High-density binding to Plasmodium falciparum circumsporozoite protein repeats by inhibitory antibody elicited in mouse with human immunoglobulin repertoire.

Antibodies targeting the human malaria parasite Plasmodium falciparum circumsporozoite protein (PfCSP) can prevent infection and disease. PfCSP contains multiple central repeating NANP motifs; some of the most potent anti-infective antibodies against malaria bind to these repeats. Multiple antibodies can bind the repeating epitopes concurrently by engaging into homotypic Fab-Fab interactions, which results in the ordering of the otherwise largely disordered central repeat into a spiral. Here, we characterize IGHV3-33/IGKV1-5-encoded monoclonal antibody (mAb) 850 elicited by immunization of transgenic mice with human immunoglobulin loci. mAb 850 binds repeating NANP motifs with picomolar affinity, potently inhibits Plasmodium falciparum (Pf) in vitro and, when passively administered in a mouse challenge model, reduces liver burden to a similar extent as some of the most potent anti-PfCSP mAbs yet described. Like other IGHV3-33/IGKV1-5-encoded anti-NANP antibodies, mAb 850 primarily utilizes its HCDR3 and germline-encoded aromatic residues to recognize its core NANP motif. Biophysical and cryo-electron microscopy analyses reveal that up to 19 copies of Fab 850 can bind the PfCSP repeat simultaneously, and extensive homotypic interactions are observed between densely-packed PfCSP-bound Fabs to indirectly improve affinity to the antigen. Together, our study expands on the molecular understanding of repeat-induced homotypic interactions in the B cell response against PfCSP for potently protective mAbs against Pf infection.

[Development of an online intervention on suicidality-providing knowledge and reducing suicide stigma]. / Entwicklung einer Onlineintervention zum Thema Suizidalität ­ Vermittlung von Wissen und Reduzierung von Suizidstigma.

Fear of being stigmatized by others, self-stigmatization, and inadequate information can limit those affected by suicidality from seeking help. E­mental-health interventions provide a low-threshold way to reach many individuals with information about the topic. This enables those affected to prepare themselves for personal offers of help. As part of the funding priority "Suicide Prevention (A: Destigmatization)" of the German Federal Ministry of Health, a complex intervention was developed at the University Medical Center Hamburg-Eppendorf. The development and content of this online intervention are described in this article.Following a representative telephone survey of the German general population, which investigated gaps in knowledge and stigmatization tendencies on the subject of suicide, the online intervention "8 lives - lived experience reports and facts on suicide" was developed on the basis of an Australian suicide prevention project and involved persons with a lived experience of suicide. The intervention highlighted both scientific and clinical facts about suicidality as well as a socio-cultural perspective and offered self-help options and professional support services. Video reports of persons with a lived experience of suicide were shown within the intervention. The project is currently being evaluated. A continuation is planned.The intervention is a multi-layered offer in which different perspectives on the topic of suicidality are presented. Participants are addressed on a cognitive and emotional level. Given the prevalence of suicidality and the fact that the subject is still taboo, serious, evidence-based, and low-threshold prevention and information offers seem particularly relevant.

Suicide literacy and suicide stigma - results of a population survey from Germany.

BACKGROUND: While a growing number of studies analyze the magnitude and predictors of mental health literacy, little is known about suicide-specific knowledge and beliefs ("suicide literacy"). AIMS: To examine suicide literacy among the German population and to investigate associations between suicide literacy and suicide stigma. METHODS: Telephone interviews were conducted in Germany (N = 2002, response rate: 47.3%). The literacy of suicide scale (LOSS-SF) was used covering the knowledge domains "signs," "risk factors," "causes/nature" and "treatment/prevention." In multiple regression analyses, associations between the LOSS-SF and the three dimensions "stigma," "normalization/glorification," and "depression/isolation" of the stigma of suicide scale (SOSS-SF) were examined controlling for several covariates. RESULTS: Respondents showed most knowledge concerning "treatment and prevention" (>80% correct answers). Lower suicide literacy was found in the domains "risk factors" (33-60% correct answers) and "signs for suicidal ideation" (45-53%). Suicide literacy was negatively associated with age, while it was positively associated with education, own affliction, and personal contact. Moreover, suicide literacy showed negative associations with all three dimensions of the SOSS-SF. CONCLUSIONS: There are deficits in suicide literacy in the German public that may increase suicide stigma. Addressing those deficits in information-campaigns and encouraging personal contact could help decrease suicide stigma.

