The moderating effect of mental health and health insurance ownership on the relationships between physical multimorbidity and healthcare utilisation and catastrophic health expenditure in India.

BACKGROUND: The current demographic transition has resulted in the growth of the older population in India, a population group which has a higher chance of being affected by multimorbidity and its subsequent healthcare and economic consequences. However, little attention has been paid to the dual effect of mental health conditions and physical multimorbidity in India. The present study, therefore, aimed to analyse the moderating effects of mental health and health insurance ownership in the association between physical multimorbidity and healthcare utilisation and catastrophic health expenditure (CHE). METHODS: We analysed the Longitudinal Aging Study in India, wave 1 (2017-2018). We determined physical multimorbidity by assessing the number of physical conditions. We built multivariable logistic regression models to determine the moderating effect of mental health and health insurance ownership in the association between the number of physical conditions and healthcare utilisation and CHE. Wald tests were used to evaluate if the estimated effects differ across groups defined by the moderating variables. RESULTS: Overall, around one-quarter of adults aged 45 and above had physical multimorbidity, one-third had a mental health condition and 20.5% owned health insurance. Irrespective of having a mental condition and health insurance, physical multimorbidity was associated with increased utilisation of healthcare and CHE. Having an additional mental condition strengthened the adverse effect of physical multimorbidity on increased inpatient service use and experience of CHE. Having health insurance, on the other hand, attenuated the effect of experiencing CHE, indicating a protective effect. CONCLUSIONS: The coexistence of mental health conditions in people with physical multimorbidity increases the demands of healthcare service utilisation and can lead to CHE. The findings point to the need for multidisciplinary interventions for individuals with physical multimorbidity, ensuring their mental health needs are also addressed. Our results urge enhancing health insurance schemes for individuals with mental and physical multimorbidity.

Integrating the social environment with an equity perspective into the exposome paradigm: A new conceptual framework of the Social Exposome.

The importance of the social environment and social inequalities in disease etiology is well-known due to the profound research and conceptual framework on social determinants of health. For a long period, in exposome research with its classical orientation towards detrimental health effects of biological, chemical, and physical exposures, this knowledge remained underrepresented. But currently it gains great awareness and calls for innovations in rethinking the role of social environmental health determinants. To fill this gap that exists in terms of the social domain within exposome research, we propose a novel conceptual framework of the Social Exposome, to integrate the social environment in conjunction with the physical environment into the exposome concept. The iterative development process of the Social Exposome was based on a systematic compilation of social exposures in order to achieve a holistic portrayal of the human social environment - including social, psychosocial, socioeconomic, sociodemographic, local, regional, and cultural aspects, at individual and contextual levels. In order to move the Social Exposome beyond a mere compilation of exposures, three core principles are emphasized that underly the interplay of the multitude of exposures: Multidimensionality, Reciprocity, and Timing and continuity. The key focus of the conceptual framework of the Social Exposome is on understanding the underlying mechanisms that translate social exposures into health outcomes. In particular, insights from research on health equity and environmental justice have been incorporated to uncover how social inequalities in health emerge, are maintained, and systematically drive health outcomes. Three transmission pathways are presented: Embodiment, Resilience and Susceptibility or Vulnerability, and Empowerment. The Social Exposome conceptual framework may serve as a strategic map for, both, research and intervention planning, aiming to further explore the impact of the complex social environment and to alter transmission pathways to minimize health risks and health inequalities and to foster equity in health.

Social Inequalities in Exposure to Ambient Air Pollution: A Systematic Review in the WHO European Region.

