How does cognitive behavior therapy for dissociative seizures work? A mediation analysis of the CODES trial.

BACKGROUND: We compared dissociative seizure specific cognitive behavior therapy (DS-CBT) plus standardized medical care (SMC) to SMC alone in a randomized controlled trial. DS-CBT resulted in better outcomes on several secondary trial outcome measures at the 12-month follow-up point. The purpose of this paper is to evaluate putative treatment mechanisms. METHODS: We carried out a secondary mediation analysis of the CODES trial. 368 participants were recruited from the National Health Service in secondary / tertiary care in England, Scotland, and Wales. Sixteen mediation hypotheses corresponding to combinations of important trial outcomes and putative mediators were assessed. Twelve-month trial outcomes considered were final-month seizure frequency, Work and Social Adjustment Scale (WSAS), and the SF-12v2, a quality-of-life measure providing physical (PCS) and mental component summary (MCS) scores. Mediators chosen for analysis at six months (broadly corresponding to completion of DS-CBT) included: (a) beliefs about emotions, (b) a measure of avoidance behavior, (c) anxiety and (d) depression. RESULTS: All putative mediator variables except beliefs about emotions were found to be improved by DS-CBT. We found evidence for DS-CBT effect mediation for the outcome variables dissociative seizures (DS), WSAS and SF-12v2 MCS scores by improvements in target variables avoidance behavior, anxiety, and depression. The only variable to mediate the DS-CBT effect on the SF-12v2 PCS score was avoidance behavior. CONCLUSIONS: Our findings largely confirmed the logic model underlying the development of CBT for patients with DS. Interventions could be additionally developed to specifically address beliefs about emotions to assess whether it improves outcomes.

Moderators of cognitive behavioural therapy treatment effects and predictors of outcome in the CODES randomised controlled trial for adults with dissociative seizures.

OBJECTIVE: We explored moderators of cognitive behavioural therapy (CBT) treatment effects and predictors of outcome at 12-month follow-up in the CODES Trial (N = 368) comparing CBT plus standardised medical care (SMC) vs SMC-alone for dissociative seizures (DS). METHODS: We undertook moderator analyses of baseline characteristics to determine who had benefited from being offered CBT 12 months post-randomisation. Outcomes included: monthly DS frequency, psychosocial functioning (Work and Social Adjustment Scale - WSAS), and health-related quality of life (Mental Component Summary (MCS) and Physical Component Summary (PCS) SF-12v2 scores). When moderating effects were absent, we tested whether baseline variables predicted change irrespective of treatment allocation. RESULTS: Moderator analyses revealed greater benefits (p < 0.05) of CBT on DS frequency for participants with more (≥22) symptoms (Modified PHQ-15) or ≥ 1 current (M.I.N.I.-confirmed) comorbid psychiatric diagnosis at baseline. The effect of CBT on PCS scores was moderated by gender; women did better than men in the CBT + SMC group. Predictors of improved outcome included: not receiving disability benefits, lower anxiety and/or depression scores (PCS, MCS, WSAS); shorter duration, younger age at DS onset, employment, fewer symptoms and higher educational qualification (PCS, WSAS); stronger belief in the diagnosis and in CBT as a "logical" treatment (MCS). Some variables that clinically might be expected to moderate/predict outcome (e.g., maladaptive personality traits, confidence in treatment) were not shown to be relevant. CONCLUSION: Patient complexity interacted with treatment. CBT was more likely to reduce DS frequency in those with greater comorbidity. Other patient characteristics predicted outcome regardless of the received intervention.

Mediators of increased self-harm and suicidal ideation in sexual minority youth: a longitudinal study.

