Healthy Ageing: prevention of loneliness among elderly people : evaluation of a complex intervention in public health practice

Introduction Concerns about the ageing population and formal responsibilities of local governments to promote social cohesion and to enhance participation of vulnerable groups in society placed loneliness prevention high on the local policy agenda of Dutch municipalities in the past decade. The study described in this thesis was part of the Healthy Ageing programme of the Academic Collaborative Centre AGORA and aimed to contribute to more effective, evidence-based and problem-oriented approaches to healthy ageing at the local level. Aim The general aim of this thesis was to evaluate the effectiveness of a local intervention project – called Healthy Ageing – targeting loneliness among non-institutionalised elderly people. Healthy Ageing consisted of five intervention components, namely, a mass media campaign, information meetings, psychosocial group courses, social activities organised by neighbours, Neighbours Connected, and training of intermediaries. Methods First, the influence of socio-demographic and health characteristics on changes in loneliness over time and municipal differences in the prevalence of loneliness were investigated. Data were gathered from 9,641 persons who participated in the Elderly Health Survey of the community health service, GGD Noord- en Oost- Gelderland (former GGD Gelre-IJssel), in 2005 or 2010. Second, the overall-effect of Healthy Ageing on the initial outcome loneliness literacy, intermediate outcome social support, and ultimate outcome loneliness was evaluated using a quasi-experimental pre-test post-test design, including an intervention and control community. Baseline and follow-up measurements, in 2008 and 2010 respectively, were available for 858 non-institutionalized elderly people. The Loneliness Literacy Scale was developed within the context of this thesis and was pre-tested in a separate study among 303 elderly persons who also participated in the quasi-experimental study. Finally, delivery, reach, and acceptance of the individual intervention components was studied in several satellite studies. Data were collected by different means, e.g. project records and surveys among participants. Furthermore, the acceptability of the mass media communication materials, information meetings, and psychosocial courses of Healthy Ageing was studied by in-depth interviews with 14 clients of the meal delivery service in the intervention community.   Results Overall and across municipalities, average loneliness scores did not significantly differ between 2005 and 2010. However, among the subgroup with mobility disabilities, loneliness was significantly higher in 2010. Furthermore, mobility disabilities and marital status were the most important factors explaining differences between municipalities. With regard to the evaluation of Healthy Ageing, the satellite studies showed that the reach and intensity of the intervention components were modest. Furthermore, from the interviews it appeared that the mass media communication materials were not successful in attracting attention because interviewees did not expect health information from these communication channels, the perceived personal relevance of the message was low, and the presentation was not attractive. Moreover, the content of the intervention components was not well received because the objectives and intervention components did not connect well with the priority group’s daily life. In addition, it appeared from the quasi-experimental study that 39% of the study participants from the intervention community was familiar with Healthy Ageing at follow-up. Overall, the intervention group scored more favourably on the loneliness literacy subscales, motivation (4.4%), perceived social support (8.2%), and subjective norm (11.5%) than the control group. However, no overall effects were observed for the intermediate and ultimate outcomes, total social support and loneliness after two years. Conclusion Given the modest overall intervention exposure, the effect of Healthy Ageing on the loneliness literacy subscale, motivation, is plausible, whereas on the subscales, perceived social support and subjective norm, probable, and on the subscale, self-efficacy, unlikely. Furthermore, whether the initial effects will carry forward to the intermediate and ultimate outcomes needs to be confirmed. The modest effects of Healthy Ageing can partly be explained by the challenges on organisational level which delayed and suppressed project implementation. Furthermore, the project might have benefited from a more systematic approach in order to ensure better alignment between the intervention components and formulated objectives. Finally, target group differentiation is highly recommended. This evaluation of Healthy Ageing illustrates how researchers can cope with the evaluation challenges of complex interventions which cannot be fully controlled. In turn, this provides valuable lessons for the development of intervention programmes and evaluation designs in public health practice.</p

The Novel Immune Checkpoint GPR56 Is Expressed on Tumor-Infiltrating Lymphocytes and Selectively Upregulated upon TCR Signaling