Ambient air pollution is a long-standing and significant public health issue. The aim of this review is to systematically examine the peer-reviewed evidence on social inequalities and ambient air pollution in the World Health Organization European Region. Articles published between 2010 and 2017 were analyzed in the review. In total 31 articles were included in the review. There is good evidence from ecological studies that higher deprivation indices and low economic position are usually linked with higher levels of pollutants such as particulate matter (particulate matter under 2.5 and 10 microns in diameter, PM2.5, PM10) and oxides of nitrogen (e.g., NO2, and NOx). There is also evidence that ethnic minorities experience a mixed exposure in comparison to the majority population being sometimes higher and sometimes lower depending on the ethnic minority under consideration. The studies using data at the individual level in this review are mainly focused on pregnant women or new mothers, in these studies deprivation and ethnicity are more likely to be linked to higher exposures of poor air quality. Therefore, there is evidence in this review that the burden of higher pollutants falls disproportionally on different social groups.

Social Inequalities in Environmental Resources of Green and Blue Spaces: A Review of Evidence in the WHO European Region.

Residential green and blue spaces and their potential health benefits have received increasing attention in the context of environmental health inequalities, because an unequal social distribution of these resources may contribute to inequalities in health outcomes. This systematic review synthesised evidence of environmental inequalities, focusing on availability and accessibility measures of green and blue spaces. Studies in the World Health Organisation (WHO) European Region published between 2010 and 2017 were considered for the review. In total, 14 studies were identified, where most of them (n = 12) analysed inequalities of green spaces. The majority had an ecological study design that mostly applied deprivation indices on the small area level, whereas cross-sectional studies on the individual level mostly applied single social measures. Ecological studies consistently showed that deprived areas had lower green space availability than more affluent areas, whereas mixed associations were found for single social dimensions in cross-sectional studies on the individual level. In order to gain more insights into how various social dimensions are linked to the distribution of environmental resources within the WHO European Region, more studies are needed that apply comparable methods and study designs for analysing social inequalities in environmental resources.

Social Inequalities in Environmental Noise Exposure: A Review of Evidence in the WHO European Region.

Environmental noise is an important public health problem, being among the top environmental risks to health. The burden of noise exposure seems to be unequally distributed in societies. Up to now there is fragmentary evidence regarding which social groups are most affected. The aim of this review was to systematically assess published evidence on social inequalities in environmental noise exposure in the WHO European Region, taking different sociodemographic and socioeconomic dimensions as well as subjective and objective measures of environmental noise exposure into account. Articles published in English in a peer reviewed journal between 2010 and 2017 were included in the review. Eight studies were finally included in the review, four of them analysed aggregated data and four analysed individual data. Though results of social inequalities in noise exposures were mixed between and within studies, there was a trend that studies using indicators of material deprivation and deprivation indices showed higher environmental noise exposures in groups with lower socioeconomic position. More research on the social distribution of environmental noise exposure on a small spatial scale is needed, taking into account aspects of vulnerability and procedural justice.

Relations between Objective and Perceived Built Environments and the Modifying Role of Individual Socioeconomic Position. A Cross-Sectional Study on Traffic Noise and Urban Green Space in a Large German City.

Perceived annoyance due to traffic noise and lack of urban green space is mostly determined using data from self-administered questionnaires. However, there is still no clear evidence to what extent such perceived measures are related to objectively assessed environmental data and whether socioeconomic dimensions modify such relationships. In a cross-sectional study in Dortmund, Germany, georeferenced home addresses from parents with preschool aged children were used to analyse relations between exposures to objectively measured green space and traffic noise and subjective annoyance due to noise and lack of green space with the additional consideration of socioeconomic characteristics as effect modifiers. Higher perceived annoyance correlated with higher objectively measured traffic noise and lower objectively measured green, respectively. Stratified logistic regression models indicated a modifying role of socioeconomic characteristics. The strengths of associations between objectively measured environmental exposures and perceived annoyance differed by socioeconomic strata. Especially for noise, odds ratios were higher in low socioeconomic strata than in high socioeconomic strata. Therefore, using objective measures of the built environment as a proxy for individual perception should be made with caution as negative relations between objectively assessed built environments and health could be underestimated when considering individual socioeconomic position only as a confounder.

Gender inequalities in mental wellbeing in 26 European countries: do welfare regimes matter?