BACKGROUND: Sexual minority youth have elevated suicidal ideation and self-harm compared with heterosexual young people; however, evidence for mediating mechanisms is predominantly cross-sectional. Using a longitudinal design, we investigated self-esteem and depressive symptoms as mediators of increased rates of suicidal ideation or self-harm (SISH) among sexual minority youth, and the roles of childhood gender nonconformity (CGN) and sex as moderators of these relationships. METHOD: In total, 4274 youth from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort reported sexual orientation at age 15 years, and past-year SISH at age 20 years. Self-esteem and depressive symptoms were assessed at ages 17 and 18 years, respectively. CGN was measured at 30-57 months. Covariates included sociodemographic variables and earlier measures of mediator and outcome variables. Mediation pathways were assessed using structural equation modelling. RESULTS: Sexual minority youth (almost 12% of the sample) were three times more likely than heterosexual youth to report past-year SISH (95% confidence interval 2.43-3.64) at 20 years. Two mediation pathways were identified: a single mediator pathway involving self-esteem and a multiple-mediated pathway involving self-esteem and depressive symptoms. Although CGN was associated with past-year SISH, it did not moderate any mediation pathways and there was no evidence for moderation by sex. CONCLUSIONS: Lower self-esteem and increased depressive symptoms partly explain the increased risk for later suicidal ideation and self-harm in sexual minority youth. Preventive strategies could include self-esteem-enhancing or protecting interventions, especially in female sexual minority youth, and treatment of depression.

Changes in newspaper coverage of mental illness from 2008 to 2016 in England.

AIMS: Since 2008 England's anti-stigma programme Time to Change has lobbied media outlets about stigmatising coverage and worked with them to promote accurate and non-stigmatising coverage. While this may have an impact on coverage and hence attitudes, it is also possible that coverage can change in response to improving attitudes, through the creation of a market demand for less stigmatising coverage. This study evaluates English newspaper coverage of mental health topics between 2008 and 2016. METHOD: Articles covering mental health in 27 newspapers were retrieved using keyword searches on two randomly chosen days each month in 2008-2016, excluding 2012 and 2015 due to restricted resources. Content analysis used a structured coding framework. Univariate logistic regression models were used to estimate the odds of each hypothesised element occurring in 2016 compared with 2008 and Wald tests to assess the overall statistical significance of the year variable as the predictor. RESULTS: The sample retrieved almost doubled between 2008 (n = 882) and 2016 (n = 1738). We found a significant increase in the proportion of anti-stigmatising articles (odds ratio (OR) 2.26 (95% confidence interval (CI) 1.86-2.74)) and a significant decrease in stigmatising articles (OR 0.62 (95% CI 0.51-0.75)). Reports on all diagnoses except for schizophrenia were more often anti-stigmatising than stigmatising. CONCLUSIONS: This is the first clear evidence of improvement in coverage since the start of Time to Change. However, coverage of schizophrenia may be less affected by this positive shift than that of other diagnoses. The increase in the level of coverage identified in 2016 requires further investigation, as it may also influence public conceptualisation of what constitutes mental illness, attitudes to mental illness in general and/or specific diagnoses. While most anti-stigma programmes are not diagnosis specific, we suggest their evaluation would benefit from a diagnosis specific approach to allow fuller interpretation of their effects. This could include media analysis driven by hypotheses based on diagnoses to ascertain whether variations by diagnosis over time occur both in the nature and in the proportion of coverage.

Salbutamol-induced electrophysiological changes show no correlation with electrophysiological changes during hyperinsulinaemic-hypoglycaemic clamp in young people with Type 1 diabetes.

AIMS: Hypoglycaemia causes QT-interval prolongation and appears pro-arrhythmogenic. Salbutamol, a ß2 -adrenoreceptor agonist also causes QT-interval prolongation. We hypothesized that the magnitude of electrophysiological changes induced by salbutamol and hypoglycaemia might relate to each other and that salbutamol could be used as a non-invasive screening tool for predicting an individual's electrophysiological response to hypoglycaemia. METHODS: Eighteen individuals with Type 1 diabetes were administered 2.5 mg of nebulized salbutamol. Participants then underwent a hyperinsulinaemic-hypoglycaemic clamp (2.5 mmol/l for 1 h). During both experiments, heart rate and serum potassium (and catecholamines during the clamp) were measured and a high-resolution electrocardiogram (ECG) was recorded at pre-set time points. Cardiac repolarization was measured by QT-interval duration adjusted for heart rate (QTc ), T-wave amplitude (Tamp ), T-peak to T-end interval duration (Tp Tend ) and T-wave area symmetry (Tsym ). The maximum changes vs. baseline in both experiments were assessed for their linear dependence. RESULTS: Salbutamol administration caused QTc and Tp Tend prolongation and a decrease in Tamp and Tsym . Hypoglycaemia caused increased plasma catecholamines, hypokalaemia, QTc and Tp Tend prolongation, and a decrease in Tamp and Tsym . No significant correlations were found between maximum changes in QTc [r = 0.15, 95% confidence interval (95% CI) -0.341 to 0.576; P = 0.553), Tp Tend (r = 0.075, 95% CI -0.406 to 0.524; P = 0.767), Tsym (r = 0.355, 95% CI -0.132 to 0.706; P = 0.149) or Tamp (r = 0.148, 95% CI -0.347 to 0.572; P = 0.558) in either experiment. CONCLUSIONS: Both hypoglycaemia and salbutamol caused pro-arrhythmogenic electrophysiological changes in people with Type 1 diabetes but were not related in any given individual. Salbutamol does not appear useful in assessing an individual's electrophysiological response to hypoglycaemia.

