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Major depression is a complex disorder with no single, direct causal mechanism. Morbidity has been linked to genetic processes, developmental history, and unique environmental exposures. Epigenetic mechanisms, especially DNA methylation, are also likely important factors in the pathogenesis of major depressive disorder (MDD). A community-based twin sample has many advantages for epigenetic studies, given the shared genetic and developmental histories of same-sex twin pairs. This article describes the rationale and study design for the Mood and Methylation Study in which 133 twin pairs (101 monozygotic and 32 dizygotic), both discordant and concordant for lifetime history of MDD, were evaluated on a large number of variables related to MDD. The twins also provided blood samples for an epigenome-wide association study of differentially methylated regions (DMR) relevant to MDD. Although MDD is typically considered a disorder of the central nervous system, it is unfeasible to obtain a large sample of brain tissues. However, epigenetic variation is not limited to the affected tissue but can also be detected in peripheral blood leukocytes. Thus, this study focused on monocytes for the major analyses. Additional plans for the study include gene expression analysis from the same set of twins using RNA-seq and validation of significant DMRs in postmortem brain tissues from a separate sample. Moreover, sufficient samples have been collected to perform future ‘multi-omic’ analyses, including metabolome, microbiome, and transcriptome. Our long-term goal is to understand how epigenomic and other ‘omic’ factors can be manipulated for diagnostic, preventive, and therapeutic purposes for MDD and its related conditions.
During the 1st week of life the energy contained in the body of the average piglet increases by a factor between four and five. To achieve this increase the piglet must ingest metabolizable energy (ME) at a rate which is about four times its maintenance requirement. Well over half the ME supplied in the milk of the sow is in the form of emulsified fat. Whilst the piglet is being suckled, its intake is controlled by litter size, availability of teats and productiveness of the mammary gland. At 3 weeks of age the normal piglet requires about 7.8 MJ digestible energy to sustain a live growth rate of 280 g/day. At this stage the growth comprises about 40 g protein and about 68 g fat. This means that the required intake for a newly weaned piglet on a typical starter diet should be about 475 g/day. In practice such intakes are rarely achieved for several days, therefore weaning causes severe disruption of intake and of the growth curve and there are other factors involved including social disturbance and stress. Further problems are caused by the provision of diets which are unsuited to the physiology of the piglet's immature digestive tract. The sudden loss of the IgA component and indeed other protective factors contained in the dam's milk can be extremely serious, and the reduction in food intake is effectively a defence strategy by the piglet to cope with its new circumstances and try to maintain physiological homoeostasis. In some circumstances the use of antibacterial agents, organic acids or probiotics may be beneficial, but the approach is less reliable than careful formulation of the diet to avoid provocative ingredients such as soya-bean and rapeseed meal.
Results of East Antarctic (20−160° E) sea-ice motion derived from drifting buoys (collected in eight selected years between 1985 and 1997) are compared with sea-ice motion derived from sequential images from the 37 and 85.5 GHz channels of the Scanning Multichannel Microwave Radiometer (SMMR, 1979−87) and the Special Sensor Microwave/Imager (SSM/I, 1987−97). For the latitudes of interest, buoys yield velocity fields at 2 hourly resolution/while SMMR and SSM/I provide daily data. The spatial coverage of the drifting buoys is relatively sparse compared to the complete coverage of the southern sea-ice zone by SMMR and SSM/I, but the accuracy of the buoy position is better than ±280 m, while the resolution for the 85.5 GHz channel is only about 12.5 km, and about 25 km for the 37 GHz channel. The buoy measurements represent point motion, equal to the velocity of an individual ice floe, while the satellite data derived via the maximum cross-correlation method represent the motion of surface patterns within a gridcell. Comparison of the mean distributions of daily velocity derived from the datasets shows that while the broad-scale velocity patterns agree, the magnitude of the satellite-derived sea-ice velocities is significantly lower (typically by 40% or less) than the velocities derived from buoy measurements. This is in contrast with previous studies for the Arctic Ocean and the Weddell Sea, Antarctica. To elucidate differences in the velocity magnitude, individual trajectories from a number of drift regimes off East Antarctica are directly compared. Discrepancies between the two datasets are discussed with regard to the difference in spatial resolution of the data, the data-collection and −processing methods and the observed region.
