Inter-cellular forces orchestrate contact inhibition of locomotion.

Contact inhibition of locomotion (CIL) is a multifaceted process that causes many cell types to repel each other upon collision. During development, this seemingly uncoordinated reaction is a critical driver of cellular dispersion within embryonic tissues. Here, we show that Drosophila hemocytes require a precisely orchestrated CIL response for their developmental dispersal. Hemocyte collision and subsequent repulsion involves a stereotyped sequence of kinematic stages that are modulated by global changes in cytoskeletal dynamics. Tracking actin retrograde flow within hemocytes in vivo reveals synchronous reorganization of colliding actin networks through engagement of an inter-cellular adhesion. This inter-cellular actin-clutch leads to a subsequent build-up in lamellar tension, triggering the development of a transient stress fiber, which orchestrates cellular repulsion. Our findings reveal that the physical coupling of the flowing actin networks during CIL acts as a mechanotransducer, allowing cells to haptically sense each other and coordinate their behaviors.

The impact of moderator by confounder interactions in the assessment of treatment effect modification: a simulation study.

BACKGROUND: When performed in an observational setting, treatment effect modification analyses should account for all confounding, where possible. Often, such studies only consider confounding between the exposure and outcome. However, there is scope for misspecification of the confounding adjustment when estimating moderation as the effects of the confounders may themselves be influenced by the moderator. The aim of this study was to investigate bias in estimates of treatment effect modification resulting from failure to account for an interaction between a binary moderator and a confounder on either treatment receipt or the outcome, and to assess the performance of different approaches to account for such interactions. METHODS: The theory behind the reason for bias and factors that impact the magnitude of bias is explained. Monte Carlo simulations were used to assess the performance of different propensity scores adjustment methods and regression adjustment where the adjustment 1) did not account for any moderator-confounder interactions, 2) included moderator-confounder interactions, and 3) was estimated separately in each moderator subgroup. A real-world observational dataset was used to demonstrate this issue. RESULTS: Regression adjustment and propensity score covariate adjustment were sensitive to the presence of moderator-confounder interactions on outcome, whilst propensity score weighting and matching were more sensitive to the presence of moderator-confounder interactions on treatment receipt. Including the relevant moderator-confounder interactions in the propensity score (for methods using this) or the outcome model (for regression adjustment) rectified this for all methods except propensity score covariate adjustment. For the latter, subgroup-specific propensity scores were required. Analysis of the real-world dataset showed that accounting for a moderator-confounder interaction can change the estimate of effect modification. CONCLUSIONS: When estimating treatment effect modification whilst adjusting for confounders, moderator-confounder interactions on outcome or treatment receipt should be accounted for.

The impact of Patient and Public Involvement in the SlowMo study: Reflections on peer innovation.

BACKGROUND: The SlowMo study demonstrated the effects of SlowMo, an eight-session digitally supported reasoning intervention, on paranoia in a large-scale randomized-controlled trial with 362 participants with schizophrenia-spectrum psychosis. AIM: The current evaluation aimed to investigate the impact of Patient and Public Involvement (PPI) in the SlowMo study. METHOD: PPI members were six women and three men from Sussex, Oxford and London with experience of using mental health services for psychosis. They received training and met at least 3-monthly throughout the project. The impact of PPI was captured quantitatively and qualitatively through (i) a PPI log of recommendations and implementation; (ii) written subjective experiences of PPI members; (iii) meeting minutes; and (iv) outputs produced. RESULTS: The PPI log revealed 107 recommendations arising from PPI meetings, of which 87 (81%) were implemented. Implementation was greater for recruitment-, data collection- and organization-related actions than for dissemination and emergent innovations. Qualitative feedback revealed impacts on study recruitment, data collection, PPI participants' confidence, knowledge, career aspirations and society more widely. Outputs produced included a film about psychosis that aired on BBC primetime television, novel webpages and journal articles. Barriers to PPI impact included geography, travel, funding, co-ordination and well-being. DISCUSSION: A future challenge for PPI impact will be the extent to which peer innovation (innovative PPI-led ideas) can be supported within research study delivery. PATIENT AND PUBLIC CONTRIBUTION: Planned Patient and Public Contribution in SlowMo comprised consultation and collaboration in (i) design, (ii) recruitment, (iii) qualitative interviews and analysis of service users' experiences of SlowMo therapy and (iv) dissemination.

