Cause and context: place-based approaches to investigate how environments affect mental health

Objectives Our surroundings affect our mood, our recovery from stress, our behavior, and, ultimately, our mental health. Understanding how our surroundings influence mental health is central to creating healthy cities. However, the traditional observational methods now dominant in the psychiatric epidemiology literature are not sufficient to advance such an understanding. In this essay we consider potential alternative strategies, such as randomizing people to places, randomizing places to change, or harnessing natural experiments that mimic randomized experiments. Methods We discuss the strengths and weaknesses of these methodological approaches with respect to (1) defining the most relevant scale and characteristics of context, (2) disentangling the effects of context from the effects of individuals’ preferences and prior health, and (3) generalizing causal effects beyond the study setting. Results Promising alternative strategies include creating many small-scale randomized place-based trials, using the deployment of place-based changes over time as natural experiments, and using fluctuations in the changes in our surroundings in combination with emerging data collection technologies to better understand how surroundings influence mood, behavior, and mental health. Conclusions Improving existing research strategies will require interdisciplinary partnerships between those specialized in mental health, those advancing new methods for place effects on health, and those who seek to optimize the design of local environments

Pediatric Anesthesia and Neurodevelopmental Impairments: A Bayesian Meta-analysis

Experimental evidence of anesthesia-induced neurotoxicity has caused serious concern about the long-term effect of commonly used volatile anesthetic agents on young children. Several observational studies based on existing data have been conducted to address this concern with inconsistent results. We conducted a meta-analysis to synthesize the epidemiologic evidence on the association of anesthesia/surgery with neurodevelopmental outcomes in children. Using Bayesian meta-analytic approaches, we estimated the synthesized odds ratios (OR) and 95% credible interval (CrI) as well as the predictive distribution of a future study given the synthesized evidence. Data on 7 unadjusted and 6 adjusted measures of association were abstracted from 7 studies. The synthesized OR based on the 7 unadjusted measures for the association of anesthesia/surgery with an adverse behavioral or developmental outcome was 1.9 (95% CrI, 1.2-3.0). The most likely unadjusted OR from a future study was estimated to be 2.2 (95% CrI, 0.6-6.1). The synthesized OR based on the 6 adjusted measures for the association of anesthesia/surgery with an adverse behavioral or developmental outcome was 1.4 (95% CrI, 0.9-2.2). The most likely adjusted OR from a future study was estimated to be 1.5 (95% CrI, 0.5-4.0). We conclude that existent epidemiologic evidence suggests a modestly elevated risk of adverse behavioral or developmental outcomes in children who were exposed to anesthesia/surgery during early childhood. The evidence, however, is considerably uncertain

Global turnover of histone post-translational modifications and variants in human cells

<p>Abstract</p> <p>Background</p> <p>Post-translational modifications (PTMs) on the N-terminal tails of histones and histone variants regulate distinct transcriptional states and nuclear events. Whereas the functional effects of specific PTMs are the current subject of intense investigation, most studies characterize histone PTMs/variants in a non-temporal fashion and very few studies have reported kinetic information about these histone forms. Previous studies have used radiolabeling, fluorescence microscopy and chromatin immunoprecipitation to determine rates of histone turnover, and have found interesting correlations between increased turnover and increased gene expression. Therefore, histone turnover is an understudied yet potentially important parameter that may contribute to epigenetic regulation. Understanding turnover in the context of histone modifications and sequence variants could provide valuable additional insight into the function of histone replacement.</p> <p>Results</p> <p>In this study, we measured the metabolic rate of labeled isotope incorporation into the histone proteins of HeLa cells by combining stable isotope labeling of amino acids in cell culture (SILAC) pulse experiments with quantitative mass spectrometry-based proteomics. In general, we found that most core histones have similar turnover rates, with the exception of the H2A variants, which exhibit a wider range of rates, potentially consistent with their epigenetic function. In addition, acetylated histones have a significantly faster turnover compared with general histone protein and methylated histones, although these rates vary considerably, depending on the site and overall degree of methylation. Histones containing transcriptionally active marks have been consistently found to have faster turnover rates than histones containing silent marks. Interestingly, the presence of both active and silent marks on the same peptide resulted in a slower turnover rate than either mark alone on that same peptide. Lastly, we observed little difference in the turnover between nearly all modified forms of the H3.1, H3.2 and H3.3 variants, with the notable exception that H3.2K36me2 has a faster turnover than this mark on the other H3 variants.</p> <p>Conclusions</p> <p>Quantitative proteomics provides complementary insight to previous work aimed at quantitatively measuring histone turnover, and our results suggest that turnover rates are dependent upon site-specific post-translational modifications and sequence variants.</p

Metacognition, Social Cognition, and Mentalizing In Psychosis: Are These Distinct Constructs When It Comes To Subjective Experience Or Are We Just Splitting Hairs?

