Predicting recurrence of depression using cardiac complexity in individuals tapering antidepressants

It is currently unknown whether the complexity and variability of cardiac dynamics predicts future depression and whether within-subject change herein precedes the recurrence of depression. We tested this in an innovative repeated single-subject study in individuals who had a history of depression and were tapering their antidepressants. In 50 individuals, electrocardiogram (ECG) derived Interbeat-interval (IBI) time-series data were collected for 5 min every morning and evening, for 4 months. Usable data were obtained from 14 participants who experienced a transition (i.e., a clinically significant increase in depressive symptoms) and 14 who did not. The mean, standard deviation, Higuchi dimension and multiscale entropy, calculated from IBIs, were examined for time trends. These quantifiers were also averaged over a baseline period and compared between the groups. No consistent trends were observed in any quantifier before increases in depressive symptoms within individuals. The entropy baseline levels significantly differed between the two groups (morning: P value < 0.001, Cohen’s d = −2.185; evening: P value < 0.001, Cohen’s d = −1.797) and predicted the recurrence of depressive symptoms, in the current sample. Moreover, higher mean IBIs and Higuchi dimensions were observed in individuals who experienced transitions. While we found little evidence to support the existence of within- individual warning signals in IBI time-series data preceding an upcoming depressive transition, our results indicate that individuals who taper antidepressants and showed lower entropy of cardiac dynamics exhibited a higher chance of recurrence of depression. Hence, entropy could be a potential digital phenotype for assessing the risk of recurrence of depression in the short term while tapering antidepressants

A risk profile for identifying community-dwelling elderly with a highrisk of recurrent falling: results of a 3-year prospective study

Introduction: The aim of the prospective study reported here was to develop a risk profile that can be used to identify community-dwelling elderly at a high risk of recurrent falling. Materials and methods: The study was designed as a 3-year prospective cohort study. A total of 1365 community-dwelling persons, aged 65 years and older, of the population-based Longitudinal Aging Study Amsterdam participated in the study. During an interview in 1995/1996, physical, cognitive, emotional and social aspects of functioning were assessed. A follow-up on the number of falls and fractures was conducted during a 3-year period using fall calendars that participants filled out weekly. Recurrent fallers were identified as those who fell at least twice within a 6-month period during the 3-year follow-up. Results: The incidence of recurrent falls at the 3-year follow-up point was 24.9% in women and 24.4% in men. Of the respondents, 5.5% reported a total of 87 fractures that resulted from a fall, including 20 hip fractures, 21 wrist fractures and seven humerus fractures. Recurrent fallers were more prone to have a fall-related fracture than those who were not defined as recurrent fallers (11.9% vs. 3.4%; OR: 3.8; 95% CI: 2.3-6.1). Backward logistic regression analysis identified the following predictors in the risk profile for recurrent falling: two or more previous falls, dizziness, functional limitations, weak grip strength, low body weight, fear of falling, the presence of dogs/cats in the household, a high educational level, drinking 18 or more alcoholic consumptions per week and two interaction terms (high educationx18 or more alcohol consumptions per week and two or more previous falls x fear of falling) (AUC=0.71). Discussion: At a cut-off point of 5 on the total risk score (range 0-30), the model predicted recurrent falling with a sensitivity of 59% and a specificity of 71%. At a cut-off point of 10, the sensitivity and specificity were 31% and 92%, respectively. A risk profile including nine predictors that can easily be assessed seems to be a useful tool for the identification of community-dwelling elderly with a high risk of recurrent falling. © International Osteoporosis Foundation and National Osteoporosis Foundation 2006

Risk Ahead: Actigraphy-Based Early-Warning Signals of Increases in Depressive Symptoms During Antidepressant Discontinuation

Antidepressant discontinuation increases the risk of experiencing depressive symptoms. In a repeated single-subject design, we tested whether transitions in depression were preceded by increases in actigraphy-based critical-slowing-down-based early-warning signals (EWSs; variance, kurtosis, autocorrelation), circadian-rhythm-based indicators, and decreases in mean activity levels. Four months of data from 16 individuals with a transition in depression and nine without a transition in depression were analyzed using a moving-window method. As expected, more participants with a transition showed at least one EWS (50% true positives; 22.2% false positives). Increases in circadian rhythm variables (25.0% true positives vs. 44.4% false positives) and decreases in activity levels (37.5% true positives vs. 44.4% false positives) were more common in participants without a transition. None of the tested risk indicators could confidently predict upcoming transitions in depression, but some evidence was found that critical-slowing-down-based EWSs were more common in participants with a transition

Information-Derived Mechanistic Hypotheses for Structural Cardiotoxicity

Adverse events resulting from drug therapy can be a cause of drug withdrawal, reduced and or restricted clinical use, as well as a major economic burden for society. To increase the safety of new drugs, there is a need to better understand the mechanisms causing the adverse events. One way to derive new mechanistic hypotheses is by linking data on drug adverse events with the drugs’ biological targets. In this study, we have used data mining techniques and mutual information statistical approaches to find associations between reported adverse events collected from the FDA Adverse Event Reporting System and assay outcomes from ToxCast, with the aim to generate mechanistic hypotheses related to structural cardiotoxicity (morphological damage to cardiomyocytes and/or loss of viability). Our workflow identified 22 adverse event-assay outcome associations. From these associations, 10 implicated targets could be substantiated with evidence from previous studies reported in the literature. For two of the identified targets, we also describe a more detailed mechanism, forming putative adverse outcome pathways associated with structural cardiotoxicity. Our study also highlights the difficulties deriving these type of associations from the very limited amount of data available

Vascular health in patients in remission of Cushing's syndrome is comparable to that in BMI-matched controls.