The Dunn Worry Questionnaire and the Paranoia Worries Questionnaire: new assessments of worry.

BACKGROUND: The cognitive process of worry, which keeps negative thoughts in mind and elaborates the content, contributes to the occurrence of many mental health disorders. Our principal aim was to develop a straightforward measure of general problematic worry suitable for research and clinical treatment. Our secondary aim was to develop a measure of problematic worry specifically concerning paranoid fears. METHODS: An item pool concerning worry in the past month was evaluated in 250 non-clinical individuals and 50 patients with psychosis in a worry treatment trial. Exploratory factor analysis and item response theory (IRT) informed the selection of scale items. IRT analyses were repeated with the scales administered to 273 non-clinical individuals, 79 patients with psychosis and 93 patients with social anxiety disorder. Other clinical measures were administered to assess concurrent validity. Test-retest reliability was assessed with 75 participants. Sensitivity to change was assessed with 43 patients with psychosis. RESULTS: A 10-item general worry scale (Dunn Worry Questionnaire; DWQ) and a five-item paranoia worry scale (Paranoia Worries Questionnaire; PWQ) were developed. All items were highly discriminative (DWQ a = 1.98-5.03; PWQ a = 4.10-10.7), indicating small increases in latent worry lead to a high probability of item endorsement. The DWQ was highly informative across a wide range of the worry distribution, whilst the PWQ had greatest precision at clinical levels of paranoia worry. The scales demonstrated excellent internal reliability, test-retest reliability, concurrent validity and sensitivity to change. CONCLUSIONS: The new measures of general problematic worry and worry about paranoid fears have excellent psychometric properties.

The COMMAND trial of cognitive therapy to prevent harmful compliance with command hallucinations: predictors of outcome and mediators of change.

BACKGROUND: Acting on harmful command hallucinations is a major clinical concern. Our COMMAND CBT trial approximately halved the rate of harmful compliance (OR = 0.45, 95% CI 0.23-0.88, p = 0.021). The focus of the therapy was a single mechanism, the power dimension of voice appraisal, was also significantly reduced. We hypothesised that voice power differential (between voice and voice hearer) was the mediator of the treatment effect. METHODS: The trial sample (n = 197) was used. A logistic regression model predicting 18-month compliance was used to identify predictors, and an exploratory principal component analysis (PCA) of baseline variables used as potential predictors (confounders) in their own right. Stata's paramed command used to obtain estimates of the direct, indirect and total effects of treatment. RESULTS: Voice omnipotence was the best predictor although the PCA identified a highly predictive cognitive-affective dimension comprising: voices' power, childhood trauma, depression and self-harm. In the mediation analysis, the indirect effect of treatment was fully explained by its effect on the hypothesised mediator: voice power differential. CONCLUSION: Voice power and treatment allocation were the best predictors of harmful compliance up to 18 months; post-treatment, voice power differential measured at nine months was the mediator of the effect of treatment on compliance at 18 months.

Beyond total treatment effects in randomised controlled trials: Baseline measurement of intermediate outcomes needed to reduce confounding in mediation investigations.

