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

第9章 大学コンソーシアムひょうご神戸 社会連携助成事業 : 「平常時・災害時における歴史資料の保全・修復ができる人材の育成事業

In recent years, there has been a considerable amount of research on the use of regularization methods for inference and prediction in quantitative genetics. Such research mostly focuses on selection of markers and shrinkage of their effects. In this review paper, the use of ridge regression for prediction in quantitative genetics using single-nucleotide polymorphism data is discussed. In particular, we consider (i) the theoretical foundations of ridge regression, (ii) its link to commonly used methods in animal breeding, (iii) the computational feasibility, and (iv) the scope for constructing prediction models with nonlinear effects (e.g., dominance and epistasis). Based on a simulation study we gauge the current and future potential of ridge regression for prediction of human traits using genome-wide SNP data. We conclude that, for outcomes with a relatively simple genetic architecture, given current sample sizes in most cohorts (i.e., N<10,000) the predictive accuracy of ridge regression is slightly higher than the classical genome-wide association study approach of repeated simple regression (i.e., one regression per SNP). However, both capture only a small proportion of the heritability. Nevertheless, we find evidence that for large-scale initiatives, such as biobanks, sample sizes can be achieved where ridge regression compared to the classical approach improves predictive accuracy substantially

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

Monitoring nutrient¯ows and economic performance in African farming systems (NUTMON) II. Tool development

Abstract Farm-NUTMON is a research tool that integrates the assessment of stocks and¯ows of the macro-nutrients nitrogen, phosphorus and potassium on the one hand and economic farm analysis on the other. The tool is applicable at both the farm and the activity level. It includes a structured questionnaire, a database, and two simple static models (NUTCAL for calculation of nutrient¯ows and the ECCAL for calculation of economic parameters). Finally, a user interface facilitates data entry, data manipulation and extracts data from the database to produce input for both models. Farm-NUTMON allows (i) estimation of the extent to which farmers generate income from soil nutrient mining, (ii) assessment of the impact of changes in farm management techniques on nutrient balance and economic performance at activity level and farm level, and (iii) calculation of the economic impact of exogenous changes on the farm and activity level.

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

Loneliness Literacy Scale: Development and Evaluation of an Early Indicator for Loneliness Prevention

To develop and evaluate the Loneliness Literacy Scale for the assessment of short-term outcomes of a loneliness prevention programme among Dutch elderly persons. Scale development was based on evidence from literature and experiences from local stakeholders and representatives of the target group. The scale was pre-tested among 303 elderly persons aged 65 years and over. Principal component analysis and internal consistency analysis were used to affirm the scale structure, reduce the number of items and assess the reliability of the constructs. Linear regression analysis was conducted to evaluate the association between the literacy constructs and loneliness. The four constructs “motivation”, “self-efficacy”, “perceived social support” and “subjective norm” derived from principal component analysis captured 56 % of the original variance. Cronbach’s coefficient α was above 0.7 for each construct. The constructs “self-efficacy” and “perceived social support” were positively and “subjective norm” was negatively associated with loneliness. To our knowledge this is the first study developing a short-term indicator for loneliness prevention. The indicator contributes to the need of evaluating public health interventions more close to the intervention activities. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11205-013-0322-y) contains supplementary material, which is available to authorized users

Green functions for nearest- and next-nearest-neighbor hopping on the Bethe lattice

We calculate the local Green function for a quantum-mechanical particle with hopping between nearest and next-nearest neighbors on the Bethe lattice, where the on-site energies may alternate on sublattices. For infinite connectivity the renormalized perturbation expansion is carried out by counting all non-self-intersecting paths, leading to an implicit equation for the local Green function. By integrating out branches of the Bethe lattice the same equation is obtained from a path integral approach for the partition function. This also provides the local Green function for finite connectivity. Finally, a recently developed topological approach is extended to derive an operator identity which maps the problem onto the case of only nearest-neighbor hopping. We find in particular that hopping between next-nearest neighbors leads to an asymmetric spectrum with additional van-Hove singularities.Comment: 16 pages, 7 figures; minor change

CD20 positive CD8 T cells are a unique and transcriptionally-distinct subset of T cells with distinct transmigration properties

Abstract The presence of T cells that are dimly positive for the B cell marker CD20 is well-established in autoimmunity and correlates with disease severity in various diseases. Further, we previously identified that the level of CD20-positive T cells was three–fourfold elevated in ascites fluid of ovarian carcinoma patients, together suggesting a role in both autoimmunity and cancer. In this respect, treatment of autoimmune patients with the CD20-targeting antibody Rituximab has also been shown to target and deplete CD20-positive T cells, previously identified as IFN-gamma producing, low proliferative, CD8 cytotoxic T cells with an effector memory (EM) differentiation state. However, the exact phenotype and relevance of CD20-positive T cells remains unclear. Here, we set out to identify the transcriptomic profile of CD20-positive T cells using RNA sequencing. Further, to gain insight into potential functional properties of CD20 expression in T cells, CD20 was ectopically expressed on healthy human T cells and phenotypic, functional, migratory and adhesive properties were determined in vitro and in vivo. Together, these assays revealed a reduced transmigration and an enhanced adhesive profile combined with an enhanced activation status for CD20-positive T cells