BACKGROUND: Nature and extent of welfare regimes and social policies are important determinants of health and health inequalities. This study examines the association of gender and mental wellbeing in European countries and investigates whether type of welfare regime plays a role in this association. METHOD: Data of 19 366 women and 14 338 men of the third round of the European Quality of Life Survey (2011-12) was used to analyse mental wellbeing, assessed by the World Health Organization 5-Mental Wellbeing Index. Multilevel logistic regression analyses were performed to analyse the association between gender and good mental wellbeing first at country-level, and secondly the between country variation was analysed and welfare regimes were included as explanatory variables. RESULTS: We observed cross-national variation in good mental wellbeing. At country levels gender inequalities in good mental wellbeing were observed in 7 out of 26 countries. In analyses considering all countries together gender inequalities in good mental wellbeing were identified independent of further individual socio-demographic variables and independent of the welfare regimes that people lived in [women vs. men: OR = 0.76; (95% CI = 0.71-0.81)]. Gender inequalities in good mental wellbeing were not modified by welfare regimes. CONCLUSION: There are cross-national differences in good mental wellbeing between European countries. Gender inequalities with a lower prevalence of good mental wellbeing among women are common in European countries. This study suggests that welfare regimes do not modify these gender inequalities in mental wellbeing.

Environmental noise and incident mental health problems: A prospective cohort study among school children in Germany.

BACKGROUND: Environmental noise is considered a threat to public health as 20% of the EU population is exposed to health influencing noise levels. An association of noise and mental health problems in children has been suggested by some studies, but results are not consistent and there are no longitudinal studies of this association. Our aim was to investigate the influence of different environmental noise sources at children's homes on incident mental health problems in school-aged children. METHOD: A cohort study of children from first (t0) to fourth grade (t1) of primary school was conducted. Different environmental noise sources (day/night separately) at children's home were assessed via parental annoyance reports. Increased noise exposure between t0 and t1 was the exposure variable. Incident mental health problems were assessed with the parental version of the Strengths and Difficulties Questionnaire (SDQ). RRs and 95% CIs were analysed to investigate the association between different noise sources and incident mental health problems. RESULTS: The study population consisted of 583 boys and 602 girls. The most common increase in noise exposure between t0 and t1 was road traffic noise day (26.38%). After adjusting for covariates exposure to road traffic night was significantly associated with the total difficulties score (RR=2.06; 95% CI=1.25-3.40), emotional symptoms (RR=1.69, 95% CI=1.04-2.72), and conduct problems (RR=1.57, 95% CI=1.04-2.38). Noise by neighbours during the day was associated with conduct problems (RR=1.62, 95% CI=1.11-2.40) and hyperactivity (RR=1.69, 95% CI=1.08-2.65). Aircraft noise day and construction work day were not associated with any of the SDQ categories at a significant level. CONCLUSION: Environmental noise is an important public health problem. This is the first study to investigate the association of a broad range of noise sources and incident mental health problems in children in a cohort study. Our results suggest that exposure to noise at children's home is associated with mental health problems such as emotional symptoms, conduct problems and hyperactivity.

Material, psychosocial and sociodemographic determinants are associated with positive mental health in Europe: a cross-sectional study.

OBJECTIVES: To investigate the association between psychosocial, sociodemographic and material determinants of positive mental health in Europe. DESIGN: Cross-sectional analysis of survey data. SETTING: 34 European countries. PARTICIPANTS: Representative Europe-wide sample consisting of 21 066 men and 22 569 women aged 18 years and over, from 34 European countries participating in the third wave of the European Quality of Life Survey (2011-2012). OUTCOME: Positive mental health as measured by the WHO-5-Mental Well-being Index, while the lowest 25% centile indicated poor positive mental health. RESULTS: The prevalence of poor positive mental health was 30% in women and 24% in men. Material, as well as psychosocial, and sociodemographic factors were independently associated with poor positive mental health in a Europe-wide sample from 34 European countries. When studying all factors together, the highest OR for poor positive mental health was reported for social exclusion (men: OR=1.73, 95% CI 1.59 to 1.90; women: OR=1.69, 95% CI 1.57 to 1.81) among the psychosocial factors. Among the material factors, material deprivation had the highest impact (men: OR=1.96, 95% CI 1.78 to 2.15; women: OR=1.93, 95% CI 1.79 to 2.08). CONCLUSIONS: This study gives the first overview on determinants of positive mental health at a European level and could be used as the basis for preventive policies in the field of positive mental health in Europe.