High-throughput single-cell sequencing of paired TCRα and TCRß genes for the direct expression-cloning and functional analysis of murine T-cell receptors.

Precise clonal and functional assessments of the T cell receptor (TCR) repertoire diversity require paired TCRα and TCRß gene sequence information at monoclonal level. However, available single-cell strategies are typically limited in throughput and often do not provide full-length DNA templates for direct gene cloning. Here, we describe a high-throughput strategy for the unbiased amplification and automated sequence analysis of paired TCRα and TCRß genes from primary mouse T cells. The platform links cell phenotype and TCR gene sequence information at single-cell level. Furthermore, it enables direct functional analyses through the efficient cloning of both genes and the generation of stable TCR expressing cell lines. This highly efficient workflow is a powerful tool to determine the diversity and quality of the murine T-cell repertoire in various settings, for example in vaccine development, infectious diseases, autoimmunity, or cancer.

Development and evaluation of e-mental health interventions to reduce stigmatization of suicidality - a study protocol.

BACKGROUND: Worldwide, approximately 800,000 persons die by suicide every year; with rates of suicide attempts estimated to be much higher. Suicidal persons often suffer from a mental disorder but stigma, lack of available and suitable support, and insufficient information on mental health limit help seeking. The use of internet-based applications can help individuals inform themselves about mental disorders, assess the extent of their own concerns, find local treatment options, and prepare for contact with health care professionals. This project aims to develop and evaluate e-mental health interventions to improve knowledge about suicidality and to reduce stigmatization of those affected. In developing these interventions, a representative telephone survey was conducted to detect knowledge gaps and stigmatizing attitudes in the general population. METHODS: First, a national representative telephone survey with N = 2000 participants in Germany was conducted. Second, e-mental health interventions are developed to address knowledge gaps and public stigma detected in the survey. These comprise an evidence-based health information package about suicidality, information on regional support services, a self-administered depression test-including suicidality-and an interactive online intervention including personal stories. The development is based on a trialogical exchange of experience between persons affected by suicidality, relatives of affected persons, and clinical experts. Australian researchers who developed an e-mental health intervention for individuals affected by rural suicide were invited to a workshop in order to contribute their knowledge and expertise. Third, the online intervention will be evaluated by a mixed methods design. DISCUSSION: From representative telephone survey data, content can be developed to address specific attitudes and knowledge via the e-mental health interventions. These interventions will be easily accessed and provide an opportunity to reach people who tend not to seek professional services, prefer to inform themselves in advance and/or wish to remain anonymous. Evaluation of the online intervention will provide information on any changes in participants' self-stigma and perceived-stigma of suicidality, and any increase in participants' knowledge on suicidality or self-efficacy expectations. TRIAL REGISTRATION: German Clinical Trial Register DRKS00015071 on August 6, 2018.

Dickkopf-3 acts as a modulator of B cell fate and function.

The mechanisms responsible for the generation of a mature B1 and B2 cell compartment are still poorly understood. In this study, we demonstrated that absence of Dickkopf-3 (DKK3) led to changes in the composition of the B cell compartment, which were due to an altered development and maintenance program of B cells. Development of B2 cells was impaired at the pre- and immature B cell stage, resulting in decreased numbers of follicular B cells in adult DKK3-deficient mice. Furthermore, DKK3 limited B1 cell self-maintenance in the periphery, by decreasing the survival and proliferation behavior of B1 cells. DKK3 may act via the BCR signaling pathway, as Ca(2+) influx upon BCR stimulation was increased and SiglecG, a molecule shown to inhibit Calcium signaling, was downregulated in the absence of DKK3. DKK3-deficient mice exhibited altered Ab responses and an increased secretion of the cytokine IL-10. Additionally, DKK3 limited autoimmunity in a model of systemic lupus erythematosus. In summary, we identified DKK3 as a novel modulator interfering with B cell fate as well as the maintenance program of B cells, leading to changes in B cell immune responses.

Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance.