Research using the integrated model of metacognition has suggested that the construct of metacognition could quantify the spectrum of activities that, if impaired, might cause many of the subjective disturbances found in psychosis. Research on social cognition and mentalizing in psychosis, however, has also pointed to underlying deficits in how persons make sense of their experience of themselves and others. To explore the question of whether metacognitive research in psychosis offers unique insight in the midst of these other two emerging fields, we have offered a review of the constructs and research from each field. Following that summary, we discuss ways in which research on metacognition may be distinguished from research on social cognition and mentalizing in three broad categories: (1) experimental procedures, (2) theoretical advances, and (3) clinical applications or indicated interventions. In terms of its research methods, we will describe how metacognition makes a unique contribution to understanding disturbances in how persons make sense of and interpret their own experiences within the flow of life. We will next discuss how metacognitive research in psychosis uniquely describes an architecture which when compromised – as often occurs in psychosis – results in the loss of persons’ sense of purpose, possibilities, place in the world and cohesiveness of self. Turning to clinical issues, we explore how metacognitive research offers an operational model of the architecture which if repaired or restored should promote the recovery of a coherent sense of self and others in psychosis. Finally, we discuss the concrete implications of this for recovery-oriented treatment for psychosis as well as the need for further research on the commonalities of these approaches

Early Childhood Exposure to Anesthesia and Risk of Developmental and Behavioral Disorders in a Sibling Birth Cohort

Background: In vitro and in vivo studies of anesthetics have demonstrated serious neurotoxic effects on the developing brain. However, the clinical relevance of these findings to children undergoing anesthesia remains unclear. Using data from a sibling birth cohort, we assessed the association between exposure to anesthesia in the setting of surgery in patients younger than 3 years and the risk of developmental and behavioral disorders. Methods: We constructed a retrospective cohort of 10,450 siblings who were born between 1999 and 2005 and who were enrolled in the New York State Medicaid program. The exposed group was 304 children without a history of developmental or behavioral disorders who underwent surgery when they were younger than 3 years. The unexposed group was 10,146 children who did not receive any surgical procedures when they were younger than 3 years. Exposed children were entered into analysis at the date of surgery. Unexposed children were entered into analysis at age 10 months (the mean age at which exposed children underwent surgery). Both exposed and unexposed children were followed until diagnosis with a developmental or behavioral disorder, loss to follow-up, or the end of 2005. The association of exposure to anesthesia with subsequent developmental and behavioral disorders was assessed with both proportional hazards modeling, and pair-matched analysis. Results: The incidence of developmental and behavioral disorders was 128.2 diagnoses per 1000 person-years for the exposed cohort and 56.3 diagnoses per 1000 person-years for the unexposed cohort. With adjustment for sex and history of birth-related medical complications, and clustering by sibling status, the estimated hazard ratio of developmental or behavioral disorders associated with any exposure to anesthesia when they were younger than 3 years was 1.6 (95% confidence interval [CI]: 1.4, 1.8). The risk increased from 1.1 (95% CI: 0.8, 1.4) for 1 operation to 2.9 (94% CI: 2.5, 3.1) for 2 operations and 4.0 (95% CI: 3.5, 4.5) for ≥3 operations. The relative risk in a matched analysis of 138 sibling pairs was 0.9 (95% CI: 0.6, 1.4). Conclusion: The risk of being subsequently diagnosed with developmental and behavioral disorders in children who were enrolled in a state Medicaid program and who had surgery when they were younger than 3 years was 60% greater than that of a similar group of siblings who did not undergo surgery. More tightly matched pairwise analyses indicate that the extent to which the excess risk is causally attributable to anesthesia or mediated by unmeasured factors remains to be determined