Killing of rat basophilic leukemia cells by lethal toxin from Clostridium sordellii: critical role of phosphatidylinositide 3'-OH kinase/Akt signaling.

Clostridium sordellii lethal toxin (TcsL) belongs to the family of clostridial glucosylating toxins. TcsL exhibits glucosyltransferase activity to inactivate Rho and Ras proteins. On cultured cells, TcsL causes actin reorganization ("cytopathic effect") and apoptotic cell death ("cytotoxic effect"). This study is based on the concept that the cytotoxic effects of TcsL depend on the glucosylation of critical substrate proteins rather than on the glucosyltransferase activity per se. The cytotoxic effects of TcsL depend on the glucosyltransferase activity of TcsL, as neither chemically inactivated TcsL nor a glucosyltransferase-deficient mutant version of TcsL caused it. The TcsL homologous toxin B from Clostridium difficile serotype F strain 1470 (TcdBF) also failed to cause cytotoxic effects. Correlation of the toxins' respective protein substrate specificities highlighted (H/K/N)Ras as critical substrate proteins for the cytotoxic effects. (H/K/N)Ras are critical upstream regulators of phosphatidylinositide 3'-OH kinase (PI3K)/Akt survival signaling. Tauroursodeoxycholic acid (TUDCA) classified to activate PI3K/Akt signaling downstream of apoptosis-inducing stimuli prevented the cytotoxic effects of TcsL. In conclusion, (H/K/N)Ras glucosylation and subsequent inhibition of PI3K/Akt signaling are critical for the cytotoxic effects of TcsL.

A 29-amino acid fragment of Clostridium botulinum C3 protein enhances neuronal outgrowth, connectivity, and reinnervation.

Small GTPases of the Rho family play versatile roles in the formation and development of axons and dendrites, effects often studied by the Rho-inactivating C3 transferase (C3bot) from Clostridium botulinum. Recently, we reported that transferase-deficient C3bot also exerted axonotrophic activity. Using overlapping peptides from the C3bot sequence, we identified a small peptide of 29 amino acids (covering residues 154-182) from the C-terminal region of C3bot that promotes both axonal and dendritic growth, as well as branching of hippocampal neurons, at submicromolar concentrations. Several C3bot constructs, including the short peptide, enhanced the number of axonal segments from mid- to higher-order segments. C3bot(154-182) also increased the number of synaptophysin-expressing terminals, up-regulated various synaptic proteins, and functionally increased the glutamate uptake. Staining against the vesicular glutamate and GABA transporters further revealed that the effect was attributable to a higher number of glutamatergic and GABAergic inputs on proximal dendrites of enhanced green fluorescent protein (EGFP)-transfected neurons. Using organotypical slice cultures, we also detected trophic effects of C3bot(154-182) on length and density of outgrowing fibers from the entorhinal cortex that were comparable to the effects elicited by full-length C3bot. In addition, an enhanced reinnervation was observed in a hippocampal-entorhinal lesion model. In summary, the neurotrophic effect of C3bot is executed by a C-terminal peptide fragment covering aa 154-182 of C3; it triggers dendritic and axonal growth and branching as well as increased synaptic connectivity. In contrast to full-length C3, this C3 peptide selectively acts on neurons but not on glial cells.

Clostridium difficile toxins: more than mere inhibitors of Rho proteins.