In healthy individuals, T cells react against incoming pathogens, but remain tolerant to self-antigens, thereby preventing autoimmune reactions. CD4 regulatory T cells are major contributors in induction and maintenance of peripheral tolerance, but a regulatory role has been also reported for several subsets of CD8 T cells. To determine the molecular basis of peripheral CD8 T-cell tolerance, we exploited a double transgenic mouse model in which CD8 T cells are neonatally tolerized following interaction with a parenchymal self-antigen. These tolerant CD8 T cells have regulatory capacity and can suppress T cells in an antigen-specific manner during adulthood. Dickkopf-3 (DKK3) was found to be expressed in the tolerant CD8 T cells and to be essential for the observed CD8 T-cell tolerance. In vitro, genetic deletion of DKK3 or blocking with antibodies restored CD8 T-cell proliferation and IL-2 production in response to the tolerizing self-antigen. Moreover, exogenous DKK3 reduced CD8 T-cell reactivity. In vivo, abrogation of DKK3 function reversed tolerance, leading to eradication of tumors expressing the target antigen and to rejection of autologous skin grafts. Thus, our findings define DKK3 as a immune modulator with a crucial role for CD8 T-cell tolerance.

Education and suicidal ideation in Europe: A systematic review and meta-analysis.

BACKGROUND: Understanding predictors of suicidal ideation (SI) is crucial for preventing suicides. Given Europe's high suicide rates and the complex nature of SI, it is essential to also examine social determinants like education as potential risk factors for SI in this region. This systematic review and meta-analysis investigates the association between formal/vocational education and SI in Europe. METHODS: Electronic databases (PubMed, Web of Science, PsycINFO, PSYNDEX) were searched until November 2022. Included studies involved European populations examining associations between education and SI. Pooled Odds Ratios (OR) with 95 % confidence intervals (CI) were calculated using random-effects models. Heterogeneity was assessed with the heterogeneity variance τ2 and I2 statistic; subgroup analyses were performed based on study characteristics. Risk of bias was assessed using an adaption of the Newcastle-Ottawa Scale. RESULTS: From 20,564 initial studies, 41 were included in the meta-analysis (outlier-adjusted, 96,809 study participants). A negative, insignificant association (OR = 0.86, 95 % CI: 0.75; 1.00) was observed between education and SI, with significant heterogeneity (τ2 = 0.09, I2 = 73 %). Subgroup analyses indicated that population type, age group, categorization of education, timeframe of SI assessment, and study quality significantly moderated the effect size. LIMITATIONS: Heterogeneity across studies limits generalizability. The cross-sectional design precludes establishing causal relationships, and social desirability bias may have underestimated the association between education and SI. CONCLUSIONS: This systematic review and meta-analysis suggests a trend towards a protective effect of education on the emergence of SI in Europe. Future research, preferably with longitudinal study design examining various covariates, should systematically consider educational inequalities in SI.

Root Maturation of an Immature Dens Invaginatus Despite Unsuccessful Revitalization Procedure: A Case Report and Recommendations for Educational Purposes.

BACKGROUND: The clinical management of teeth with complex dens invaginatus (DI) malformations and apical periodontitis may be challenging due to the lack of routine. The aim of this case report is to describe the endodontic treatment of an immature tooth with DI and to discuss strategies for preclinical training for teeth with such malformations. CASE REPORT: A 9-year-old male presented with an immature maxillary incisor with DI (Oehlers Type II) and apical periodontitis which was diagnosed by cone beam computed tomography (CBCT). Revitalization was initially attempted but then abandoned after failure to generate a stable blood clot. Nevertheless, considerable increase in both root length and thickness could be detected after medication with calcium hydroxide followed by root canal filling with MTA as an apical plug. CONCLUSIONS: The endodontic management of teeth with DI requires thorough treatment planning. In immature teeth, under certain conditions, root maturation may occur even with conventional apexification procedures. From an educational perspective, different strategies including CBCT and 3D-printed transparent tooth models for visualization of the complex internal morphology and redesigned 3D-printed replica with various degrees of difficulty for endodontic training, can be used to overcome the challenges associated with endodontic treatment of such teeth.

Endodontic Outcome of Root Canal Treatment Using Different Obturation Techniques: A Clinical Study.

