Drugs Associated with More Suicidal Ideations Are also Associated with More Suicide Attempts

In randomized controlled trials (RCTs), some drugs, including CB1 antagonists for obesity treatment, have been shown to cause increased suicidal ideation. A key question is whether drugs that increase or are associated with increased suicidal ideations are also associated with suicidal behavior, or whether drug-induced suicidal ideations are unlinked epiphenomena that do not presage the more troubling and potentially irrevocable outcome of suicidal behavior. This is difficult to determine in RCTs because of the rarity of suicidal attempts and completions.To determine whether drugs associated with more suicidal ideations are also associated with more suicide attempts in large spontaneous adverse event (AE) report databases.Generalized linear models with negative binomial distribution were fitted to Food and Drug Administration (FDA) Adverse Event (AE) Reporting System (AERS) data from 2004 to 2008. A total of 1,404,470 AEs from 832 drugs were analyzed as a function of reports of suicidal ideations; other non-suicidal adverse reactions; drug class; proportion of reports from males; and average age of subject for which AE was filed. Drug was treated as the unit of analysis, thus the statistical models effectively had 832 observations.Reported suicide attempts and completed suicides per drug.832 drugs, ranging from abacavir to zopiclone, were evaluated. The 832 drugs, as primary suspect drugs in a given adverse event, accounted for over 99.9% of recorded AERS. Suicidal ideations had a significant positive association with suicide attempts (p<.0001) and had an approximately 131-fold stronger magnitude of association than non-suicidal AERs, after adjusting for drug class, gender, and age.In AE reports, drugs that are associated with increased suicidal ideations are also associated with increased suicidal attempts or completions. This association suggests that drug-induced suicidal ideations observed in RCTs plausibly represent harbingers that presage the more serious suicide attempts and completions and should be a cause for concern

Social disorganization and history of child sexual abuse against girls in sub-Saharan Africa : a multilevel analysis

Background: Child sexual abuse (CSA) is a considerable public health problem. Less focus has been paid to the role of community level factors associated with CSA. The aim of this study was to examine the association between neighbourhood-level measures of social disorganization and CSA. Methods: We applied multiple multilevel logistic regression analysis on Demographic and Health Survey data for 6,351 adolescents from six countries in sub-Saharan Africa between 2006 and 2008. Results: The percentage of adolescents that had experienced CSA ranged from 1.04% to 5.84%. There was a significant variation in the odds of reporting CSA across the communities, suggesting 18% of the variation in CSA could be attributed to community level factors. Respondents currently employed were more likely to have reported CSA than those who were unemployed (odds ratio [OR] = 2.05, 95% confidence interval [CI] 1.48 to 2.83). Respondents from communities with a high family disruption rate were 57% more likely to have reported CSA (OR=1.57, 95% CI 1.14 to 2.16). Conclusion: We found that exposure to CSA was associated with high community level of family disruption, thus suggesting that neighbourhoods may indeed have significant important effects on exposure to CSA. Further studies are needed to explore pathways that connect the individual and neighbourhood levels, that is, means through which deleterious neighbourhood effects are transmitted to individuals

Genetic Association Analysis Using Sibship Data: A Multilevel Model Approach

Family based association study (FBAS) has the advantages of controlling for population stratification and testing for linkage and association simultaneously. We propose a retrospective multilevel model (rMLM) approach to analyze sibship data by using genotypic information as the dependent variable. Simulated data sets were generated using the simulation of linkage and association (SIMLA) program. We compared rMLM to sib transmission/disequilibrium test (S-TDT), sibling disequilibrium test (SDT), conditional logistic regression (CLR) and generalized estimation equations (GEE) on the measures of power, type I error, estimation bias and standard error. The results indicated that rMLM was a valid test of association in the presence of linkage using sibship data. The advantages of rMLM became more evident when the data contained concordant sibships. Compared to GEE, rMLM had less underestimated odds ratio (OR). Our results support the application of rMLM to detect gene-disease associations using sibship data. However, the risk of increasing type I error rate should be cautioned when there is association without linkage between the disease locus and the genotyped marker

Surveillance for endometrial cancer with transvaginal ultrasonography of breast cancer patients under tamoxifen treatment

The association of endometrial thickness with the risk of developing endometrial cancer (EC) within 2 years was investigated in a consecutive cohort of 1205 breast cancer patients under tamoxifen treatment, undergoing transvaginal ultrasonography (TVUS) for follow-up purpose (asymptomatic, 1068) or for abnormal uterine bleeding (AUB, 137). Linkage with tumour registry allowed for the follow-up of 3184.3 person-years. According to underlying incidence, 1.85 EC cases were expected in the study cohort while 12 were observed (observed/expected ratio=6.49, 95% CI 3.35–11.33; asymptomatic=4.09, 95% CI 1.65–8.43, symptomatic=35.71, 95% CI 11.59–83.34). No EC was observed with thickness (half layer) <3 mm. Raising this threshold increased specificity with a substantial loss of sensitivity (⩾3, ⩾4, ⩾6, ⩾9 mm; spec.=25.8, 44.5, 76.1, 91.5%, sens.=100, 91.6, 75.0, 66.6%). The presence of AUB was rather specific (88.94%) but poorly sensitive (41.67%). A combination of AUB presence/absence and thickness allowed the best accuracy (AUB + thickness ⩾3, ⩾4 or ⩾5; sens.=100, 81.6 or 91.6%; spec.=22.8, 40.4, or 56.7%). Breast cancer patients under tamoxifen might be selected for further invasive assessment on the basis of AUB and endometrial thickness assessed at TVUS