Inferring polydomy: a review of functional, spatial and genetic methods for identifying colony boundaries.

Identifying the boundaries of a social insect colony is vital for properly understanding its ecological function and evolution. Many species of ants are polydomous: colonies inhabit multiple, spatially separated, nests. Ascertaining which nests are parts of the same colony is an important consideration when studying polydomous populations. In this paper, we review the methods that are used to identify which nests are parts of the same polydomous colony and to determine the boundaries of colonies. Specifically, we define and discuss three broad categories of approach: identifying nests sharing resources, identifying nests sharing space, and identifying nests sharing genes. For each of these approaches, we review the theoretical basis, the limitations of the approach and the methods that can be used to implement it. We argue that all three broad approaches have merits and weaknesses, and provide a methodological comparison to help researchers select the tool appropriate for the biological question they are investigating.

Conformationally restricted calpain inhibitors.

The cysteine protease calpain-I is linked to several diseases and is therefore a valuable target for inhibition. Selective inhibition of calpain-I has proved difficult as most compounds target the active site and inhibit a broad spectrum of cysteine proteases as well as other calpain isoforms. Selective inhibitors might not only be potential drugs but should act as tools to explore the physiological and pathophysiological roles of calpain-I. α-Mercaptoacrylic acid based calpain inhibitors are potent, cell permeable and selective inhibitors of calpain-I and calpain-II. These inhibitors target the calcium binding domain PEF(S) of calpain-I and -II. Here X-ray diffraction analysis of co-crystals of PEF(S) revealed that the disulfide form of an α-mercaptoacrylic acid bound within a hydrophobic groove that is also targeted by a calpastatin inhibitory region and made a greater number of favourable interactions with the protein than the reduced sulfhydryl form. Measurement of the inhibitory potency of the α-mercaptoacrylic acids and X-ray crystallography revealed that the IC50 values decreased significantly on oxidation as a consequence of the stereo-electronic properties of disulfide bonds that restrict rotation around the S-S bond. Consequently, thioether analogues inhibited calpain-I with potencies similar to those of the free sulfhydryl forms of α-mercaptoacrylic acids.

Guessing imagined and live chance events: adults behave like children with live events.

An established finding is that adults prefer to guess before rather than after a chance event has happened. This is interpreted in terms of aversion to guessing when relatively incompetent: After throwing, the fall could be known. Adults (N=71, mean age 18;11, N=28, mean age 48;0) showed this preference with imagined die-throwing as in the published studies. With live die-throwing, children (N=64, aged 6 and 8 years; N=50, aged 5 and 6 years) and 15-year-olds (N=93, 46) showed the opposite preference, as did 17 adults. Seventeen-year-olds (N=82) were more likely to prefer to guess after throwing with live rather than imagined die-throwing. Reliance on imagined situations in the literature on decision-making under uncertainty ignores the possibility that adults imagine inaccurately how they would really feel: After a real die has been thrown, adults, like children, may feel there is less ambiguity about the outcome.

Children's working understanding of the knowledge gained from seeing and feeling.

