Divorce and the multidimensionality of men and women's mental health: the role of social-relational and socio-economic conditions

Research consistently reveals that the divorced generally face more mental health problems than the married. Less attention however has been paid to positive mental health indicators. Insight in these however may help policy makers and care providers to see both the broader picture and stimulate active coping. Using data from the European Social Survey (2006–2007), differences in both feelings of depression, and in feelings of self-esteem, autonomy, and competence between the married (N = 14,072) and divorced (N = 4,304) are estimated for women and men separately. Drawing on stress and coping theories, we map how specific social-relational and socio-economic conditions relate. Analyses reveal that divorce is related not only to more feelings of depression, but also to lower levels of self-esteem and competence. Difference scores in mental health based on marital status are also found to differ significantly between men and women for competence, with the difference being more pronounced in men. Additionally, social-relational and socio-economic conditions explain much of the gap in depression scores – and to a lesser extent, in self-esteem and competence scores – between the married and divorced. Finally, some interesting gender differences were found in how social-relational and socio-economic conditions relate to mental health when divorced, with women especially seeming to benefit from advantageous socio-economic conditions

mRNA-LNP vaccines tuned for systemic immunization induce strong antitumor immunity by engaging splenic immune cells

mRNA vaccines have recently proved to be highly effective against SARS-CoV-2. Key to their success is the lipid-based nanoparticle (LNP), which enables efficient mRNA expression and endows the vaccine with adjuvant properties that drive potent antibody responses. Effective cancer vaccines require long-lived, qualitative CD8 T cell responses instead of antibody responses. Systemic vaccination appears to be the most effective route, but necessitates adaptation of LNP composition to deliver mRNA to antigen-presenting cells. Using a design-of-experiments methodology, we tailored mRNA-LNP compositions to achieve high-magnitude tumor-specific CD8 T cell responses within a single round of optimization. Optimized LNP compositions resulted in enhanced mRNA uptake by multiple splenic immune cell populations. Type I interferon and phagocytes were found to be essential for the T cell response. Surprisingly, we also discovered a yet unidentified role of B cells in stimulating the vaccine-elicited CD8 T cell response. Optimized LNPs displayed a similar, spleen-centered biodistribution profile in non-human primates and did not trigger histopathological changes in liver and spleen, warranting their further assessment in clinical studies. Taken together, our study clarifies the relationship between nanoparticle composition and their T cell stimulatory capacity and provides novel insights into the underlying mechanisms of effective mRNA-LNP-based antitumor immunotherapy

A clinically annotated post-mortem approach to study multi-organ somatic mutational clonality in normal tissues

Recent research on normal human tissues identified omnipresent clones of cells, driven by somatic mutations known to be responsible for carcinogenesis (e.g., in TP53 or NOTCH1). These new insights are fundamentally changing current tumor evolution models, with broad oncological implications. Most studies are based on surgical remnant tissues, which are not available for many organs and rarely in a pan-organ setting (multiple organs from the same individual). Here, we describe an approach based on clinically annotated post-mortem tissues, derived from whole-body donors that are routinely used for educational purposes at human anatomy units. We validated this post-mortem approach using UV-exposed and unexposed epidermal skin tissues and confirm the presence of positively selected NOTCH1/2-, TP53- and FAT1-driven clones. No selection signals were detected in a set of immune genes or housekeeping genes. Additionally, we provide the first evidence for smoking-induced clonal changes in oral epithelia, likely underlying the origin of head and neck carcinogenesis. In conclusion, the whole-body donor-based approach provides a nearly unlimited healthy tissue resource to study mutational clonality and gain fundamental mutagenic insights in the presumed earliest stages of tumor evolution

Tuning LNPs to target antigen presenting cells in spleen induces CD8 T-cell responses and tumor regression in mice