Bivariate random-effects meta-analysis and the estimation of between-study correlation

BACKGROUND: When multiple endpoints are of interest in evidence synthesis, a multivariate meta-analysis can jointly synthesise those endpoints and utilise their correlation. A multivariate random-effects meta-analysis must incorporate and estimate the between-study correlation (ρ(B)). METHODS: In this paper we assess maximum likelihood estimation of a general normal model and a generalised model for bivariate random-effects meta-analysis (BRMA). We consider two applied examples, one involving a diagnostic marker and the other a surrogate outcome. These motivate a simulation study where estimation properties from BRMA are compared with those from two separate univariate random-effects meta-analyses (URMAs), the traditional approach. RESULTS: The normal BRMA model estimates ρ(B )as -1 in both applied examples. Analytically we show this is due to the maximum likelihood estimator sensibly truncating the between-study covariance matrix on the boundary of its parameter space. Our simulations reveal this commonly occurs when the number of studies is small or the within-study variation is relatively large; it also causes upwardly biased between-study variance estimates, which are inflated to compensate for the restriction on [Formula: see text] (B). Importantly, this does not induce any systematic bias in the pooled estimates and produces conservative standard errors and mean-square errors. Furthermore, the normal BRMA is preferable to two normal URMAs; the mean-square error and standard error of pooled estimates is generally smaller in the BRMA, especially given data missing at random. For meta-analysis of proportions we then show that a generalised BRMA model is better still. This correctly uses a binomial rather than normal distribution, and produces better estimates than the normal BRMA and also two generalised URMAs; however the model may sometimes not converge due to difficulties estimating ρ(B). CONCLUSION: A BRMA model offers numerous advantages over separate univariate synthesises; this paper highlights some of these benefits in both a normal and generalised modelling framework, and examines the estimation of between-study correlation to aid practitioners

IACT observations of gamma-ray bursts: prospects for the Cherenkov Telescope Array

Gamma rays at rest frame energies as high as 90 GeV have been reported from gamma-ray bursts (GRBs) by the Fermi Large Area Telescope (LAT). There is considerable hope that a confirmed GRB detection will be possible with the upcoming Cherenkov Telescope Array (CTA), which will have a larger effective area and better low-energy sensitivity than current-generation imaging atmospheric Cherenkov telescopes (IACTs). To estimate the likelihood of such a detection, we have developed a phenomenological model for GRB emission between 1 GeV and 1 TeV that is motivated by the high-energy GRB detections of Fermi-LAT, and allows us to extrapolate the statistics of GRBs seen by lower energy instruments such as the Swift-BAT and BATSE on the Compton Gamma-ray Observatory. We show a number of statistics for detected GRBs, and describe how the detectability of GRBs with CTA could vary based on a number of parameters, such as the typical observation delay between the burst onset and the start of ground observations. We also consider the possibility of using GBM on Fermi as a finder of GRBs for rapid ground follow-up. While the uncertainty of GBM localization is problematic, the small field-of-view for IACTs can potentially be overcome by scanning over the GBM error region. Overall, our results indicate that CTA should be able to detect one GRB every 20 to 30 months with our baseline instrument model, assuming consistently rapid pursuit of GRB alerts, and provided that spectral breaks below 100 GeV are not a common feature of the bright GRB population. With a more optimistic instrument model, the detection rate can be as high as 1 to 2 GRBs per year.Comment: 28 pages, 24 figures, 4 tables, submitted to Experimental Astronom

Rehabilitation of memory following brain injury (ReMemBrIn): study protocol for a randomised controlled trial

Background Impairments of memory are commonly reported by people with traumatic brain injuries (TBI). Such deficits are persistent, debilitating, and can severely impact quality of life. Currently, many do not routinely receive follow-up appointments for residual memory problems following discharge. Methods/Design This is a multi-centre, randomised controlled trial investigating the clinical and cost-effectiveness of a group-based memory rehabilitation programme. Three hundred and twelve people with a traumatic brain injury will be randomised from four centres. Participants will be eligible if they had a traumatic brain injury more than 3 months prior to recruitment, have memory problems, are 18 to 69 years of age, are able to travel to one of our centres and attend group sessions, and are able to give informed consent. Participants will be randomised in clusters of 4 to 6 to the group rehabilitation intervention or to usual care. Intervention groups will receive 10 weekly sessions of a manualised memory rehabilitation programme, which has been developed in previous pilot studies. The intervention will include restitution strategies to retrain impaired memory functions and compensation strategies to enable participants to cope with their memory problems. All participants will receive a follow-up postal questionnaire and an assessment by a research assistant at 6 and 12 months post-randomisation. The primary outcome is the Everyday Memory Questionnaire at 6 months. Secondary outcomes include the Rivermead Behavioural Memory Test-3, General Health Questionnaire-30, health related quality of life, cost-effectiveness analysis determined by the EQ-5D and a service use questionnaire, individual goal attainment, European Brain Injury Questionnaire (patient and relative versions), and the Everyday Memory Questionnaire-relative version. The primary analysis will be based on intention to treat. A mixed-model regression analysis of the Everyday Memory Questionnaire at 6 months will be used to estimate the effect of the group memory rehabilitation programme. Discussion The study will hopefully provide robust evidence regarding the clinical and cost-effectiveness of a group-based memory rehabilitation intervention for civilians and military personnel following TBI. We discuss our decision-making regarding choice of outcome measures and control group, and the unique challenges to recruiting people with memory problems to trials