In three experiments (N = 48 3- to 4-year olds; 100 3- to 5-year olds; 54 4-year-olds), children who could see or feel a target toy, recognized when they had sufficient information to answer 'Which one is it?' and when they needed additional access. They were weaker at taking the informative modality of access when the choice was between seeing more of a partially visible toy and feeling it; at doing so when the target was completely hidden; and at reporting seeing or feeling as their source of knowledge of the target's identity having experienced both. Working understanding of the knowledge gained from seeing and feeling (identifying the target efficiently) was not necessarily in advance of explicit understanding (reporting the informative source).

Lay public's understanding of equipoise and randomisation in randomised controlled trials.

OBJECTIVES: To research the lay public's understanding of equipoise and randomisation in randomised controlled trials (RCTs) and to look at why information on this may not be not taken in or remembered, as well as the effects of providing information designed to overcome barriers. DESIGN: Investigations were informed by an update of systematic review on patients' understanding of consent information in clinical trials, and by relevant theory and evidence from experimental psychology. Nine investigations were conducted with nine participants. SETTING: Access (return to education), leisure and vocational courses at Further Education Colleges in the Midlands, UK. PARTICIPANTS: Healthy adults with a wide range of educational backgrounds and ages. INVESTIGATIONS: Participants read hypothetical scenarios and wrote brief answers to subsequent questions. Sub-samples of participants were interviewed individually to elaborate on their written answers. Participants' background assumptions concerning equipoise and randomisation were examined and ways of helping participants recognise the scientific benefits of randomisation were explored. MAIN OUTCOME MEASURES: Judgments on allocation methods; treatment preferences; the acceptability of random allocation; whether or not individual doctors could be completely unsure about the best treatment; whether or not doctors should reveal treatment preferences under conditions of collective equipoise; and how sure experts would be about the best treatment following random allocation vs doctor/patient choice. Assessments of understanding hypothetical trial information. RESULTS: Recent literature continues to report trial participants' failure to understand or remember information about randomisation and equipoise, despite the provision of clear and readable trial information leaflets. In current best practice, written trial information describes what will happen without offering accessible explanations. As a consequence, patients may create their own incorrect interpretations and consent or refusal may be inadequately informed. In six investigations, most participants identified which methods of allocation were random, but judged the random allocation methods to be unacceptable in a trial context; the mere description of a treatment as new was insufficient to engender a preference for it over a standard treatment; around half of the participants denied that a doctor could be completely unsure about the best treatment. A majority of participants judged it unacceptable for a doctor to suggest letting chance decide when uncertain of the best treatment, and, in the absence of a justification for random allocation, participants did not recognise scientific benefits of random allocation over normal treatment allocation methods. The pattern of results across three intervention studies suggests that merely supplementing written trial information with an explanation is unlikely to be helpful. However, when people manage to focus on the trial's aim of increasing knowledge (as opposed to making treatment decisions about individuals), and process an explanation actively, they may be helped to understand the scientific reasons for random allocation. CONCLUSIONS: This research was not carried out in real healthcare settings. However, participants who could correctly identify random allocation methods, yet judged random allocation unacceptable, doubted the possibility of individual equipoise and saw no scientific benefits of random allocation over doctor/patient choice, are unlikely to draw upon contrasting views if invited to enter a real clinical trial. This suggests that many potential trial participants may have difficulty understanding and remembering trial information that conforms to current best practice in its descriptions of randomisation and equipoise. Given the extent of the disparity between the assumptions underlying trial design and the assumptions held by the lay public, the solution is unlikely to be simple. Nevertheless, the results suggest that including an accessible explanation of the scientific benefits of randomisation may be beneficial provided potential participants are also enabled to reflect on the trial's aim of advancing knowledge, and to think actively about the information presented. Further areas for consideration include: the identification of effective combinations of written and oral information; helping participants to reflect on the aim of advancing knowledge; and an evidence-based approach to leaflet construction.

Can one written word mean many things? Prereaders' assumptions about the stability of written words' meanings.