International audienceIntravenous (i‧v.) delivery of vaccines is emerging as an appealing approach to evoke high-quality T-cell responses needed to combat tumors. Messenger RNA (mRNA) holds huge potential to use in vaccination because of its ease of production, intrinsic adjuvant activity and the high versatility in antigen design, but also requires a potent delivery vehicle to enable antigen expression and immune activation. Lipid based nanoparticles (LNP) are currently the clinically most advanced tool to protect mRNA from degradation and efficiently deliver it inside cells. Yet, i‧v administered LNPs generally tend to distribute to the liver. We hypothesized LNPs can be altered to target antigen presenting cells in the spleen and hereby orchestrate specific and durable immune responses against cancer antigens. By using a design of experiment methodology we were able to screen LNPs in a cost and time effective manner. LNP compositions that were evaluated solely differed in the molar ratios of ionizable lipid, phospholipid, cholesterol and PEG-lipid and the choice of the PEG-lipid. Bayesian Regression modeling enabled us to identify LNP compositions conferring maximum immunogenicity upon i‧v. administration. To link LNP compositions to T cell responses and biodistribution, we prepared the same LNPs packaging either the viral oncoprotein E7 as an antigen or Cy-5 labelled luciferase mRNA. The optimized LNP compositions showed increased localization in the spleen (of mice and non-human primates) and uptake by antigen presenting cells. Furthermore, they induced high magnitude CD8 T cell responses that conferred strong antitumor immunity and prolonged survival of TC-1 tumor bearing mice. Mechanistically, type I interferons and phagocytes were found to be essential for eliciting strong T-cell responses. Unexpectedly, we identified B cells as major mediators of the vaccine- elicited T-cell response, revealing a previously undocumented role of these cells in the immune response to mRNA LNPs. Our data highlight the potential of optimizing LNP compositions by tailoring of the molar ratio of the lipids compromising the LNPs and provide insight in the cell types involved in the mRNA LNP-induced immune response. Collectively, our results illustrate the great promise of intravenous mRNA LNP vaccination for the treatment of cancer

Rationally designed mRNA-loaded lipid nanoparticles provoke strong antitumor T cell immunity which critically depends on specific immune cell subsets

International audienc

Personalised rehabilitation to improve return to work in patients with persistent spinal pain syndrome type II after spinal cord stimulation implantation : a study protocol for a 12-month randomised controlled trial : the OPERA study

Background: For patients with therapy-refractory persistent spinal pain syndrome type II (PSPS-T2), spinal cord stimulation (SCS) may serve as an effective minimally invasive treatment. Despite the evidence that SCS can improve return to work (RTW), only 9.5 to 14% of patients implanted with SCS are effectively capable of returning to work. Thus, it seems that current post-operative interventions are not effective for achieving RTW after SCS implantation in clinical practice. The current objective is to examine whether a personalised biopsychosocial rehabilitation programme specifically targeting RTW alters the work ability in PSPS-T2 patients after SCS implantation compared to usual care. Methods: A two-arm, parallel-group multicentre randomised controlled trial will be conducted including 112 patients who will be randomised (1:1) to either (a) a personalised biopsychosocial RTW rehabilitation programme of 14 weeks or (b) a usual care arm, both with a follow-up period until 12 months after the intervention. The primary outcome is work ability. The secondary outcomes are work status and participation, pain intensity, health-related quality of life, physical activity and functional disability, functional capacities, sleep quality, kinesiophobia, self-management, anxiety, depression and healthcare expenditure. Discussion: Within the OPERA project, we propose a multidisciplinary personalised biopsychosocial rehabilitation programme specifically targeting RTW for patients implanted with SCS, to tackle the high socio-economic burden of patients that are not re-entering the labour market. The awareness is growing that the burden of PSPS-T2 on our society is expected to increase over time due to the annual increase of spinal surgeries. However, innovative and methodologically rigorous trials exploring the potential to decrease the socio-economic burden when patients initiate a trajectory with SCS are essentially lacking

Divorce and the Multidimensionality of Men and Women’s Mental Health: The Role of Social-Relational and Socio-Economic Conditions

Research consistently reveals that the divorced generally face more mental health problems than the married. Less attention however has been paid to positive mental health indicators. Insight in these however may help policy makers and care providers to see both the broader picture and stimulate active coping. Using data from the European Social Survey (2006–2007), differences in both feelings of depression, and in feelings of self-esteem, autonomy, and competence between the married (N = 14,072) and divorced (N = 4,304) are estimated for women and men separately. Drawing on stress and coping theories, we map how specific social-relational and socio-economic conditions relate. Analyses reveal that divorce is related not only to more feelings of depression, but also to lower levels of self-esteem and competence. Difference scores in mental health based on marital status are also found to differ significantly between men and women for competence, with the difference being more pronounced in men. Additionally, social-relational and socio-economic conditions explain much of the gap in depression scores – and to a lesser extent, in self-esteem and competence scores – between the married and divorced. Finally, some interesting gender differences were found in how social-relational and socio-economic conditions relate to mental health when divorced, with women especially seeming to benefit from advantageous socio-economic conditions