Modulation of emotional appraisal by false physiological feedback during fMRI

BACKGROUND James and Lange proposed that emotions are the perception of physiological reactions. Two-level theories of emotion extend this model to suggest that cognitive interpretations of physiological changes shape self-reported emotions. Correspondingly false physiological feedback of evoked or tonic bodily responses can alter emotional attributions. Moreover, anxiety states are proposed to arise from detection of mismatch between actual and anticipated states of physiological arousal. However, the neural underpinnings of these phenomena previously have not been examined. METHODOLOGY/PRINCIPAL FINDINGS We undertook a functional brain imaging (fMRI) experiment to investigate how both primary and second-order levels of physiological (viscerosensory) representation impact on the processing of external emotional cues. 12 participants were scanned while judging face stimuli during both exercise and non-exercise conditions in the context of true and false auditory feedback of tonic heart rate. We observed that the perceived emotional intensity/salience of neutral faces was enhanced by false feedback of increased heart rate. Regional changes in neural activity corresponding to this behavioural interaction were observed within included right anterior insula, bilateral mid insula, and amygdala. In addition, right anterior insula activity was enhanced during by asynchronous relative to synchronous cardiac feedback even with no change in perceived or actual heart rate suggesting this region serves as a comparator to detect physiological mismatches. Finally, BOLD activity within right anterior insula and amygdala predicted the corresponding changes in perceived intensity ratings at both a group and an individual level. CONCLUSIONS/SIGNIFICANCE Our findings identify the neural substrates supporting behavioural effects of false physiological feedback, and highlight mechanisms that underlie subjective anxiety states, including the importance of the right anterior insula in guiding second-order "cognitive" representations of bodily arousal state

Modulation of emotional appraisal by false physiological feedback during fMRI

BACKGROUND James and Lange proposed that emotions are the perception of physiological reactions. Two-level theories of emotion extend this model to suggest that cognitive interpretations of physiological changes shape self-reported emotions. Correspondingly false physiological feedback of evoked or tonic bodily responses can alter emotional attributions. Moreover, anxiety states are proposed to arise from detection of mismatch between actual and anticipated states of physiological arousal. However, the neural underpinnings of these phenomena previously have not been examined. METHODOLOGY/PRINCIPAL FINDINGS We undertook a functional brain imaging (fMRI) experiment to investigate how both primary and second-order levels of physiological (viscerosensory) representation impact on the processing of external emotional cues. 12 participants were scanned while judging face stimuli during both exercise and non-exercise conditions in the context of true and false auditory feedback of tonic heart rate. We observed that the perceived emotional intensity/salience of neutral faces was enhanced by false feedback of increased heart rate. Regional changes in neural activity corresponding to this behavioural interaction were observed within included right anterior insula, bilateral mid insula, and amygdala. In addition, right anterior insula activity was enhanced during by asynchronous relative to synchronous cardiac feedback even with no change in perceived or actual heart rate suggesting this region serves as a comparator to detect physiological mismatches. Finally, BOLD activity within right anterior insula and amygdala predicted the corresponding changes in perceived intensity ratings at both a group and an individual level. CONCLUSIONS/SIGNIFICANCE Our findings identify the neural substrates supporting behavioural effects of false physiological feedback, and highlight mechanisms that underlie subjective anxiety states, including the importance of the right anterior insula in guiding second-order "cognitive" representations of bodily arousal state

Automated Analysis of Cryptococcal Macrophage Parasitism Using GFP-Tagged Cryptococci

The human fungal pathogens Cryptococcus neoformans and C. gattii cause life-threatening infections of the central nervous system. One of the major characteristics of cryptococcal disease is the ability of the pathogen to parasitise upon phagocytic immune effector cells, a phenomenon that correlates strongly with virulence in rodent models of infection. Despite the importance of phagocyte/Cryptococcus interactions to disease progression, current methods for assaying virulence in the acrophage system are both time consuming and low throughput. Here, we introduce the first stable and fully characterised GFP–expressing derivatives of two widely used cryptococcal strains: C. neoformans serotype A type strain H99 and C. gattii serotype B type strain R265. Both strains show unaltered responses to environmental and host stress conditions and no deficiency in virulence in the macrophage model system. In addition, we report the development of a method to effectively and rapidly investigate macrophage parasitism by flow cytometry, a technique that preserves the accuracy of current approaches but offers a four-fold improvement in speed