High levels of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) are associated with a survival benefit in various cancer types and the targeted (re)activation of TILs is an attractive therapeutic anti-cancer approach that yields curative responses. However, current T cell targeting strategies directed at known immune checkpoints have not increased objective response rates for all cancer types, including for epithelial ovarian cancer (EOC). For this reason, the identification of new immune checkpoints that regulate T cell immunity remains of great interest. One yet largely uninvestigated checkpoint of potential interest is the G protein-coupled receptor 56 (GPR56), which belongs to the adhesion GPCR family. GPR56 was originally reported to function in cerebral cortical development and in anti-depressant response, but also in cancer. Recently, GPR56 was identified as an inhibitory receptor expressed on human NK cells that by cis-interaction with the tetraspanin CD81 attenuated the cytotoxic activity of NK cells. This NK cell checkpoint could be blocked by an GPR56 antibody, leading to increased cytotoxicity. Interestingly, GPR56 expression has also been reported on cytokine producing memory CD8 T lymphocytes and may thus represent a T cell checkpoint as well. Here, GPR56 mRNA expression was characterized in the context of TILs, with GPR56 expression being detected predominantly in tumor infiltrating CD8 T cells with a cytotoxic and (pre-)exhausted phenotype. In accordance with this mRNA profile, TILs from ovarian cancer patients expressed GPR56 primarily within the effector memory and central memory T cell subsets. On T cells from healthy donors the expression was limited to effector memory and terminally differentiated T cells. Notably, GPR56 expression further increased on TILs upon T cell receptor (TCR)-mediated stimulation in co-cultures with cancer cells, whereas GPR56 expression on healthy primary human T cells did not. Further, the ectopic expression of GPR56 significantly reduced the migration of GPR56-positive T cells. Taken together, GPR56 is a potential immune-checkpoint in EOC found on (pre-)exhausted CD8 TILs that may regulate migratory behavior

Multivariate analysis reveals shared genetic architecture of brain morphology and human behavior.

Human variation in brain morphology and behavior are related and highly heritable. Yet, it is largely unknown to what extent specific features of brain morphology and behavior are genetically related. Here, we introduce a computationally efficient approach for multivariate genomic-relatedness-based restricted maximum likelihood (MGREML) to estimate the genetic correlation between a large number of phenotypes simultaneously. Using individual-level data (N = 20,190) from the UK Biobank, we provide estimates of the heritability of gray-matter volume in 74 regions of interest (ROIs) in the brain and we map genetic correlations between these ROIs and health-relevant behavioral outcomes, including intelligence. We find four genetically distinct clusters in the brain that are aligned with standard anatomical subdivision in neuroscience. Behavioral traits have distinct genetic correlations with brain morphology which suggests trait-specific relevance of ROIs. These empirical results illustrate how MGREML can be used to estimate internally consistent and high-dimensional genetic correlation matrices in large datasets

EGFR-selective activation of CD27 co-stimulatory signaling by a bispecific antibody enhances anti-tumor activity of T cells

A higher density of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment, particularly cytotoxic CD8 + T cells, is associated with improved clinical outcome in various cancers. However, local inhibitory factors can suppress T cell activity and hinder anti-tumor immunity. Notably, TILs from various cancer types express the co-stimulatory Tumor Necrosis Factor receptor CD27, making it a potential target for co-stimulation and re-activation of tumor-infiltrated and tumor-reactive T cells. Anti-cancer therapeutics based on exploiting CD27-mediated T cell co-stimulation have proven safe, but clinical responses remain limited. This is likely because current monoclonal antibodies fail to effectively activate CD27 signaling, as this receptor requires higher-order receptor cross-linking. Here, we report on a bispecific antibody, CD27xEGFR, that targets both CD27 and the tumor antigen, epidermal growth factor receptor (EGFR). By targeting EGFR, which is commonly expressed on carcinomas, CD27xEGFR induced cancer cell-localized crosslinking and activation of CD27. The design of CD27xEGFR includes an Fc-silent domain, which is designed to minimize potential toxicity by reducing Fc gamma receptor-mediated binding and activation of immune cells. CD27xEGFR bound to both of its targets simultaneously and triggered EGFR-restricted co-stimulation of T cells as measured by T cell proliferation, T cell activation markers, cytotoxicity and IFN-γ release. Further, CD27xEGFR augmented T cell cytotoxicity in a panel of artificial antigen-presenting carcinoma cell line models, leading to Effector-to-Target ratio-dependent elimination of cancer cells. Taken together, we present the in vitro characterization of a novel bispecific antibody that re-activates T cell immunity in EGFR-expressing cancers through targeted co-stimulation of CD27. </p

Effect evaluation of a two-year complex intervention to reduce loneliness in non-institutionalised elderly Dutch people

Background: Public health policy calls for intervention programmes to reduce loneliness in the ageing population. So far, numerous loneliness interventions have been developed, with effectiveness demonstrated for few of these interventions. The loneliness intervention described in this manuscript distinguishes itself from others by including multiple intervention components and targeting individuals and their environment. Intervention components included a mass media campaign, information meetings, psychosocial group courses, social activities organised by neighbours, and training of intermediaries. The aim of this manuscript is to study the effects of this integrated approach on initial and long-term outcomes. Methods: A quasi-experimental pre-test post-test intervention study was conducted among non-institutionalised elderly people aged 65 years and over to evaluate the effectiveness of the intervention by comparing the intervention community and the control community. Data on outputs, initial and long-term outcomes, and the overall goal were collected by self-administered questionnaires. Data of 858 elderly people were available for the analyses. To assess the effect linear regression analyses with adjustments for age, gender, church attendance, and mental health were used. In addition, the process evaluation provided information about the reach of the intervention components. Results: After two years, 39% of the elderly people were familiar with the intervention programme. The intervention group scored more favourably than the control group on three subscales of the initial outcome, motivation (-4.4%, 95% CI-8.3-0.7), perceived social support (-8.2%, 95% CI-13.6-2.4), and subjective norm (-11.5%, 95% CI-17.4-5.4). However, no overall effects were observed for the long-term outcome, social support, and overall goal, loneliness. Conclusions: Two years after its initiation the reach of the intervention programme was modest. Though no effect of the complex intervention was found on social support and loneliness, more favourable scores on loneliness literacy subscales were induced