BACKGROUND: Random allocation avoids confounding bias when estimating the average treatment effect. For continuous outcomes measured at post-treatment as well as prior to randomisation (baseline), analyses based on (A) post-treatment outcome alone, (B) change scores over the treatment phase or (C) conditioning on baseline values (analysis of covariance) provide unbiased estimators of the average treatment effect. The decision to include baseline values of the clinical outcome in the analysis is based on precision arguments, with analysis of covariance known to be most precise. Investigators increasingly carry out explanatory analyses to decompose total treatment effects into components that are mediated by an intermediate continuous outcome and a non-mediated part. Traditional mediation analysis might be performed based on (A) post-treatment values of the intermediate and clinical outcomes alone, (B) respective change scores or (C) conditioning on baseline measures of both intermediate and clinical outcomes. METHODS: Using causal diagrams and Monte Carlo simulation, we investigated the performance of the three competing mediation approaches. We considered a data generating model that included three possible confounding processes involving baseline variables: The first two processes modelled baseline measures of the clinical variable or the intermediate variable as common causes of post-treatment measures of these two variables. The third process allowed the two baseline variables themselves to be correlated due to past common causes. We compared the analysis models implied by the competing mediation approaches with this data generating model to hypothesise likely biases in estimators, and tested these in a simulation study. We applied the methods to a randomised trial of pragmatic rehabilitation in patients with chronic fatigue syndrome, which examined the role of limiting activities as a mediator. RESULTS: Estimates of causal mediation effects derived by approach (A) will be biased if one of the three processes involving baseline measures of intermediate or clinical outcomes is operating. Necessary assumptions for the change score approach (B) to provide unbiased estimates under either process include the independence of baseline measures and change scores of the intermediate variable. Finally, estimates provided by the analysis of covariance approach (C) were found to be unbiased under all the three processes considered here. When applied to the example, there was evidence of mediation under all methods but the estimate of the indirect effect depended on the approach used with the proportion mediated varying from 57% to 86%. CONCLUSION: Trialists planning mediation analyses should measure baseline values of putative mediators as well as of continuous clinical outcomes. An analysis of covariance approach is recommended to avoid potential biases due to confounding processes involving baseline measures of intermediate or clinical outcomes, and not simply for increased precision.

Delivery of cognitive-behaviour therapy for psychosis: a service user preference trial.

BACKGROUND: Clinical guidelines recommend cognitive behaviour therapy (CBT) for people with psychosis, however, implementation is poor and not everyone wishes to engage with therapy. Understanding service user (SU) preferences for receiving such treatments is a priority for services. AIMS: To explore SU preferences and outcomes of different methods of delivering CBT for psychosis. METHOD: SUs experiencing psychosis could choose between treatment as usual (TAU); TAU plus telephone-delivered CBT with self-help, CBT recovery manual (TS); high support CBT (HS - TAU plus TS plus group sessions) or randomisation. Participants received their option of choice and were followed-up on several outcomes over 9 and 15 months. RESULTS: Of 89 people recruited, three chose to be randomised and 86 expressed a treatment preference (32 chose TAU, 34 chose TS, 23 chose HS). There were few differences between those who chose therapy compared to those who chose TAU. Those who had more positive impacts from their symptoms were significantly more likely to choose TAU. CONCLUSIONS: Most people had strong preferences about treatment delivery and a substantial number did not wish to receive additional therapy. These findings have to be considered when planning and allocating resources for people with psychosis.

Cells on film - the past and future of cinemicroscopy.

Movie making is now a ubiquitous experimental tool that biologists use alongside more traditional techniques such as molecular biology and biochemistry. It is no longer just cell biologists, but scientists from many other disciplines, such as immunology and neuroscience, that utilise movies to dissect their processes of interest. When did filming become such a standard laboratory technique? Who developed the use of the movie as an experimental tool? The Wellcome Library has recently restored and digitized a number of original 16-mm films from two pioneering cinemicroscopists, Ronald Canti and Michael Abercrombie, which are now freely available to the scientific community. In light of these films, this Essay will give a brief history of the early cinemicroscopists and discuss what is driving the use of movies in the laboratory today.

Confounding in longitudinal studies in addiction treatment research.

Background: The effectiveness of treatment for people with substance use disorders is usually examined using longitudinal cohorts. In these studies, treatment is often considered as a time-varying exposure. The aim of this commentary is to examine confounding in this context, when the confounding variable is time-invariant and when it is time-varying. Method: Types of confounding are described with examples and illustrated using path diagrams. Simulations are used to demonstrate the direction of confounding bias and the extent that it is accounted for using standard regression adjustment techniques. Results: When the confounding variable is time invariant or time varying and not influenced by prior treatment, then standard adjustment techniques are adequate to control for confounding bias, provided that in the latter scenario the time-varying form of the variable is used. When the confounder is time varying and affected by prior treatment status (i.e. it is a mediator of treatment), then standard methods of adjustment result in inconsistency. Conclusions: In longitudinal cohorts where treatment exposure is time varying, confounding is an issue which should be considered, even if treatment exposure is initially randomized. In these studies, standard methods of adjustment may result be inadequate, even when all confounders have been identified. This occurs when the confounder is also a mediator of treatment. This is a likely scenario in many studies in addiction.

