Effectiveness and cost-effectiveness for the treatment of depressive symptoms in refugees and asylum seekers: a multi-centred randomized controlled trial

BACKGROUND: Current evidence points towards a high prevalence of psychological distress in refugee populations, contrasting with a scarcity of resources and amplified by linguistic, institutional, financial, and cultural barriers. The objective of the study is to investigate the overall effectiveness and cost-effectiveness of a Stepped Care and Collaborative Model (SCCM) at reducing depressive symptoms in refugees, compared with the overall routine care practices within Germany's mental healthcare system (treatment-as-usual, TAU). METHODS: A multicentre, clinician-blinded, randomised, controlled trial was conducted across seven university sites in Germany. Asylum seekers and refugees with relevant depressive symptoms with a Patient Health Questionnaires score of ≥ 5 and a Refugee Health Screener score of ≥ 12. Participants were randomly allocated to one of two treatment arms (SCCM or TAU) for an intervention period of three months between April 2018 and March 2020. In the SCCM, participants were allocated to interventions tailored to their symptom severity, including watchful waiting, peer-to-peer- or smartphone intervention, psychological group therapies or mental health expert treatment. The primary endpoint was defined as the change in depressive symptoms (Patient Health Questionnaire-9, PHQ-9) after 12 weeks. The secondary outcome was the change in Montgomery Åsberg Depression Rating Scale (MADRS) from baseline to post-intervention. FINDINGS: The intention-to-treat sample included 584 participants who were randomized to the SCCM (n= 294) or TAU (n=290). Using a mixed-effects general linear model with time, and the interaction of time by randomisation group as fixed effects and study site as random effect, we found significant effects for time (p < .001) and time by group interaction (p < .05) for intention-to-treat and per-protocol analysis. Estimated marginal means of the PHQ-9 scores after 12 weeks were significantly lower in SCCM than in TAU (for intention-to-treat: PHQ-9 mean difference at T(1) 1.30, 95% CI 1.12 to 1.48, p < .001; Cohen's d=.23; baseline-adjusted PHQ-9 mean difference at T(1) 0.57, 95% CI 0.40 to 0.74, p < .001). Cost-effectiveness and net monetary benefit analyses provided evidence of cost-effectiveness for the primary outcome and quality-adjusted life years. Robustness of results were confirmed by sensitivity analyses. INTERPRETATION: The SSCM resulted in a more effective and cost-effective reduction of depressive symptoms compared with TAU. Findings suggest a suitable model to provide mental health services in circumstances where resources are limited, particularly in the context of forced migration and pandemics. FUNDING: This project is funded by the Innovationsfond and German Ministry of Health [grant number 01VSF16061]. The present trial is registered under Clinical-Trials.gov under the registration number: NCT03109028. https://clinicaltrials.gov/ct2/show/NCT0310902

Empowerment group therapy for refugees with affective disorders: results of a multi-center randomized controlled trial

Background Against the background of missing culturally sensitive mental health care services for refugees, we developed a group intervention (Empowerment) for refugees at level 3 within the stratified Stepped and Collaborative Care Model of the project Mental Health in Refugees and Asylum Seekers (MEHIRA). We aim to evaluate the effectiveness of the Empowerment group intervention with its focus on psychoeducation, stress management, and emotion regulation strategies in a culturally sensitive context for refugees with affective disorders compared to treatment-as-usual (TAU). Method At level 3 of the MEHIRA project, 149 refugees and asylum seekers with clinically relevant depressive symptoms were randomized to the Empowerment group intervention or TAU. Treatment comprised 16 therapy sessions conducted over 12 weeks. Effects were measured with the Patient Health Questionnaire-9 (PHQ-9) and the Montgomery–Åsberg Depression Rating Scale (MÅDRS). Further scales included assessed emotional distress, self-efficacy, resilience, and quality of life. Results Intention-to-treat analyses show significant cross-level interactions on both self-rated depressive symptoms (PHQ-9; F(1,147) = 13.32, p < 0.001) and clinician-rated depressive symptoms (MÅDRS; F(1,147) = 6.91, p = 0.01), indicating an improvement in depressive symptoms from baseline to post-intervention in the treatment group compared to the control group. The effect sizes for both scales were moderate (d = 0.68, 95% CI 0.21–1.15 for PHQ-9 and d = 0.51, 95% CI 0.04–0.99 for MÅDRS). Conclusion In the MEHIRA project comparing an SCCM approach versus TAU, the Empowerment group intervention at level 3 showed effectiveness for refugees with moderately severe depressive symptoms

Innate Antiviral Specialization of Ly6C+CD45+ Splenic Red Pulp Stroma Instilled by Subset-Specific Regulation of Cellular Sensitivity to Type I Interferons

Pezoldt J, Erhard F, Beckstette M, et al. Innate Antiviral Specialization of Ly6C+CD45+ Splenic Red Pulp Stroma Instilled by Subset-Specific Regulation of Cellular Sensitivity to Type I Interferons. SSRN Electronic Journal. 2020

Single-cell transcriptional profiling of splenic fibroblasts reveals subset-specific innate immune signatures in homeostasis and during viral infection.

