Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials

BACKGROUND: The nocebo effect, when a harmless substance creates harmful effects in a person who takes it, is a clinically salient yet seldom studied phenomenon that may be associated with poorer treatment outcomes, perceived adverse events, and treatment discontinuation. The covert presence of nocebo responders in clinical trials may contribute to outcome variance in both placebo and active treatment arms for important primary and secondary endpoints. Nocebo effects are thought to be driven by expectancy and conditioning. METHOD: This study analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate variables associated with the emergence of adverse outcomes in placebo-treated participants (N = 2,457). Specifically, we examined treatment-emergent adverse events (TEAEs) and discontinuation in placebo-treated individuals. Trials were commenced between 1993 and 2010 as studies of duloxetine versus active comparator and/or placebo. RESULTS: TEAEs were reported by 1,569 placebo-treated participants (63.9%), with 115 (4.7%) discontinuing from the studies due to TEAEs and 274 (11.2%) showing worsening of Hamilton Depression Rating Scale total score during placebo treatment. There was specifically no evidence to support the expectancy hypothesis, that reported TEAEs were influenced by adverse effects described in the clinical trials participant information and consent forms, or the conditioning hypothesis, that reported TEAEs would be influenced by adverse effect profiles of previous antidepressant medications used by these study participants. There was some evidence to suggest that people who had previously used complementary medications were more likely to report TEAEs. Variables specific to individual studies were the strongest predictors of TEAEs. DISCUSSION: In this study, TEAEs were very common among placebo-treated clinical trial participants. Unexpectedly, there was no evidence to associate TEAEs with adverse clinical outcomes, nor were the conditioning or expectancy hypotheses supported by these data. CONCLUSIONS: The nocebo effect is a common, covert, and poorly understood driver of clinical outcomes that requires further investigation.

Social Structural Effects on the Level and Development of the Individual Experience of Anomie in the German Population

Can one observe an increasing level of individual lack of orientation because of rapid social change in modern societies? This question is examined using data from a representative longitudinal survey in Germany conducted in 2002–04. The study examines the role of education, age, sex, region (east/west), and political orientation for the explanation of anomia and its development. First we present the different sources of anomie in modern societies, based on the theoretical foundations of Durkheim and Merton, and introduce the different definitions of anomia, including our own cognitive version. Then we deduce several hypotheses from the theory, which we test by means of longitudinal data for the period 2002–04 in Germany using the latent growth curve model as our statistical method. The empirical findings show that all the sociodemographic variables, including political orientation, are strong predictors of the initial level of anomia. Regarding the development of anomia over time (2002–04), only the region (west) has a significant impact. In particular, the results of a multi-group analysis show that western German people with a right-wing political orientation become more anomic over this period. The article concludes with some theoretical implications.

Meta-analytic model comparisons of surface- and deep-level relational diversity effects on social integration and individual effectiveness

While diversity might give an organization a competitive advantage, individuals have a tendency to prefer homogenous group settings. Prior research suggests that group members who are dissimilar (vs. similar) to their peers in terms of a given diversity attribute (e.g. demographics, attitudes, values or traits) feel less attached to their work group, experience less satisfying and more conflicted relationships with their colleagues, and consequently are less effective. However, prior empirical findings tend to be weak and inconsistent, and it remains unclear when, how and to what extent such differences affect group members’ social integration (i.e. attachment with their work group, satisfaction and conflicted relationships with their peers) and effectiveness. To address these issues the current study conducted a meta-analysis and integrated the empirical results of 129 studies. For demographic diversity attributes (such as gender, ethnicity, race, nationality, age, functional background, and tenure) the findings support the idea that demographic dissimilarity undermines individual member performance via lower levels of social integration. These negative effects were more pronounced in pseudo teams – i.e. work groups in which group members pursue individual goals, work on individual tasks, and are rewarded for their individual performance. These negative effects were however non-existent in real teams - i.e. work groups in which groups members pursue group goals, work on interdependent tasks, and are rewarded (at least partially) based on their work group’s performance. In contrast, for underlying psychological diversity attributes (such as attitudes, personality, and values), the relationship between dissimilarity and social integration was more negative in real teams than in pseudo teams, which in return translated into even lower individual performance. At the same time however, differences in underlying psychological attributes had an even stronger positive effect on dissimilar group member’s individual performance, when the negative effects of social integration were controlled for. This implies that managers should implement real work groups to overcome the negative effects of group member’s demographic dissimilarity. To harness the positive effects of group members’ dissimilarity on underlying psychological attributes, they need to make sure that dissimilar group members become socially integrated.