Virtual reality in the treatment of persecutory delusions: randomised controlled experimental study testing how to reduce delusional conviction.

BACKGROUND: Persecutory delusions may be unfounded threat beliefs maintained by safety-seeking behaviours that prevent disconfirmatory evidence being successfully processed. Use of virtual reality could facilitate new learning. AIMS: To test the hypothesis that enabling patients to test the threat predictions of persecutory delusions in virtual reality social environments with the dropping of safety-seeking behaviours (virtual reality cognitive therapy) would lead to greater delusion reduction than exposure alone (virtual reality exposure). METHOD: Conviction in delusions and distress in a real-world situation were assessed in 30 patients with persecutory delusions. Patients were then randomised to virtual reality cognitive therapy or virtual reality exposure, both with 30 min in graded virtual reality social environments. Delusion conviction and real-world distress were then reassessed. RESULTS: In comparison with exposure, virtual reality cognitive therapy led to large reductions in delusional conviction (reduction 22.0%, P = 0.024, Cohen's d = 1.3) and real-world distress (reduction 19.6%, P = 0.020, Cohen's d = 0.8). CONCLUSION: Cognitive therapy using virtual reality could prove highly effective in treating delusions.

Normal Values and Clinical Use of Bedside Sonographic Assessment of Postoperative Gastric Emptying: A Prospective Cohort Study.

BACKGROUND: GI dysfunction is common after abdominal surgery. However, assessment and diagnosis currently lack objective measurement. OBJECTIVE: The purpose of this study was to evaluate the feasibility and clinical use of bedside sonographic assessment of gastric emptying by measuring the time to complete emptying of a standard volume of ingested water in patients after colorectal surgery. DESIGN: This was a prospective cohort study. SETTINGS: The study was conducted at a single tertiary institution in Sydney. PATIENTS: Healthy volunteers (n = 30) were studied to establish a reference range. Gastric emptying was then measured in patients (n = 39) before and after colorectal surgery. INTERVENTION: Assessment of gastric emptying was performed on days 1 to 4 by measuring antral cross-sectional area every 10 minutes after ingestion of 250 mL of water. MAIN OUTCOME MEASURES: The time to complete emptying of water was used as a surrogate measure of gastric emptying. Information concerning postoperative outcomes, GI symptoms, and recovery was also recorded. RESULTS: The median time to complete emptying of water for healthy volunteers was 20 minutes (range, 10-40 minutes). The study protocol was completed in 30 of 39 patients. The time to complete emptying of water on day 2 had the best discriminatory power to identify patients with ileus (sensitivity, 85.71%; specificity, 82.61%). Gastric emptying was normal in 20 of 30 (67%) patients, with only 1 case of ileus (false negative). These patients had less nausea (p = 0.0003), earlier intake of solid diet (p = 0.001), and shorter hospital stay (p = 0.040) compared with patients with abnormal gastric emptying. LIMITATIONS: Ultrasound is operator dependent with a learning curve. CONCLUSIONS: Bedside sonographic assessment of gastric emptying is feasible and reliable. Assessment of antral contents with a single ultrasound 40 minutes after ingestion of water enables classification of patients into those with normal and abnormal gastric emptying. When performed on postoperative day 2, it has good sensitivity/specificity for discriminating patients with ileus.

Short-Term Outcomes for Opiate and Crack Users Accessing Treatment: The Effects of Criminal Justice Referral and Crack Use.