OBJECTIVE: To evaluate the clinical outcome of root canal treatment by obturation technique, root canal filling quality, and tooth- and patient-related variables. METHODS: This clinical study investigated the endodontic outcome of 114 teeth treated between the years 2009 and 2012. Three different obturation methods were used: (1) adhesive obturation using the continuous wave of condensation technique with Resilon® (CWR), (2) matching-taper single-cone technique with gutta-percha and AH Plus® (SCGP), and (3) matching-taper single-cone technique with gutta-percha and GuttaFlow® (SCGF). Pre- and postoperative periapical radiographs were performed to detect the presence of endodontic lesions (PAI classification) and to assess the quality of both the obturation and the restoration. Tooth- and patient-related data were collected. RESULTS: The overall endodontic success rate was 75.4% after a mean observation period of 6.3 years. There were no significant correlations between the type or overall quality of obturation and the treatment outcome. Teeth with preoperative lesions had the highest odds ratio (factor of 4.98) for endodontic failure. Tooth- and patient-related variables had no significant effect on endodontic outcome. CONCLUSIONS: The preoperative periapical status of teeth requiring endodontic treatment was a substantial prognostic factor for endodontic outcome, whereas the type of obturation material or technique did not affect it.

[Development and Psychometric Evaluation of a Short Questionnaire on Self-Efficacy Expectations in Dealing with Psychologically Difficult Situations (SWEP)]. / Entwicklung und psychometrische Überprüfung eines Kurzfragebogens zur Selbstwirksamkeitserwartung im Umgang mit psychisch belastenden Situationen (SWEP).

OBJECTIVE: Development and psychometric evaluation of a German 6-item instrument to assess self-efficacy expectations to seek support in psychologically difficult situations (SWEP). METHODS: Development of items, determination of distribution characteristics, factor structure, and internal consistency of the scale based on a paper-pencil survey (N=269) and a survey of an online intervention on suicide prevention (N=802). RESULTS: Principal component analysis revealed the SWEP scale to be a one-dimensional construct with high internal consistency (Cronbach's α=.83 and α=.89). We found content-plausible correlations to other constructs and initial evidence of a high retest reliability. CONCLUSION: The SWEP provides a reliable, valid, brief instrument for assessing self-efficacy expectations of being able to seek support.

Public attitudes towards sexual behavior-Results of the German Health and Sexuality Survey (GeSiD).

Population-level data on predictors for attitudes towards sexual behavior are missing for Germany. The current study investigated sexual attitudes in the German population with regard to sociodemographic and sociocultural factors. Data originated from the German Health and Sexuality Survey (GeSiD; N = 4,955) carried out from October 2018 to September 2019. Computer-assisted face to face interviews were conducted with a large self-administered component due to the sensitive topics of the survey. Public acceptance towards several aspects of sexual behavior (extramarital sex, abortion, same sex sexual activities, sex work, promiscuity, sex without love) was investigated. Age, gender, education, religious aspects and migration background were introduced as predictors into logistic regression analyses. Overall, respondents rather rejected promiscuity (61%) and extramarital sex (81%) and rather supported same sex sexual activities (63-70%). Male respondents more likely rejected same sex sexual activities and abortion. Higher education was associated with more acceptance towards the sexual behaviors whereas first generation migrants, Muslim faith and religious devoutness were associated with less acceptance. Results indicate that gender is relevant in terms of sexual attitudes with male respondents tending to have more traditional and heteronormative gender role values. Furthermore, education, culture and religion play an important role concerning the liberality towards sexual behaviors. Acculturation processes of second generation migrants may lead to an adaptation of values. Comprehensive and culturally sensitive sex education may focus on differences concerning sexuality-related norms and values.

Evaluation of an online suicide prevention program to improve suicide literacy and to reduce suicide stigma: A mixed methods study.