Results of three experiments confirmed previous findings that in a moving word task, prereaders 3 to 5 years of age judge as if the meaning of a written word changes when it moves from a matching to a nonmatching toy (e.g., when the word "dog" moves from a dog to a boat). We explore under what circumstances children make such errors, we identify new conditions under which children were more likely correctly to treat written words' meanings as stable: when the word was placed alongside a nonmatching toy without having been alongside a matching toy previously, when two words were moved from a matching toy to a nonmatching toy, and when children were asked to change what the print said. Under these conditions, children more frequently assumed that physical forms had stable meanings as they do with other forms of external representation.

When can children handle referential opacity? Evidence for systematic variation in 5- and 6-year-old children's reasoning about beliefs and belief reports.

Five- and 6-year-olds (N=51) heard stories in which a character sorted items into two locations. Either the character had a false belief about one of the items (e.g., thought a tin contained biscuits, not Lego), or was only partially informed of an item's dual identity (e.g., did not know that a tie was a present). Children found it easier to reject a report of the character's belief that described the true state of affairs when the character had a false belief (e.g., Is Fred's uncle thinking "where shall I put this Lego?"), than to reject one in which an object known to the character was described using a term of which she was ignorant (e.g., Is Mum thinking "where shall I put this present?"). Similarly, children found it easier to predict the character's incorrect sorting of the target items for false belief (with food not toys) than for dual identity (in the wardrobe not with things to take on a visit). Correct reasoning about beliefs and reports of beliefs that misrepresent an object does not imply mastery of the fact that beliefs represent an object in a particular way.

Children's suggestibility in relation to their understanding about sources of knowledge.

In the experiments reported here, children chose either to maintain their initial belief about an object's identity or to accept the experimenter's contradicting suggestion. Both 3- to 4-year-olds and 4- to 5-year-olds were good at accepting the suggestion only when the experimenter was better informed than they were (implicit source monitoring). They were less accurate at recalling both their own and the experimenter's information access (explicit recall of experience), though they performed well above chance. Children were least accurate at reporting whether their final belief was based on what they were told or on what they experienced directly (explicit source monitoring). Contrasting results emerged when children decided between contradictory suggestions from two differentially informed adults: Three- to 4-year-olds were more accurate at reporting the knowledge source of the adult they believed than at deciding which suggestion was reliable. Decision making in this observation task may require reflective understanding akin to that required for explicit source judgments when the child participates in the task.

Five-year-olds' handling of reference and description in the domains of language and mental representation.

Children's concurrent success on false belief tasks and their handling of two labels for one object (e.g., bunny/rabbit) has been interpreted as demonstrating understanding about the essential features of representation. Three experiments reveal the limitations in 5-year-olds' understanding for both mental and linguistic representations. We report relatively poor performance on a task involving two labels for one object (e.g., dice/eraser) which required children to treat another's knowledge as representing only some of the feature of its real referent: Dice but not eraser. Five year olds who made errors also had difficulty handling the fact that a written word 'dice' referring to such a dice/eraser, can also be applied to a standard dice but not to a standard eraser. These children lacked metalinguistic awareness of words as entities that both refer and describe.

Children's ability to make tentative interpretations of ambiguous messages.

Consistent with prior research, 5- and 6-year-old children overestimated their knowledge of the intended referent of ambiguous messages. Yet they correctly revised their interpretations of ambiguous messages in light of contradicting information that followed immediately, while maintaining their initial interpretations of unambiguous messages (Experiment 1). Children of this age were able to integrate information over two successive ambiguous messages to identify the intended referent (Experiment 2). However, unlike 7- and 8-year-olds, they were no more likely to search for further information following ambiguous messages compared with unambiguous ones (Experiment 3). We conclude that although 5- and 6-year-olds' interpretations of ambiguous messages are not tentative at the outset, they can use source monitoring skills to treat them as tentative retrospectively, at least over short time spans.

Children's difficulties handling dual identity.

Thirty-nine 6-year-old children participated in a longitudinal study using tasks that required handling of dual identity. Pre- and posttest sessions employed tasks involving a protagonist who was partially informed about an object or person; for example, he knew an item as a ball but not as a present. Children who judged correctly that the protagonist did not know the ball was a present (thereby demonstrating some understanding of the consequences of limited information access), often judged incorrectly (1) that he knew that there was a present in the box, and (2) that he would search as if fully informed. Intervening sessions added contextual support and tried to clarify the experimenter's communicative intentions in a range of ways. Despite signs of general improvement, the distinctive pattern of errors persisted in every case. These findings go beyond previous studies of children's handling of limited information access, and are hard to accommodate within existing accounts of developing understanding of the mind.