CONTEXT: In active Cushing's syndrome (CS), patients suffer from endothelial dysfunction and premature atherosclerosis. However, it is uncertain to what extent vascular health recovers after long-term remission. This is highly relevant as this topic relates to future development of cardiovascular disease. OBJECTIVE: To investigate whether micro- and macrovascular health is impaired after long-term remission of CS, in patients with no or adequately treated co-morbidities. DESIGN AND SETTING: Cross-sectional case-control study in two tertiary referral centers. PATIENTS AND MAIN OUTCOME MEASURES: 63 patients (remission of CS for ≥ 4 years) and 63 healthy, well-matched controls were compared. In group A (58 patients and 58 controls) serum biomarkers associated with endothelial dysfunction, intima media thickness, pulse wave velocity and pulse wave analysis were studied. In group B (14 patients and 14 controls) endothelium-dependent and-independent vasodilatation was studied in conduit arteries (flow mediated dilation of the brachial artery) and forearm skeletal muscle resistance arteries (vasodilator response to intra-arterial acetylcholine, sodium-nitroprusside and N(G)-monomethyl-L-arginine using venous occlusion plethysmography). RESULTS: There were no significant differences between the outcome measures of vascular health of patients and controls in group A and B. CONCLUSION: Vascular health of patients in long-term remission of Cushing's syndrome seems to be comparable to that of healthy gender-, age and BMI matched controls, provided that the patients have no, or adequately controlled co-morbidities. Therefore, the effects of hypercortisolism per se on the vasculature may be reversible. This accentuates the need for stringent treatment of metabolic co-morbidities in these patients

The United States, PMSCs and the state monopoly on violence: Leading the way towards norm change

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2013 Sage.The proliferation of private military and security companies (PMSCs) in Iraq and Afghanistan has raised many questions regarding the use of armed force by private contractors. This article addresses the question of whether the increased acceptance of PMSCs indicates a transformation of the international norm regarding the state monopoly on the legitimate use of armed force. Drawing on theoretical approaches to the analysis of norm change, the article employs four measures to investigate possible changes in the strength and meaning of this norm: modifications in state behaviour, state responses to norm violation, the promulgation of varying interpretations of the norm in national and international laws and regulations, and changes in norm discourse. Based on an analysis of empirical evidence from the United States of America and its allies, the article concludes that these measures suggest that the USA is leading the way towards a transformation of the international norm of the state monopoly on violence, involving a revised meaning. Although this understanding has not yet been formally implemented in international law, it has allowed a growing number of countries to tolerate, accept or legalize the use of armed force by PMSCs in the international arena.The Alexander von Humboldt Foundation and the Peace Research Institute Frankfurt

Stronger diversity effects with increased environmental stress : a study of multitrophic interactions between oak, powdery mildew and ladybirds

Recent research has suggested that increasing neighbourhood tree species diversity may mitigate the impact of pests or pathogens by supporting the activities of their natural enemies and/or reducing the density of available hosts. In this study, we attempted to assess these mechanisms in a multitrophic study system of young oak (Quercus), oak powdery mildew (PM, caused by Erysiphe spp.) and a mycophagous ladybird (Psyllobora vigintiduo-punctata). We assessed ladybird mycophagy on oak PM in function of different neighbourhood tree species compositions. We also evaluated whether these species interactions were modulated by environmental conditions as suggested by the Stress Gradient Hypothesis. We adopted a complementary approach of a field experiment where we monitored oak saplings subjected to a reduced rainfall gradient in a young planted forest consisting of different tree species mixtures, as well as a lab experiment where we independently evaluated the effect of different watering treatments on PM infections and ladybird mycophagy. In the field experiment, we found effects of neighbourhood tree species richness on ladybird mycophagy becoming more positive as the target trees received less water. This effect was only found as weather conditions grew drier. In the lab experiment, we found a preference of ladybirds to graze on infected leaves from trees that received less water. We discuss potential mechanisms that might explain this preference, such as emissions of volatile leaf chemicals. Our results are in line with the expectations of the Natural Enemies Hypothesis and support the hypothesis that biodiversity effects become stronger with increased environmental stress

Huntingtin gene repeat size variations affect risk of lifetime depression

Huntington disease (HD) is a severe neuropsychiatric disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. Although HD is frequently complicated by depression, it is still unknown to what extent common HTT CAG repeat size variations in the normal range could affect depression risk in the general population. Using binary logistic regression, we assessed the association between HTT CAG repeat size and depression risk in two well-characterized Dutch cohorts─the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons─including 2165 depressed and 1058 non-depressed persons. In both cohorts, separately as well as combined, there was a significant non-linear association between the risk of lifetime depression and HTT CAG repeat size in which both relatively short and relatively large alleles were associated with an increased risk of depression (β = −0.292 and β = 0.006 for the linear and the quadratic term, respectively; both P < 0.01 after adjustment for the effects of sex, age, and education level). The odds of lifetime depression were lowest in persons with a HTT CAG repeat size of 21 (odds ratio: 0.71, 95% confidence interval: 0.52 to 0.98) compared to the average odds in the total cohort. In conclusion, lifetime depression risk was higher with both relatively short and relatively large HTT CAG repeat sizes in the normal range. Our study provides important proof-of-principle that repeat polymorphisms can act as hitherto unappreciated but complex genetic modifiers of depression