BACKGROUND/AIMS: The English drug treatment population doubled in size between 1998 and 2008, increasingly characterised by crack cocaine use and criminal justice system (CJS) referral. We assessed short-term (median 3.5 month) behaviour changes following participation in drug treatment and the moderating effect of CJS referral/crack use. METHODS: Opiate and/or crack cocaine users (n = 1,267) were recruited from 342 agencies. Outcome effects were assessed via interaction term regression, clustered at participant level, controlling for client characteristics. Treatment retention effects were tested via Cox proportional hazard models. RESULTS: Statistically significant improvements in health, drug use and offensive behaviour were observed (e.g. heroin use from 87 to 51%, acquisitive offending from 47 to 23%). Referral route was not associated with variation in outcomes. Crack use at baseline was associated with a greater chance of non-fatal overdose at follow-up (p = 0.035, 95% CI 1.08-8.20) but a greater reduction in offending income (p = 0.002, 95% CI £104-£419). CONCLUSION: Despite changes in the English drug treatment population, equivalent short-term improvements in client behaviour were observed a decade earlier. Outcomes for CJS-referred clients were comparable to non-CJS. Crack use at treatment entry offered some scope for greater improvements in offending but may be a barrier to cessation of mortality-associated risky behaviour.

Worry processes in patients with persecutory delusions.

OBJECTIVES: Worry may be common in patients with paranoia and a contributory causal factor in the occurrence of the delusions. A number of psychological mechanisms have been linked to the occurrence of worry in emotional disorders but these are yet to be investigated in psychosis. The primary aim of the study was to test the links between five main worry mechanisms - perseverative thinking, catastrophizing, stop rules, metacognitive beliefs, and intolerance of uncertainty - and the cognitive style of worry in patients with persecutory delusions. METHOD: One hundred and fifty patients with persecutory delusions completed assessments of paranoia, worry, and worry mechanisms. RESULTS: Worry in patients with psychosis was associated with the following: a perseverative thinking style, an 'as many as can' stop rule, a range of metacognitive beliefs (cognitive confidence, worry as uncontrollable and the need to control thoughts), and intolerance of uncertainty. Higher levels of worry were associated with higher levels of paranoia. There was also evidence that intolerance of uncertainty and the metacognitive belief concerning the need to control thoughts were independently associated with paranoia. CONCLUSIONS: Worry in patients with persecutory delusions may well be understood by similar underlying mechanisms as worry in emotional disorders. This supports the use of interventions targeting worry, suitably modified, for patients with psychosis. PRACTITIONER POINTS: Worry is a significant concern for patients with paranoia Worry in paranoia is likely to be caused by similar mechanisms as worry in emotional disorders The results support the recent trial findings that standard techniques for treating worry in anxiety, suitably modified, are applicable for patients with paranoia LIMITATIONS: The findings are limited by the self-report nature of measures and by the study design which precludes any assumptions about the direction of causality between the psychological mechanisms and worry.

Self-Confidence and Paranoia: An Experimental Study Using an Immersive Virtual Reality Social Situation.

BACKGROUND: Paranoia may build directly upon negative thoughts about the self. There have been few direct experimental tests of this hypothesis. AIMS: The aim of the study was to test the immediate effects of manipulating self-esteem in individuals vulnerable to paranoia. METHOD: A two condition cross-over experimental test was conducted. The participants were 26 males reporting paranoid ideation in the past month. Each participant experienced a neutral immersive virtual reality (VR) social environment twice. Before VR participants received a low self-confidence manipulation or a high self-confidence manipulation. The order of manipulation type was randomized. Paranoia about the VR avatars was assessed. RESULTS: The low self-confidence manipulation, relative to the high self-confidence manipulation, led to significantly more negative social comparison in virtual reality and higher levels of paranoia. CONCLUSIONS: Level of self-confidence affects the occurrence of paranoia in vulnerable individuals. The clinical implication is that interventions designed to improve self-confidence may reduce persecutory ideation.

Targeting Recovery in Persistent Persecutory Delusions: A Proof of Principle Study of a New Translational Psychological Treatment (the Feeling Safe Programme).