Surface- and deep-level dissimilarity effects on social integration and individual effectiveness related outcomes in work groups:a meta-analytic integration

Prior research linking demographic (e.g., age, ethnicity/race, gender, and tenure) and underlying psychological (e.g., personality, attitudes, and values) dissimilarity variables to individual group member's work-related outcomes produced mixed and contradictory results. To account for these findings, this study develops a contingency framework and tests it using meta-analytic and structural equation modelling techniques. In line with this framework, results showed different effects of surface-level (i.e., demographic) dissimilarity and deep-level (i.e., underlying psychological) dissimilarity on social integration, and ultimately on individual effectiveness related outcomes (i.e., turnover, task, and contextual performance). Specifically, surface-level dissimilarity had a negative effect on social integration under low but not under high team interdependence. In return, social integration fully mediated the negative relationship between surface-level dissimilarity and individual effectiveness related outcomes under low interdependence. In contrast, deep-level dissimilarity had a negative effect on social integration, which was stronger under high and weaker under low team interdependence. Contrary to our predictions, social integration did not mediate the negative relationship between deep-level dissimilarity and individual effectiveness related outcomes but suppressed positive direct effects of deep-level dissimilarity on individual effectiveness related outcomes. Possible explanations for these counterintuitive findings are discussed. © 2011 The British Psychological Society.

Individual mRNA expression profiles reveal the effects of specific microRNAs

BACKGROUND: MicroRNAs (miRNAs) are oligoribonucleotides with an important role in regulation of gene expression at the level of translation. Despite imperfect target complementarity, they can also significantly reduce mRNA levels. The validity of miRNA target gene predictions is difficult to assess at the protein level. We sought, therefore, to determine whether a general lowering of predicted target gene mRNA expression by endogenous miRNAs was detectable within microarray gene expression profiles. RESULTS: The target gene sets predicted for each miRNA were mapped onto known gene expression data from a range of tissues. Whether considering mean absolute target gene expression, rank sum tests or 'ranked ratios', many miRNAs with significantly reduced target gene expression corresponded to those known to be expressed in the cognate tissue. Expression levels of miRNAs with reduced target mRNA levels were higher than those of miRNAs with no detectable effect on mRNA expression. Analysis of microarray data gathered after artificial perturbation of expression of a specific miRNA confirmed the predicted increase or decrease in influence of the altered miRNA upon mRNA levels. Strongest associations were observed with targets predicted by TargetScan. CONCLUSION: We have demonstrated that the effect of a miRNA on its target mRNAs' levels can be measured within a single gene expression profile. This emphasizes the extent of this mode of regulation in vivo and confirms that many of the predicted miRNA-mRNA interactions are correct. The success of this approach has revealed the vast potential for extracting information about miRNA function from gene expression profiles.

Effects of environment and an introduced invertebrate species on the structure of benthic macroinvertebrate species at the catchment level

Biotic interactions such as predation and competition can influence aquatic communities at small spatial scales, but they are expected to be overridden by environmental factors at large scales. The continuing threat to freshwater biodiversity of biological invasions indicates that biotic factors do, however, have important structuring roles. In Irish rivers, the native amphipod Gammarus duebeni celticus has become locally extinct, ostensibly through differential predation by the more aggressive and introduced G. pulex. This mechanism explains impacts of G. pulex at within-river spatial scales on native macroinvertebrate community diversity, including declines in ephemeropterans, plecopterans, dipterans and oligochaetes. To determine if these patterns are predictable at larger spatial scales, we assessed patterns in native macroinvertebrate communities across river sites of the Erne catchment in 1998 and 1999, in conjunction with the distribution of G. pulex and G. d. celticus. In both years, G. pulex dominated invaded sites, whereas G. d. celticus occurred at low abundance in uninvaded sites. In both years, invaded sites had lower diversity and fewer pollution sensitive invertebrate species than un-invaded sites. Community ordination in 1998 showed that invaded sites had higher conductivity, smaller substrate particle size and comprised a lower proportion of pollution sensitive taxa including Ephemeroptera and Plecoptera. In contrast, in 1999, conductivity was the only variable explaining site ordination along axis 1, but was unable to separate sites with respect to invasion status. A second explanatory axis separated sites with respect to invasion status, with invaded sites having fewer taxa, including lower abundance of ephemeropterans, dipterans and plecopterans. Laboratory experiments examined the potential role of differential predation between the two Gammarus species in explaining these taxon specific patterns in the field. Survival of the ephemeropterans, Ephemerella ignita and Ecdyonurus venosus and the isopod, Asellus aquaticus, was lower when interacting with G. pulex than with G. d. celticus. This study indicates that G. putex may alter invertebrate community structure at scales beyond those detected within individual rivers. However, effects may be influenced by gradients in physico-chemistry, which may be temporal or depend on catchment characteristics. Invasions by amphipods have increased globally, thus comprehensive assessments of their impacts and of other aquatic invaders, may only be apparent when studies are conducted at a range of spatio-temporal scales.