Our understanding of the composition and functions of splenic stromal cells remains incomplete. Here, based on analysis of over 20,000 single cell transcriptomes of splenic fibroblasts, we characterized the phenotypic and functional heterogeneity of these cells in healthy state and during virus infection. We describe eleven transcriptionally distinct fibroblastic cell clusters, reassuring known subsets and revealing yet unascertained heterogeneity amongst fibroblasts occupying diverse splenic niches. We further identify striking differences in innate immune signatures of distinct stromal compartments in vivo. Compared to other fibroblasts and to endothelial cells, Ly6C+ fibroblasts of the red pulp were selectively endowed with enhanced interferon-stimulated gene expression in homeostasis, upon systemic interferon stimulation and during virus infection in vivo. Collectively, we provide an updated map of fibroblastic cell diversity in the spleen that suggests a specialized innate immune function for splenic red pulp fibroblasts

Protective Efficacy and Immunogenicity of a Combinatory DNA Vaccine against Influenza A Virus and the Respiratory Syncytial Virus

<div><p>The Respiratory Syncytial Virus (RSV) and Influenza A Virus (IAV) are both two major causative agents of severe respiratory tract infections in humans leading to hospitalization and thousands of deaths each year. In this study, we evaluated the immunogenicity and efficacy of a combinatory DNA vaccine in comparison to the single component vaccines against both diseases in a mouse model. Intramuscular electroporation with plasmids expressing the hemagglutinin (HA) of IAV and the F protein of RSV induced strong humoral immune responses regardless if they were delivered in combination or alone. In consequence, high neutralizing antibody titers were detected, which conferred protection against a lethal challenge with IAV. Furthermore, the viral load in the lungs after a RSV infection could be dramatically reduced in vaccinated mice. Concurrently, substantial amounts of antigen-specific, polyfunctional CD8⁺ T-cells were measured after vaccination. Interestingly, the cellular response to the hemagglutinin was significantly reduced in the presence of the RSV-F encoding plasmid, but not vice versa. Although these results indicate a suppressive effect of the RSV-F protein, the protective efficacy of the combinatory vaccine was comparable to the efficacy of both single-component vaccines. In conclusion, the novel combinatory vaccine against RSV and IAV may have great potential to reduce the rate of severe respiratory tract infections in humans without increasing the number of necessary vaccinations.</p></div

Protective efficacy and immunogenicity of a combinatory DNA vaccine against influenza A virus and the respiratory syncytial virus

The Respiratory Syncytial Virus (RSV) and Influenza A Virus (IAV) are both two major causative agents of severe respiratory tract infections in humans leading to hospitalization and thousands of deaths each year. In this study, we evaluated the immunogenicity and efficacy of a combinatory DNA vaccine in comparison to the single component vaccines against both diseases in a mouse model. Intramuscular electroporation with plasmids expressing the hemagglutinin (HA) of IAV and the F protein of RSV induced strong humoral immune responses regardless if they were delivered in combination or alone. In consequence, high neutralizing antibody titers were detected, which conferred protection against a lethal challenge with IAV. Furthermore, the viral load in the lungs after a RSV infection could be dramatically reduced in vaccinated mice. Concurrently, substantial amounts of antigen-specific, polyfunctional $CD8^{+}$ T-cells were measured after vaccination. Interestingly, the cellular response to the hemagglutinin was significantly reduced in the presence of the RSV-F encoding plasmid, but not vice versa. Although these results indicate a suppressive effect of the RSV-F protein, the protective efficacy of the combinatory vaccine was comparable to the efficacy of both single-component vaccines. In conclusion, the novel combinatory vaccine against RSV and IAV may have great potential to reduce the rate of severe respiratory tract infections in humans without increasing the number of necessary vaccinations

Experimental setup.

<p>Experimental setup.</p

Protection from RSV challenge.

<p>Balb/c mice were immunized according to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0072217#pone-0072217-t001" target="_blank">Table 1</a>. Five weeks after the second immunization, the mice were challenged with 10⁶ PFU RSV (A/Long). The weight loss of each animal was monitored daily and the means and SEM (n = 5–6) are indicated for each group up to day 5 post challenge (<b>A</b>). At day 5, viral loads in lung homogenates (vRNA copies/ml) were measured by qRT-PCR. Each animal is represented by one dot and the means of each group are marked by the line. The detection limit of the qRT-PCR was 4280 copies/ml (<b>B</b>). (p<0.05): <b>*</b> vs. naïve; <b>^#</b> vs. (HA)^hi (1 way-ANOVA, Tukey post-test).</p

Expression analysis.

<p>293T cells were transiently transfected with the IAV-HA or RSV-F expressing plasmids either alone or in combination. To guarantee same amounts of input DNA, pcDNA3.1 was added to the transfection samples of a single plasmid. The transfections were done with 0.05, 0.5 or 5 µg per plasmid and cell lysates were prepared 48 h after transfection. The expression of the viral surface proteins was detected by Western blot analyses under either denaturing conditions for the detection with an anti-HA antibody or non-reducing conditions for the detection with an anti-RSV-F antibody. The detection of α-tubulin served as a loading control (<b>A</b>). A semi-quantitative, densitometry analysis was performed with the software Wasabi! for the lysates obtained after transfecting 5 µg of DNA. Listed are the RLUs detected in the different Western blots (<b>B</b>).</p