BACKGROUND: Many patients do not respond adequately to current pharmacological or psychological treatments for psychosis. Persistent persecutory delusions are common in clinical services, and cause considerable patient distress and impairment. Our aim has been to build a new translational personalized treatment, with the potential for wide use, that leads to high rates of recovery in persistent persecutory delusions. We have been developing, and evaluating individually, brief modular interventions, each targeting a key causal factor identified from our cognitive model. These modules are now combined in "The Feeling Safe Programme". AIMS: To test the feasibility of a new translational modular treatment for persistent persecutory delusions and provide initial efficacy data. METHOD: 12 patients with persistent persecutory delusions in the context of non-affective psychosis were offered the 6-month Feeling Safe Programme. After assessment, patients chose from a personalized menu of treatment options. Four weekly baseline assessments were carried out, followed by monthly assessments. Recovery in the delusion was defined as conviction falling below 50% (greater doubt than certainty). RESULTS: 11 patients completed the intervention. One patient withdrew before the first monthly assessment due to physical health problems. An average of 20 sessions (SD = 4.4) were received. Posttreatment, 7 out of 11 (64%) patients had recovery in their persistent delusions. Satisfaction ratings were high. CONCLUSIONS: The Feeling Safe Programme is feasible to use and was associated with large clinical benefits. To our knowledge this is the first treatment report focused on delusion recovery. The treatment will be tested in a randomized controlled trial.

The Perseverative Thinking Questionnaire in Patients with Persecutory Delusions.

BACKGROUND: Ruminative negative thinking has typically been considered as a factor maintaining common emotional disorders and has recently been shown to maintain persecutory delusions in psychosis. The Perseverative Thinking Questionnaire (PTQ) (Ehring et al., 2011) is a transdiagnostic measure of ruminative negative thinking that shows promise as a "content-free" measure of ruminative negative thinking. AIMS: The PTQ has not previously been studied in a psychosis patient group. In this study we report for the first time on the psychometric properties of Ehring et al.'s PTQ in such a group. METHOD: The PTQ was completed by 142 patients with current persecutory delusions and 273 non-clinical participants. Participants also completed measures of worry and paranoia. A confirmatory factor analysis was performed on the clinical group's PTQ responses to assess the factor structure of the measure. Differences between groups were used to assess criterion reliability. RESULTS: A three lower-order factor structure of the PTQ (core characteristics of ruminative negative thinking, perceived unproductiveness, and capturing mental capacity) was replicated in the clinical sample. Patients with persecutory delusions were shown to experience significantly higher levels of ruminative negative thinking on the PTQ than the general population sample. The PTQ demonstrated high internal reliability. CONCLUSIONS: This study did not include test-retest data, and did not compare the PTQ against a measure of depressive rumination but, nevertheless, lends support for the validity of the PTQ as a measure of negative ruminative thinking in patients with psychosis.

Cognitive therapy for people with schizophrenia spectrum disorders not taking antipsychotic drugs: a single-blind randomised controlled trial.

BACKGROUND: Antipsychotic drugs are usually the first line of treatment for schizophrenia; however, many patients refuse or discontinue their pharmacological treatment. We aimed to establish whether cognitive therapy was effective in reducing psychiatric symptoms in people with schizophrenia spectrum disorders who had chosen not to take antipsychotic drugs. METHODS: We did a single-blind randomised controlled trial at two UK centres between Feb 15, 2010, and May 30, 2013. Participants aged 16-65 years with schizophrenia spectrum disorders, who had chosen not to take antipsychotic drugs for psychosis, were randomly assigned (1:1), by a computerised system with permuted block sizes of four or six, to receive cognitive therapy plus treatment as usual, or treatment as usual alone. Randomisation was stratified by study site. Outcome assessors were masked to group allocation. Our primary outcome was total score on the positive and negative syndrome scale (PANSS), which we assessed at baseline, and at months 3, 6, 9, 12, 15, and 18. Analysis was by intention to treat, with an ANCOVA model adjusted for site, age, sex, and baseline symptoms. This study is registered as an International Standard Randomised Controlled Trial, number 29607432. FINDINGS: 74 individuals were randomly assigned to receive either cognitive therapy plus treatment as usual (n=37), or treatment as usual alone (n=37). Mean PANSS total scores were consistently lower in the cognitive therapy group than in the treatment as usual group, with an estimated between-group effect size of -6.52 (95% CI -10.79 to -2.25; p=0.003). We recorded eight serious adverse events: two in patients in the cognitive therapy group (one attempted overdose and one patient presenting risk to others, both after therapy), and six in those in the treatment as usual group (two deaths, both of which were deemed unrelated to trial participation or mental health; three compulsory admissions to hospital for treatment under the mental health act; and one attempted overdose). INTERPRETATION: Cognitive therapy significantly reduced psychiatric symptoms and seems to be a safe and acceptable alternative for people with schizophrenia spectrum disorders who have chosen not to take antipsychotic drugs. Evidence-based treatments should be available to these individuals. A larger, definitive trial is needed. FUNDING: National Institute for Health Research.