Quantifying the positive effects of sponsor level, length, prominence and relatedness on recall and residual recall rates over time

This study is the first multi-year examination of the relative influence of the four main variables said to influence sponsorship recall. Sponsor recall data were collected from season ticket holders (STHs) of 10 professional sports teams, over periods ranging from 3 to 5 years per team. Across those teams and over that time, 309 sponsor–team relationships were examined, and sponsor recall data from over 117,000 individual STHs were collected. Sponsorship length and level were shown to have the strongest impact on recall, followed by relatedness and prominence. These variables affected both the recall of current sponsors and the decay rates of residual recall following the end of a sponsorship. The average rates of sponsor recall growth and decline have been derived from these data, giving managers a tool by which to benchmark sport sponsorship recall performance.

Park proximity, quality and recreational physical activity among mid-older aged adults: moderating effects of individual factors and area of residence

The transition from active employment to retirement is a potentially critical period for promoting maintenance or development of recreational physical activity in older age. Park proximity and quality might be important correlates of recreational physical activity in this age group. However, research on park-physical activity relationships among mid-older aged adults is limited and inconclusive. Furthermore, while knowledge of individual moderators of park-physical activity relationships is crucial for tailoring interventions, this knowledge is also limited. We investigated relationships between perceived park proximity, park quality and recreational physical activity among mid-older aged adults. Additionally, we examined the potential moderating effects of gender, education level, retirement status, functional limitations and area of residence on these relationships.

How can an invasive grass affect fire behavior in a tropical savanna? A community and individual plant level approach

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

The influence of individual and colony level variation in behavior on colony performance in ants

In my dissertation I investigated the influence of behavioral variation between and within ant colonies on group performance. In particular, I analyzed how evolution shapes behavior in response to ecological conditions, and whether within-group diversity improves productivity as suggested by theory. Our field and laboratory experiments showed that behavioral diverse groups are more productive. Different aggression levels within colonies were beneficial under competitive field situations, whereas diversity in brood care and exploratory behavior were favored in non-competitive laboratory situations. We then examined whether population density and social parasite presence shape aggression through phenotypic plasticity and/or natural selection. The importance of selection was indicated by the absence of density or parasite effects on aggression in a field manipulation. Indeed, more aggressive colonies fared better under high density and during parasite attack. When analyzing the proximate causes of individual behavioral variation, ovarian development was shown to be linked to division of labor and aggressiveness. Finally, our studies show that differences in the collective behavior can be linked to immune defense and productivity. My dissertation demonstrates that behavioral variation should be studied on multiple scales and when possible combined with physiological analyses to better understand the evolution of animal personalities in social groups.rn

Social Support at the Workplace, Motivation to Transfer, and Training Transfer: A Multi-Level Indirect Effects Model

Supervisor support, peer support and transfer motivation have been identified as important predictors for training transfer. Transfer motivation is supposed to mediate the support–training transfer relationship. Especially after team training interventions that include all team members (i.e., intact-team training), individual perception of these factors might be shared among team members. However, an integration of the team level in the training transfer process is rare, yet still needed. Analyzing 194 employees from 34 teams in the context of intact-team training interventions, we found similar relationships and processes at both levels of analysis: Social support enhances transfer motivation at the individual and team levels. Furthermore, motivation to transfer increases training transfer and serves as a connecting mechanism in the social support–training transfer link. The results underline the importance of (1) considering multiple levels in theories and research about the training transfer process and (2) ensuring the practice of individual-directed support and a shared, supportive climate within teams.