Low-threshold e-health approaches in prevention to reduce suicide stigma are scarce. We developed an online program containing video reports on lived experience of suicide and evidence-based information on suicidality. We evaluated the program by a mixed methods design. We examined pre-post-changes of program completers (n = 268) in suicide literacy, suicide stigma (self and perceived), and self-efficacy expectation of being able to seek support in psychologically difficult situations using linear mixed models. To examine reported changes and helpful program elements 12-26 weeks after program completion, we content analyzed transcripts of telephone interviews (n = 16). Program completers showed more suicide literacy (Cohen's d = .74; p < .001), higher self-efficacy expectations to seek support (d = .09; p < .01), lower self-stigma (subscales glorification/normalization: d = -.13, p = .04; isolation/depression: d = -.14; p = .04; stigma: d = -.10; p = .07; n = 168) compared to baseline. We found no significant differences in perceived suicide stigma. We identified lived experience reports, the possibility of sharing own narrative on stigma and suicidality, and information on support as helpful elements. The current online program can increase suicide literacy and self-efficacy expectations to seek support and reduce self-stigma. We recommend a larger randomized controlled trial with longer follow-up to confirm these findings.

Glycosylated nanoparticle-based PfCSP vaccine confers long-lasting antibody responses and sterile protection in mouse malaria model.

The development of an effective and durable vaccine remains a central goal in the fight against malaria. Circumsporozoite protein (CSP) is the major surface protein of sporozoites and the target of the only licensed Plasmodium falciparum (Pf) malaria vaccine, RTS,S/AS01. However, vaccine efficacy is low and short-lived, highlighting the need for a second-generation vaccine with superior efficacy and durability. Here, we report a Helicobacter pylori apoferritin-based nanoparticle immunogen that elicits strong B cell responses against PfCSP epitopes that are targeted by the most potent human monoclonal antibodies. Glycan engineering of the scaffold and fusion of an exogenous T cell epitope enhanced the anti-PfCSP B cell response eliciting strong, long-lived and protective humoral immunity in mice. Our study highlights the power of rational vaccine design to generate a highly efficacious second-generation anti-infective malaria vaccine candidate and provides the basis for its further development.

Ethnic and migration-related inequalities in health anxiety: A systematic review and meta-analysis.

Background: Health anxiety exists on a continuum ranging from the absence of health awareness to the obsessive fear of having a serious illness despite reassurance. Its pathological manifestation can be diagnosed as hypochondriacal or illness anxiety or somatic symptom disorder. Health anxiety is associated with psychological distress and adverse life events, among others, and leads to considerable economic burden. Compared to the majority population, migrants, and ethnic minorities often face major health inequalities. Several mental illnesses and psychosomatic complaints are more common among these groups. To date, potential ethnic and migration-related inequalities in health anxiety have not been clearly described. However, they are of high relevance for the provision of adequate health care of this diverse and potentially vulnerable group. Thus, we conducted a systematic review and meta-analysis of health anxiety in migrants and ethnic minorities. Methods: A systematic literature search of PubMED, Web of Science, PsycINFO, and PSYNDEX was conducted, covering all studies published until 1st of December 2021. Studies were selected if they employed validated measurement tools of health anxiety and examined migrants and/or ethnic minorities in comparison with the majority population. Meta-analytic methods were applied by using a random-effect model. The study quality was assessed with the Effective Public Health Practice Project Quality Assessment Tool (EPHPP). Results: We identified 18 studies from 445 studies initially screened. Of these, 14 studies conducted in North America with a total number of 5,082 study participants were included in the meta-analysis. The pooled effect size indicated a higher risk of health anxiety in migrants and ethnic minorities compared to the majority population (OR 1.39, 95%-CI 1.01-1.92). The results proved not to be robust according to publication bias (adjusted OR 1.18, 95%-CI 0.83-1.69) and fail-safe N (2/3 < benchmark N = 75) and are limited due to heterogeneity (I 2 = 57%), small sample sizes and an overall low quality of included studies. Conclusion: To address the diversity of migrants and ethnic minorities, inter-sectional approaches across different countries are needed in research to shed further light on social inequalities in health anxiety linked to migration. Systematic review registration: PROSPERO, registration number CRD42022298458.

Stigmatization from Work-Related COVID-19 Exposure: A Systematic Review with Meta-Analysis.