Information presentation and decisions to enter clinical trials: a hypothetical trial of hormone replacement therapy.

We examined recruitment to an imaginary trial of hormone replacement therapy (HRT) following two different styles of information about HRT. We predicted that for treatments which, like HRT, are available outside a trial, people offered the facts as currently known would be less likely to remain unsure about the relative costs and benefits, and so less likely to agree to enter a randomised trial. In contrast, when the information provided reflected the current state of uncertainty which justified the trial, we predicted that people would be less likely to form a preference for one treatment arm over the other, and so more likely to agree to enter a trial. One hundred women aged 25-40 years were informed about HRT via a video and an information leaflet. For half the participants the information was framed in a way which emphasised the current state of uncertainty about the relative costs and benefits of HRT, and in that respect it reflected the justification for a trial. This version was considered to be similar in style to information commonly provided to potential trial participants. For half the participants the same information was framed in a way which offered explicit numerical detail about currently known facts, and in that respect it was considered to be similar in style to information commonly available to doctors prior to a trial. Women learned as much about HRT in the two conditions, but women given the explicit versions were more likely (i) to hold a stronger view about whether or not they would take HRT (ratings were not elicited from the first 30 participants in this condition. N = 20, p < 0.05 1 tailed) and (ii) to refuse entry to the trial (N = 50, p < 0.05 2 tailed). Those who, given the explicit version, agreed rather than refused to enter the trial, scored higher on believing that others control their health (p < 0.01 2 tailed).

High rates of infant macrosomia: a comparison of a Canadian native and a non-native population.

The Cree of James Bay have the highest ever reported mean birth weight and a high prevalence of infant macrosomia. This study was designed to examine independent risk factors for infant macrosomia among the Cree, to compare these to risk factors among non-Native Canadians and to determine if ethnic differences persist after adjusting for differences in the distribution of other risk factors. Macrosomia was defined as birth weight >90(th) percentile for gestational age of a reference population. Independent determinants of macrosomia were examined in 385 Cree and 5644 non-Native women. The potential effect of ethnicity (Cree vs. non-Native) was determined after statistically adjusting for age, parity, pregravid weight, height, net rate of weight gain, gestational diabetes mellitus (GDM) and smoking status. The prevalence of macrosomia among the Cree was 34.3% vs. 11.1% among non-Natives. Although GDM significantly increased the risk for macrosomia among the Cree (odds ratio: 4.46, 95% CI: 2.24-9.26), it was not a significant risk factor among non-Natives (odds ratio: 1.15, 95% CI: 0.79-1.65). The risk for infant macrosomia remained elevated among the Cree compared with non-Natives after adjusting for other risk factors (odds ratio: 3.64, 95% CI: 2.69-4.90). In conclusion, the Cree have a high prevalence of macrosomia despite controlling for important differences in pregravid weight and GDM. Some of this variation may be due to genetic differences in fetal growth. The differential impact of GDM on macrosomia in the two ethnic groups may be due to differences in treatment strategies for GDM.

Interaction of body weight and ethnicity on risk of gestational diabetes mellitus.

BACKGROUND: The James Bay Cree of Canada have one of the highest recorded rates of gestational diabetes mellitus (GDM) among aboriginal people worldwide; the reasons for this elevated risk remain to be documented. OBJECTIVE: Our objective was to compare predictors and risk of GDM between the James Bay Cree and non-Native Canadians. DESIGN: Risk for GDM was compared between Cree and non-Native women by 1) adjusting statistically for differences in age, parity, pregravid weight, and smoking status (n = 402 Cree, 7718 non-Natives), and 2) matching Cree women with non-Native women for age and pregravid weight (n = 394 Cree, 788 non-Natives). Dietary and physical activity information was available for a subset of Cree women (n = 152). RESULTS: Age and pregravid weight were independent predictors of GDM in both Cree and non-Native women. After these predictors were controlled for, normal-weight (