Individual and population-level responses to ocean acidification

Ocean acidification is predicted to have detrimental effects on many marine organisms and ecological processes. Despite growing evidence for direct impacts on specific species, few studies have simultaneously considered the effects of ocean acidification on individuals (e.g. consequences for energy budgets and resource partitioning) and population level demographic processes. Here we show that ocean acidification increases energetic demands on gastropods resulting in altered energy allocation, i.e. reduced shell size but increased body mass. When scaled up to the population level, long-term exposure to ocean acidification altered population demography, with evidence of a reduction in the proportion of females in the population and genetic signatures of increased variance in reproductive success among individuals. Such increased variance enhances levels of short-term genetic drift which is predicted to inhibit adaptation. Our study indicates that even against a background of high gene flow, ocean acidification is driving individual- and population-level changes that will impact eco-evolutionary trajectories.

Financial fragility, trade credit and contagion effects during the crisis: a spatial econometric approach to firm-level data

The number of distressed manufacturing firms increased sharply during recessionary phase 2009-13. Financial indebtness traditionally plays a key role in assessing firm solvency but contagion effects that originate from the supply chain are usually neglected in literature. Firm interconnections, captured via the trade credit channel, represent a primary vehicle of individual shocks’ propagation, especially during an economic downturn, when liquidity tensions arise. A representative sample of 11,920 Italian manufacturing firms is considered to model a two-step econometric design, where chain reactions in terms of trade credit accumulation (i.e. default of payments to suppliers) are primarily analyzed by resorting to a spatial autoregressive approach (SAR). Spatial interactions are modeled based on a unique dataset of firm-to-firm transactions registered before the outbreak of the crisis. The second step in instead a binary outcome model where trade credit chains are considered together with data on the bank-firm relationship to assess determinants of distress likelihoods in 2009-13. Results show that outstanding trade debt is affected by the liquidity position of a firm and by positive spatial effects. Trade credit chain reactions are found to exert, in turn, a positive impact on distress likelihoods during the crisis. The latter effect is comparable in magnitude to the one exerted by individual financial rigidity, and stresses the importance to include complex interactions between firms in the analysis of the solvency behavior.

How can an invasive grass affect fire behavior in a tropical savanna? A community and individual plant level approach

Some invasive grasses have been reported to change fire behavior in invaded plant communities. Urochloa brizantha is an aggressive invasive grass in the Brazilian Cerrado, an ecosystem where fire is a common disturbance. We investigated the effects of U. brizantha on fire behavior in an open Cerrado physiognomy in Central Brazil. Using experimental burnings we compared fire behavior at both the community and the individual plant level in invaded (UJ) and non-invaded (NJ) areas burned in July. We also assessed the effect of fire season in invaded areas by comparing July (UJ) and October (UO) burnings. We evaluated the following variables: fuel load, fuel moisture, combustion efficiency, maximum fire temperature, flame height, and fire intensity. Additionally, we evaluated the temperatures reached under invasive and native grass tussocks in both seasons. Fuel load, combustion efficiency, and fire intensity were higher in NJ than in UJ, whilst flame height showed the opposite trend. Fuel amount and fire intensity were higher in October than in July. At the individual plant level, U. brizantha moisture was higher than that of native species, however, temperatures reaching ≥600 °C at ground level were more frequent under U. brizantha tussocks than under native grasses. At the community level, the invasive grass modified fire behavior towards lower intensity, lower burning efficiency, and higher flame height. These results provide essential information for the planning of prescribed burnings in invaded Cerrado areas.

Individual and group level trajectories of behavioural development in Border collies.

In order to assess dogs’ personality changes during ontogeny, a cohort of 69 Border collies was followed up from six to 18–24 months. When the dogs were 6, 12, and 18–24 months old, their owners repeatedly filled in a dog personality questionnaire (DPQ), which yielded five personality factors divided into fifteen facets. All five DPQ factors were highly correlated between the three age classes, indicating that the dogs’ personality remained consistent relative to other individuals. Nonetheless, at the group level significant changes with age were found for four of the five DPQ factors. Fearfulness, Aggression towards People, Responsiveness to Training and Aggression towards Animals increased with age; only Activity/Excitability did not change significantly over time. These changes in DPQ factor scores occurred mainly between the ages of 6 and 12 months, although some facets changed beyond this age. No sex differences were found for any of the tested factors or facets, suggesting that individual variation in personality was greater than male/female differences. There were significant litter effects for the factors Fearfulness, Aggression towards People and Activity/Excitability, indicating either a strong genetic basis for these traits or a high influence of the shared early environment. To conclude, from the age of six months, consistency in personality relative to other individuals can be observed in Border collies. However, at the group level, increases in fearful and aggressive behaviours occur up to 12 months and for some traits up to two years, highlighting the need for early interventions. Follow-up studies are needed to assess trajectories of personality development prior to six months and after two years, and to include a wider variety of breeds.