The global field of multi-family offices: An institutionalist perspective

We apply the notion of the organisational field to internationally operating multi-family offices. These organisations specialise on the preservation of enterprising and geographically dispersed families’ fortunes. They provide their services across generations and countries. Based on secondary data of Bloomberg’s Top 50 Family Offices, we show that they constitute a global organisational field that comprises two clusters of homogeneity. Clients may decide between two different configurations of activities, depending on their preferences regarding asset management, resource management, family management, and service architecture. The findings also reveal that multi-family offices make relatively similar value propositions all over the world. The distinctiveness of the clusters within the field is not driven by the embeddedness of the multi-family offices in different national environments or their various degrees of international experience. Rather, it is weakly affected by two out of four possible value propositions, namely the exclusiveness and the transparency of services

Metacognition Is Necessary for the Emergence of Motivation in People With Schizophrenia Spectrum Disorders: A Necessary Condition Analysis

Metacognition deficits are a putative cause of reduced motivation in people with schizophrenia spectrum disorders. However, it is unclear whether certain levels of metacognition are necessary for motivation to emerge. This study used a Necessary Condition Analysis (NCA) to test whether metacognition was necessary for the presence of motivation and to identify the minimum level of metacognition necessary for high motivation to be possible in people with schizophrenia spectrum disorders (N=175). Participants completed clinician-rated measures of metacognition and motivation. NCA revealed that metacognition is a necessary condition for motivation and that high levels of motivation were only possible, although not guaranteed, when at least a basic level of metacognition was present. Findings suggest that metacognition is a necessary building block for the development of motivation. Results suggest that targeting metacognition may be essential for improving motivation among people with schizophrenia spectrum disorders who do not meet this metacognition threshold

A quantitative atlas of histone modification signatures from human cancer cells

BACKGROUND: An integral component of cancer biology is the understanding of molecular properties uniquely distinguishing one cancer type from another. One class of such properties is histone post-translational modifications (PTMs). Many histone PTMs are linked to the same diverse nuclear functions implicated in cancer development, including transcriptional activation and epigenetic regulation, which are often indirectly assayed with standard genomic technologies. Thus, there is a need for a comprehensive and quantitative profiling of cancer lines focused on their chromatin modification states. RESULTS: To complement genomic expression profiles of cancer lines, we report the proteomic classification of 24 different lines, the majority of which are cancer cells, by quantifying the abundances of a large panel of single and combinatorial histone H3 and H4 PTMs, and histone variants. Concurrent to the proteomic analysis, we performed transcriptomic analysis on histone modifying enzyme abundances as a proxy for quantifying their activity levels. While the transcriptomic and proteomic results were generally consistent in terms of predicting histone PTM abundance from enzyme abundances, several PTMs were regulated independently of the modifying enzyme expression. In addition, combinatorial PTMs containing H3K27 methylation were especially enriched in breast cell lines. Knockdown of the predominant H3K27 methyltransferase, enhancer of zeste 2 (EZH2), in a mouse mammary xenograft model significantly reduced tumor burden in these animals and demonstrated the predictive utility of proteomic techniques. CONCLUSIONS: Our proteomic and genomic characterizations of the histone modification states provide a resource for future investigations of the epigenetic and non-epigenetic determinants for classifying and analyzing cancer cells

Entrepreneurial sons, patriarchy and the Colonels' experiment in Thessaly, rural Greece

Existing studies within the field of institutional entrepreneurship explore how entrepreneurs influence change in economic institutions. This paper turns the attention of scholarly inquiry on the antecedents of deinstitutionalization and more specifically, the influence of entrepreneurship in shaping social institutions such as patriarchy. The paper draws from the findings of ethnographic work in two Greek lowland village communities during the military Dictatorship (1967–1974). Paradoxically this era associated with the spread of mechanization, cheap credit, revaluation of labour and clear means-ends relations, signalled entrepreneurial sons’ individuated dissent and activism who were now able to question the Patriarch’s authority, recognize opportunities and act as unintentional agents of deinstitutionalization. A ‘different’ model of institutional change is presented here, where politics intersects with entrepreneurs, in changing social institutions. This model discusses the external drivers of institutional atrophy and how handling dissensus (and its varieties over historical time) is instrumental in enabling institutional entrepreneurship