Parquet approach to nonlocal vertex functions and electrical conductivity of disordered electrons

A diagrammatic technique for two-particle vertex functions is used to describe systematically the influence of spatial quantum coherence and backscattering effects on transport properties of noninteracting electrons in a random potential. In analogy with many-body theory we construct parquet equations for topologically distinct {\em nonlocal} irreducible vertex functions into which the {\em local} one-particle propagator and two-particle vertex of the coherent-potential approximation (CPA) enter as input. To complete the two-particle parquet equations we use an integral form of the Ward identity and determine the one-particle self-energy from the known irreducible vertex. In this way a conserving approximation with (Herglotz) analytic averaged Green functions is obtained. We use the limit of high spatial dimensions to demonstrate how nonlocal corrections to the $d=\infty$ (CPA) solution emerge. The general parquet construction is applied to the calculation of vertex corrections to the electrical conductivity. With the aid of the high-dimensional asymptotics of the nonlocal irreducible vertex in the electron-hole scattering channel we derive a mean-field approximation for the conductivity with vertex corrections. The impact of vertex corrections onto the electronic transport is assessed quantitatively within the proposed mean-field description on a binary alloy.Comment: REVTeX 19 pages, 9 EPS diagrams, 6 PS figure

"Optical conductance fluctuations: diagrammatic analysis in Landauer approach and non-universal effects"

The optical conductance of a multiple scattering medium is the total transmitted light of a diffuse incoming beam. This quantity, very analogous to the electronic conductance, exhibits universal conductance fluctuations. We perform a detailed diagrammatic analysis of these fluctuations. With a Kadanoff-Baym technique all the leading diagrams are systematically generated. A cancellation of the short distance divergencies occurs, that yields a well behaved theory. The analytical form of the fluctuations is calculated and applied to optical systems. Absorption and internal reflections reduce the fluctuations significantly.Comment: 25 pages Revtex 3.0, 18 seperate postscript figure

Meta-GWAS Accuracy and Power (MetaGAP) Calculator Shows that Hiding Heritability Is Partially Due to Imperfect Genetic Correlations across Studies

Large-scale genome-wide association results are typically obtained from a fixed-effects meta-analysis of GWAS summary statistics from multiple studies spanning different regions and/or time periods. This approach averages the estimated effects of genetic variants across studies. In case genetic effects are heterogeneous across studies, the statistical power of a GWAS and the predictive accuracy of polygenic scores are attenuated, contributing to the so-called ‘missing heritability’. Here, we describe the online Meta-GWAS Accuracy and Power (MetaGAP) calculator (available at www.devlaming.eu) which quantifies this attenuation based on a novel multi-study framework. By means of simulation studies, we show that under a wide range of genetic architectures, the statistical power and predictive accuracy provided by this calculator are accurate. We compare the predictions from the MetaGAP calculator with actual results obtained in the GWAS literature. Specifically, we use genomic-relatedness-matrix restricted maximum likelihood to estimate the SNP heritability and cross-study genetic correlation of height, BMI, years of education, and self-rated health in three large samples. These estimates are used as input parameters for the MetaGAP calculator. Results from the calculator suggest that cross-study heterogeneity has led to attenuation of statistical power and predictive accuracy in recent large-scale GWAS efforts on these traits (e.g., for years of education, we estimate a relative loss of 51–62% in the number of genome-wide significant loci and a relative loss in polygenic score R2of 36–38%). Hence, cross-study heterogeneity contributes to the missing heritability

Genomic analysis of diet composition finds novel loci and associations with health and lifestyle

We conducted genome-wide association study (GWAS) meta-analyses of relative caloric intake from fat, protein, carbohydrates and sugar in over 235,000 individuals. We identified 21 approximately independent lead SNPs. Relative protein intake exhibits the strongest relationships with poor health, including positive genetic associations with obesity, type 2 diabetes, and heart disease ( ≈ 0.15 − 0.5). Relative carbohydrate and sugar intake have negative genetic correlations with waist circumference, waist-hip ratio, and neighborhood poverty (|| ≈ 0.1 − 0.3). Overall, our results show that the relative intake of each macronutrient has a distinct genetic architecture and pattern of genetic correlations suggestive of health implications beyond caloric content