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Doxycycline for the treatment of nodding syndrome (DONS); the study protocol of a phase II randomised controlled trial.
BACKGROUND: Nodding syndrome is a poorly understood neurological disorder of unknown aetiology, affecting several thousand children in Africa. There has been a consistent epidemiological association with infection by the filarial parasite, Onchocerca volvulus and antibodies to leiomodin and DJ-1, cross-reacting with O.volvulus proteins, have been reported. We hypothesized that nodding syndrome is a neuro-inflammatory disorder, induced by antibodies to O.volvulus or its symbiont, Wolbachia, cross-reacting with human neuron proteins and that doxycycline, which kills Onchocerca through effects on Wolbachia, may be used as treatment. METHODS: This will be a two-arm, double-blind, placebo-controlled, randomised phase II trial of doxycycline 100 mg daily for six weeks in 230 participants. Participants will be patients' ages≥8 years with nodding syndrome. They will receive standard of care supportive treatment. All will be hospitalised for 1-2 weeks during which time baseline measurements including clinical assessments, EEG, cognitive and laboratory testing will be performed and antiepileptic drug doses rationalised. Participants will then be randomised to either oral doxycycline (Azudox®, Kampala Pharmaceutical Industries) 100 mg daily or placebo. Treatment will be initiated in hospital and continued at home. Participants will be visited at home at 2, 4 and 6 weeks for adherence monitoring. Study outcomes will be assessed at 6, 12, 18 and 24-month visits. Analysis will be by intention to treat. The primary efficacy outcome measure will be the proportion of patients testing positive and the levels or titires of antibodies to host neuron proteins (HNPs) and/or leiomodin at 24 months. Secondary outcome measures will include effect of the intervention on seizure control, inflammatory markers, cognitive function, disease severity and quality of life. DISCUSSION: This trial postulates that targeting O.volvulus through drugs which kill Wolbachia can modify the pathogenic processes in nodding syndrome and improve outcomes. Findings from this study are expected to substantially improve the understanding and treatment of nodding syndrome. TRIAL REGISTRATION: Registered with clinicaltrials.gov ID: NCT02850913 on 1st August, 2016.
Punishment-related memory-guided attention: Neural dynamics of perceptual modulation.
Remembering the outcomes of past experiences allows us to generate future expectations and shape selection in the long-term. A growing number of studies has shown that learned positive reward values impact spatial memory-based attentional biases on perception. However, whether memory-driven attentional biases extend to punishment-related values has received comparatively less attention. Here, we manipulated whether recent spatial contextual memories became associated with successful avoidance of punishment (potential monetary loss). Behavioral and electrophysiological measures were collected from 27 participants during a subsequent memory-based attention task, in which we tested for the effect of punishment avoidance associations. Punishment avoidance significantly amplified effects of spatial contextual memories on visual search processes within natural scenes. Compared to non-associated scenes, contextual memories paired with punishment avoidance lead to faster responses to targets presented at remembered locations. Event-related potentials elicited by target stimuli revealed that acquired motivational value of specific spatial locations, by virtue of their association with past avoidance of punishment, dynamically affected neural signatures of early visual processing (indexed by larger P1 and earlier N1 potentials) and target selection (as indicated by reduced N2pc potentials). The present results extend our understanding of how memory, attention, and punishment-related mechanisms interact to optimize perceptual decision in real world environments.
Attempting to disentangle the relationship between impulsivity and longitudinal self-harm: Epidemiological analysis of UK household survey data.
BACKGROUND:: Impulsivity may be an important risk factor in terms of future self-harm. However, the extent of this, whether it may relate to self-harm that is new in onset and/or repetition of self-harm, and the detail of any interaction with mood instability (MI) and childhood sexual abuse (CSA) requires detailed examination. AIMS:: We used the 2000 Adult Psychiatry Morbidity Survey and an 18-month follow-up data to test hypotheses relating to the role of impulsivity, CSA and MI in the inception and persistence of self-harm. METHODS:: We assessed associations of impulsivity with (1) suicidal self-harm (SSH) and (2) non-SSH (NSSH) at baseline and follow-up, controlling for confounders including MI. Finally, we tested whether impulsivity mediated the relationship between CSA and self-harm. RESULTS:: A total of 8,580 respondents were assessed at baseline and 2,406 at follow-up as planned. Impulsivity significantly predicted emergence of new NSSH at 18-month follow-up even after adjustment for MI and other confounders. Impulsivity did not significantly predict repetition of NSSH, or repetition or new inception of SSH, even before inclusion of MI in the model. However, the absolute numbers involved were small. Cross-sectionally, impulsivity was a stronger mediator of the link between CSA and SSH (13.1%) than that between CSA and NSSH (4.8%). CONCLUSION:: Impulsivity may increase the risk of future development of NSSH independently of MI, which is clinically important for risk assessment. The involvement of impulsivity in the repetition of self-harm generally appears less certain. However, impulsivity may have a role in SSH in the context of previous CSA.
The PACE trial of treatments for chronic fatigue syndrome: a response to WILSHIRE et al.