Emergence of embryonic pattern through contact inhibition of locomotion.

The pioneering cell biologist Michael Abercrombie first described the process of contact inhibition of locomotion more than 50 years ago when migrating fibroblasts were observed to rapidly change direction and migrate away upon collision. Since then, we have gleaned little understanding of how contact inhibition is regulated and only lately observed its occurrence in vivo. We recently revealed that Drosophila macrophages (haemocytes) require contact inhibition for their uniform embryonic dispersal. Here, to investigate the role that contact inhibition plays in the patterning of haemocyte movements, we have mathematically analysed and simulated their contact repulsion dynamics. Our data reveal that the final pattern of haemocyte distribution, and the details and timing of its formation, can be explained by contact inhibition dynamics within the geometry of the Drosophila embryo. This has implications for morphogenesis in general as it suggests that patterns can emerge, irrespective of external cues, when cells interact through simple rules of contact repulsion.

Components of therapy as mechanisms of change in cognitive therapy for people at risk of psychosis: analysis of the EDIE-2 trial.

BACKGROUND: Research suggests that the way in which cognitive therapy is delivered is an important factor in determining outcomes. We test the hypotheses in which the development of a shared problem list, use of case formulation, homework tasks and active intervention strategies will act as process variables. METHOD: Presence of these components during therapy is taken from therapist notes. The direct and indirect effect of the intervention is estimated by an instrumental variable analysis. RESULTS: A significant decrease in the symptom score for case formulation (coefficient = -23, 95% CI -44 to -1.7, P = 0.036) and homework (coefficient = -0.26, 95% CI -0.51 to -0.001, P = 0.049) is found. Improvement with the inclusion of active change strategies is of borderline significance (coefficient = -0.23, 95% CI -0.47 to 0.005, P = 0.056). CONCLUSIONS: There is a greater treatment effect if formulation and homework are involved in therapy. However, high correlation between components means that these may be indicators of overall treatment fidelity.

Recovery-focused cognitive-behavioural therapy for recent-onset bipolar disorder: randomised controlled pilot trial.

BACKGROUND: Despite evidence for the effectiveness of structured psychological therapies for bipolar disorder no psychological interventions have been specifically designed to enhance personal recovery for individuals with recent-onset bipolar disorder. AIMS: A pilot study to assess the feasibility and effectiveness of a new intervention, recovery-focused cognitive-behavioural therapy (CBT), designed in collaboration with individuals with recent-onset bipolar disorder intended to improve clinical and personal recovery outcomes. METHOD: A single, blind randomised controlled trial compared treatment as usual (TAU) with recovery-focused CBT plus TAU (n = 67). RESULTS: Recruitment and follow-up rates within 10% of pre-planned targets to 12-month follow-up were achieved. An average of 14.15 h (s.d. = 4.21) of recovery-focused CBT were attended out of a potential maximum of 18 h. Compared with TAU, recovery-focused CBT significantly improved personal recovery up to 12-month follow-up (Bipolar Recovery Questionnaire mean score 310.87, 95% CI 75.00-546.74 (s.e. = 120.34), P = 0.010, d = 0.62) and increased time to any mood relapse during up to 15 months follow-up (χ2 = 7.64, P<0.006, estimated hazard ratio (HR) = 0.38, 95% CI 0.18-0.78). Groups did not differ with respect to medication adherence. CONCLUSIONS: Recovery-focused CBT seems promising with respect to feasibility and potential clinical effectiveness. Clinical- and cost-effectiveness now need to be reliably estimated in a definitive trial.