Stigmatization from work-related COVID-19 exposure has not been investigated in detail yet. Therefore, we systematically searched three databases: Medline, Embase, and PsychInfo (until October 2020), and performed a grey literature search (until February 2021). We identified 46 suitable articles from 24 quantitative and 11 qualitative studies, 6 systematic reviews, 3 study protocols and 1 intervention. The assessment of stigmatization varied widely, ranging from a single-item question to a 22-item questionnaire. Studies mostly considered perceived self-stigma (27 of 35 original studies) in healthcare workers (HCWs) or hospital-related jobs (29 of 35). All articles reported on stigmatization as a result of work-related COVID-19 exposure. However, most quantitative studies were characterized by convenience sampling (17 of 24), and all studies-also those with an adequate sampling design-were considered of low methodological quality. Therefore, it is not possible to determine prevalence of stigmatization in defined occupational groups. Nevertheless, the work-related stigmatization of occupational groups with or without suspected contact to COVID-19 is a relevant problem and increases the risk for depression (odds ratio (OR) = 1.74; 95% confidence interval CI 1.29-2.36) and anxiety (OR = 1.75; 95% CI 1.29-2.37). For promoting workers' health, anti-stigma strategies and support should be implemented in the workplace.

Public Stigma Toward Persons with Suicidal Thoughts-Do Age, Sex, and Medical Condition of Affected Persons Matter?

OBJECTIVE: Suicidal persons often face public stigmatization which affects help-seeking behavior and may lead to an additional suicide risk. There is not much known about differences in stigmatizing attitudes concerning characteristics of affected persons. The present study investigates public stigma toward suicidal persons in Germany by focussing on differences concerning sex, age, and medical condition of the affected person. METHOD: A national telephone survey (N = 2,002) was conducted using case vignettes presenting a person with suicidal thoughts. Vignettes systematically varied in sex, age, and medical condition (depressive symptoms vs. cancer). Several components of stigma were assessed ("weakness of will" as a cause, separation, negative emotional reactions, and desire for social distance). RESULTS: About 44% of the respondents agreed that a cause of suicidal thoughts is "weakness of will," and two thirds disagreed that they would feel and think the same as the described person. In terms of emotional reactions, fear was more pronounced than anger. Stigmatizing attitudes were particularly pronounced when the described person was female and depressive symptoms were presented. CONCLUSIONS: Magnitude of public suicide stigma varies depending on the characteristics of the described person. Groups that are at special risk of being stigmatized should be considered in antistigma programs.

[The Stigma of Suicide Scale: Psychometric Validation of the German Short Version (SOSS-SF-D)]. / Die Stigma of Suicide Scale: psychometrische Überprüfung der deutschen Kurzversion (SOSS-SF-D).

OBJECTIVE: The Australian Stigma of Suicide Scale (SOSS-SF) was translated and tested for applicability and psychometric properties in Germany. Further, it was investigated whether the observed factors from the Australian original could be replicated in a German sample. METHODS: Based on a nation-wide, representative telephone survey (N = 2,002), the 16 items of the SOSS-SF-D were examined with a principal component analysis (varimax rotation). Mean values, standard deviations and medians as well as the z-standardized values for skewness and kurtosis were determined. RESULTS: The principal component analysis revealed 3 subscales (stigma, normalization/glorification, depression/isolation), just as in the Australian sample. Internal consistency of the subscales was acceptable (Cronbachs α: 0.64-0.78). CONCLUSION: The SOSS-SF-D is a valid and short instrument for measuring the multidimensionality of attitudes towards suicidal persons.

Changes in beliefs and attitudes toward people with depression and schizophrenia - results of a public campaign in Germany.

We examined the impact of a mental health awareness campaign on public attitudes. The campaign was embedded in the project psychenet - Hamburg Network for Mental Health. Beliefs and attitudes were examined before and after specific awareness measures in Hamburg (intervention region) and Munich (control region). Analyses were based on representative surveys (2011: N=2014; 2014: N=2006). Vignettes with symptoms suggestive of depression respectively schizophrenia were presented, followed by questions on social distance, beliefs and emotional reactions. Analyses of variance tested variations between regions over time and differences between those aware of the campaign and those not aware. In 2014, 7.3% (n=74) of the Hamburg respondents were aware of the psychenet campaign. Regarding the total sample, there were minor changes in attitudes. Differentiated according to campaign awareness among Hamburg respondents, those who were aware showed less desire for social distance toward a person with depression. Moreover, respondents aware of the campaign stated less often that a person with schizophrenia is in need of help. The campaign had small impact on attitudes. A substantial change in ingrained attitudes toward persons with mental health problems is difficult to achieve with interventions targeting the general public.