Chronic Fatigue Syndrome (CFS) is chronic disabling illness characterized by severe disabling fatigue, typically made worse by exertion. Myalgic Encephalomyelitis (ME) is thought by some to be the same disorder (then referred to as CFS/ME) and by others to be different. There is an urgent need to find effective treatments for CFS. The UK Medical Research Council PACE trial published in 2011 compared available treatments and concluded that when added to specialist medical care, cognitive behaviour therapy and graded exercise therapy were more effective in improving both fatigue and physical function in participants with CFS, than both adaptive pacing therapy and specialised medical care alone. In this paper, we respond to the methodological criticisms of the trial and a reanalysis of the trial data reported by Wilshire at al. We conclude that neither the criticisms nor the reanalysis offer any convincing reason to change the conclusions of the PACE trial.
Random forest prediction of Alzheimer's disease using pairwise selection from time series data.
Time-dependent data collected in studies of Alzheimer's disease usually has missing and irregularly sampled data points. For this reason time series methods which assume regular sampling cannot be applied directly to the data without a pre-processing step. In this paper we use a random forest to learn the relationship between pairs of data points at different time separations. The input vector is a summary of the time series history and it includes both demographic and non-time varying variables such as genetic data. To test the method we use data from the TADPOLE grand challenge, an initiative which aims to predict the evolution of subjects at risk of Alzheimer's disease using demographic, physical and cognitive input data. The task is to predict diagnosis, ADAS-13 score and normalised ventricles volume. While the competition proceeds, forecasting methods may be compared using a leaderboard dataset selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and with standard metrics for measuring accuracy. For diagnosis, we find an mAUC of 0.82, and a classification accuracy of 0.73 compared with a benchmark SVM predictor which gives mAUC = 0.62 and BCA = 0.52. The results show that the method is effective and comparable with other methods.
Maternal postnatal depression and anxiety and their association with child emotional negativity and behavior problems at two years.
Postnatal maternal depression is associated with poorer child emotional and behavioral functioning, but it is unclear whether this occurs following brief episodes or only with persistent depression. Little research has examined the relation between postnatal anxiety and child outcomes. The present study examined the role of postnatal major depressive disorder (MDD) and generalized anxiety disorder (GAD) symptom chronicity on children's emotional and behavioral functioning at 24 months. Following postnatal screening mothers (n = 296) were identified as having MDD, GAD, MDD and GAD, or no disorder at 3 months postnatal; the average age was 32.3 (SD = 5.0), 91.9% self-identified as Caucasian, and 62.2% were married. Maternal disorder symptom severity was assessed by questionnaires and structured interview at 3, 6, 10, 14, and 24 months postpartum. At 24 months, child emotional negativity and behavior were assessed using questionnaires and by direct observation. Latent trait-state-occasion modeling was used to represent maternal disorder symptom chronicity; both stable trait and time-specific occasion portions of maternal symptomatology were examined in relation to child outcomes. Only the stable trait portion of maternal MDD and GAD symptom severity were related to maternal report of child behavior problems and higher levels of emotional negativity. Persistent maternal MDD, but not GAD, symptom severity was related to higher levels of child emotional negativity as measured observationally. These data suggest that children's behavior problems and emotional negativity are adversely affected by persistent maternal depression, and possibly anxiety. This has implications for interventions to prevent negative effects of postnatal psychopathology on children. (PsycINFO Database Record
Early effects of exposure-based cognitive behaviour therapy on the neural correlates of anxiety.
Exposure-based cognitive-behaviour therapy (CBT) for anxiety disorders is an effective intervention, but the brain mechanisms driving recovery are largely unknown. In this experimental medicine study, we investigated to what degree CBT affects neural markers of anxiety at an early stage of treatment, to identify dynamic mechanistic changes which might be crucial in the process of recovery as opposed to those seen following full treatment completion. In a randomised controlled trial, unmedicated patients with panic disorder either received four weekly sessions of exposure-based CBT (N = 14) or were allocated to a waiting group (N = 14). Symptom severity was measured before and after the intervention. During functional magnetic resonance imaging (fMRI), patients performed an emotion regulation task, either viewing negative images naturally, or intentionally down-regulating negative affect using previously taught strategies. Four-session CBT led to marked reductions in symptoms and 71% of patients reached recovery status (versus 7% in the control group). This intervention normalised brain hyperactivation previously seen in panic disorder, particularly in areas linked to threat monitoring, fear memory, and maladaptive emotion regulation, such as amygdala, dorsomedial and dorsolateral prefrontal cortex, and temporal gyrus. Our findings suggest that optimal treatment doses for panic disorder might be much lower than previously thought. Furthermore, this is the first study to show that neural markers of anxiety change very early during CBT, highlighting potential neural mechanisms that might drive clinical recovery. Such knowledge is important for the development of more compact combination treatments targeting these mechanisms more effectively. (Neural Effects of Cognitive-behaviour Therapy in Panic Disorder; clinicaltrials.gov; NCT03251235).