Toxin A (TcdA) and Toxin B (TcdB) are the major pathogenicity factors of the Clostridium difficile-associated diarrhoea (CDAD). The single-chained protein toxins enter their target cells by receptor-mediated endocytosis. New data show the critical role of auto-catalytic processing for target cell entry. Inside the cell, the toxins mono-glucosylate and thereby inactivate low molecular mass GTP-binding proteins of the Rho subfamily. Toxin-treated cells respond to RhoA glucosylation with up-regulation and activation of the pro-apoptotic Rho family protein RhoB. These data reinforce the critical role of the glucosyltransferase activity for programmed cell death and show that TcdA and TcdB, generally classified as broad-spectrum inhibitors of Rho proteins, are also capable of activating Rho proteins.

Upregulation of the immediate early gene product RhoB by exoenzyme C3 from Clostridium limosum and toxin B from Clostridium difficile.

ADP-ribosylation of Rho(A,B,C) by the family of exoenzyme C3-like transferases induces reorganization of the actin cytoskeleton based on inactivation of RhoA. No data are available on the role of RhoB in C3-treated cells. In murine fibroblasts treated with the cell-permeable exoenzyme C3 from Clostridium limosum (C3), an increase in the level of RhoB was observed. This upregulation of RhoB was based on transcriptional activation, as it was responsive to inhibition by actinomycin D and accompanied by activation of the rhoB promoter. Upregulation of RhoB was not observed in cells treated with either the actin ADP-ribosylating C2 toxin from Clostridium botulinum or latrunculin B, suggesting that inactivation of Rho but not actin reorganization was required for the upregulation of RhoB. This notion was confirmed, as the Rho/Rac/Cdc42-glucosylating toxin B from Clostridium difficile (TcdB) but not the Rac/R-Ras-glucosylating variant toxin B from C. difficile strain 1470 serotype F (TcdBF) induced a strong upregulation of RhoB. Upregulation of RhoB was further observed in response to the Rac/(H-,K-,N-,R-)Ras-glucosylating lethal toxin from Clostridium sordellii. The level of active, GTP-bound RhoB was increased in TcdB-treated cells compared to untreated cells (as determined by Rhotekin pull-down assay). In contrast, no active RhoB was found in C3-treated cells. RhoB-GTP was required for the TcdB-induced apoptosis (cytotoxic effect), as this effect was responsive to inhibition by C3. In conclusion, RhoB was upregulated by Rho-/Ras-inactivating toxins, as a consequence of the inactivation of either Rho(A,B,C) or (H-,K-,N-)Ras. In TcdB-treated cells, RhoB escaped its inactivation and was required for the cytotoxic effect.

Difference in the cytotoxic effects of toxin B from Clostridium difficile strain VPI 10463 and toxin B from variant Clostridium difficile strain 1470.

Glucosylation of RhoA, Rac1, and Cdc42 by Clostridium difficile toxin B from strain VPI 10463 (TcdB) results in actin reorganization (cytopathic effect) and apoptosis (cytotoxic effect). Toxin B from variant C. difficile strain 1470 serotype F (TcdBF) differs from TcdB with regard to substrate proteins, as it glucosylates Rac1 and R-Ras but not RhoA and Cdc42. In this study, we addressed the question of whether the cellular effects of the toxins depend on their protein substrate specificity. Rat basophilic leukemia (RBL) cells were synchronized using the thymidine double-block technique. We show that cells were most sensitive to the cytotoxic effect of TcdB in S phase, as analyzed in terms of phosphatidyl serine externalization, fragmentation of nuclei, and activation of caspase-3; in contrast, TcdBF induced only a marginal cytotoxic effect, suggesting that inactivation of RhoA (but not of Rac1) was required for the cytotoxic effect. The glucosylation of Rac1 was correlated to the cytopathic effect of either toxin, suggesting a close connection of the two effects. The cytotoxic effect of TcdB was executed by caspase-3, as it was responsive to inhibition by acetyl-Asp-Met-Gln-Asp-aldehyde (Ac-DMQD-CHO), an inhibitor of caspase-3. The viability of TcdB-treated RBL cells was reduced, whereas the viability of TcdBF-treated cells was unchanged, further confirming that inactivation of RhoA is required for the cytotoxic effect. In conclusion, the protein substrate specificity of the glucosylating toxins determines their biological activity.