on for further investigations in translational research. Pursuing receptor-targeted LVs for clinical application as an alternative approach of CAR T cell generation opens up an attractive possibility to tremendously simplifying CAR T cell therapy. In conclusion, CD8-LV represents a promising tool for the in vivo CAR T cell generation with the potential to transform personalized CAR T cell therapy into a broad applicable treatment option

From Crisis to Reconciliation - Effects of Conflict Trainings and Trauma Therapies in Norther Uganda

Winkler N, Ruf M, Pfeiffer A, Ertl V, Elbert T. From Crisis to Reconciliation - Effects of Conflict Trainings and Trauma Therapies in Norther Uganda. Presented at the 4th Uganda Psychiatric Association and Gulu University Medical Students Association Scientific Conference, Gulu, Uganda

Community-Implemented Trauma Therapy for Former Child Soldiers in Northern Uganda A Randomized Controlled Trial

Ertl V, Pfeiffer A, Schauer E, Elbert T, Neuner F. Community-Implemented Trauma Therapy for Former Child Soldiers in Northern Uganda A Randomized Controlled Trial. The Journal of the American Medical Association (JAMA). 2011;306(5):503-512.Context The psychological rehabilitation of former child soldiers and their successful reintegration into postconflict society present challenges. Despite high rates of impairment, there have been no randomized controlled trials examining the feasibility and efficacy of mental health interventions for former child soldiers. Objective To assess the efficacy of a community-based intervention targeting symptoms of posttraumatic stress disorder (PTSD) in formerly abducted individuals. Design, Setting, and Participants Randomized controlled trial recruiting 85 former child soldiers with PTSD from a population-based survey of 1113 Northern Ugandans aged 12 to 25 years, conducted between November 2007 and October 2009 in camps for internally displaced persons. Participants were randomized to 1 of 3 groups: narrative exposure therapy (n=29), an academic catch-up program with elements of supportive counseling (n=28), or a waiting list (n=28). Symptoms of PTSD and trauma-related feelings of guilt were measured using the Clinician-Administered PTSD Scale. The respective sections of the Mini International Neuropsychiatric Interview were used to assess depression and suicide risk, and a locally adapted scale was used to measure perceived stigmatization. Symptoms of PTSD, depression, and related impairment were assessed before treatment and at 3 months, 6 months, and 12 months postintervention. Intervention Treatments were carried out in 8 sessions by trained local lay therapists, directly in the communities. Main Outcome Measures Change in PTSD severity, assessed over a 1-year period after treatment. Secondary outcome measures were depression symptoms, severity of suicidal ideation, feelings of guilt, and perceived stigmatization. Results PTSD symptom severity (range, 0-148) was significantly more improved in the narrative exposure therapy group than in the academic catch-up (mean change difference, -14.06 [95% confidence interval, -27.19 to -0.92]) and waiting-list (mean change difference, -13.04 [95% confidence interval, -26.79 to 0.72]) groups. Contrast analyses of the time x treatment interaction of the mixed-effects model on PTSD symptom change over time revealed a superiority of narrative exposure therapy compared with academic catch-up (F(1,234.1)=5.21, P=.02) and wait-listing (F(1,228.3)=5.28, P=.02). Narrative exposure therapy produced a larger within-treatment effect size (Cohen d=1.80) than academic catch-up (d=0.83) and wait-listing (d=0.81). Conclusion Among former Ugandan child soldiers, short-term trauma-focused treatment compared either with an academic catch-up program including supportive counseling or with wait-listing resulted in greater reduction of PTSD symptoms

Stopping the war in their minds - Rehabilitation of former Child Soldiers and war-affected children and adults. Epidemiology, Therapy and Dissemination

Ertl V, Pfeiffer A, Schauer E, Elbert T, Neuner F. Stopping the war in their minds - Rehabilitation of former Child Soldiers and war-affected children and adults. Epidemiology, Therapy and Dissemination. Presented at the Impressions from the front line – Mental Health interventions in Congo, Rwanda and Uganda, Trondheim, Norway