Sea-ice velocities derived from remotely Sensed microwave imagery of the Special Sensor Microwave/Imager (SSM/I) have been analyzed for changes over time in Antarctic Sea-ice velocity, for the period 1988–2004. Year-to-year variability in mean Antarctic annual SSM/I-derived ice Speed is Small (17 year Standard deviation (SD) = 0.008 ms–1), with greater interannual variability in the zonal (eastward positive) velocity components (17 year SD = 0.016ms–1). Seasonally, minimum ice Speed is encountered during Summer, when nearly all Antarctic Sea ice is within the marginal ice zone. Ice motion peaks during winter and Spring, due to high velocities encountered in the outer pack of the Seasonal Sea-ice zone. The correlation (R2 = 0.47) between winter Southern Annular Mode (SAM) and mean winter ice Speed highlights the importance of atmospheric forcing on Sea-ice dynamics. The Spatial pattern of the correlation of the Standardized SAM index with the June–November ice Speed exhibits a wave-3 pattern, which matches the Sea-level pressure distribution. Sea-ice Speed in the upstream regions of quasi-stationary centres of low Sea-level pressure is likely to increase (decrease) during high (low) SAMyears, and the opposite for Sea-ice Speed in the downstream regions of the centres.
In November 2013, national public health agencies in England and Scotland identified an increase in laboratory-confirmed Salmonella Mikawasima. The role of proton pump inhibitors (PPIs) as a risk factor for salmonellosis is unclear; we therefore captured information on PPI usage as part of our outbreak investigation. We conducted a case-control study, comparing each case with two controls. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Thirty-nine of 61 eligible cases were included in the study. The median age of cases was 45 years; 56% were female. Of these, 33% were admitted to hospital and 31% reported taking PPIs. We identified an association between PPIs and non-typhoidal salmonellosis (aOR 8·8, 95% CI 2·0–38·3). There is increasing evidence supporting the existence of an association between salmonellosis and PPIs; however, biological studies are needed to understand the effect of PPIs in the pathogenesis of Salmonella. We recommend future outbreak studies investigate PPI usage to strengthen evidence on the relevance of PPIs in Salmonella infection. These findings should be used to support the development of guidelines for patients and prescribers on the risk of gastrointestinal infection and PPI usage.
The existence in the cosmic rays of ultra-heavy (UH) nuclei with Z ≥ 30 was established by two separate experiments in 1966. Fleischer et al. first demonstrated the fossil tracks of such nuclei in certain meteoritic crystals and shortly afterwards Fowler established their existence in present-day cosmic rays with the detection of their tracks in photographic emulsion which had been exposed during a high altitude balloon flight. The fluxes of such nuclei are very low, only ~ 10−4 of that of iron, and the most suitable method of detection to date has been the analysis of the tracks formed by these particles in very large(several m2) arrays of plastic detector material, notably Lexan polycarbonate. Such exposures on balloons and on Skylab have provided practically all present knowledge of the UH cosmic rays. Unfortunately, the charge resolution obtained was disappointing, even though scrupulous care was taken in the handling and etching of the material, and the charge scale itself of necessity had to be based on a considerable extrapolation from the iron peak and could not be used with great confidence. The situation now, however, is in the process of being transformed. We have two satellite experiments devoted to the study of UH cosmic rays and in operation at the moment. These are the Bristol University experiment on Ariel 6 launched on 3rd June 1979 and the joint group under Israel, Waddington and Stone on HEAO-C launched in September 1979. It is therefore appropriate, I believe, if I devote this review to the new preliminary results and a comparison of this material with the published data.
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.
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.
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).
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.
Paranoia is one of the commonest symptoms of psychosis but has rarely been studied in a population at risk of developing psychosis. Based on existing theoretical models, including the proposed distinction between ‘poor me’ and ‘bad me’ paranoia, we aimed to test specific predictions about associations between negative cognition, metacognitive beliefs and negative emotions and paranoid ideation and the belief that persecution is deserved (deservedness).
We used data from 117 participants from the Early Detection and Intervention Evaluation for people at risk of psychosis (EDIE-2) trial of cognitive–behaviour therapy, comparing them with samples of psychiatric in-patients and healthy students from a previous study. Multi-level modelling was utilized to examine predictors of both paranoia and deservedness, with post-hoc planned comparisons conducted to test whether person-level predictor variables were associated differentially with paranoia or with deservedness.
Our sample of at-risk mental state participants was not as paranoid, but reported higher levels of ‘bad-me’ deservedness, compared with psychiatric in-patients. We found several predictors of paranoia and deservedness. Negative beliefs about self were related to deservedness but not paranoia, whereas negative beliefs about others were positively related to paranoia but negatively with deservedness. Both depression and negative metacognitive beliefs about paranoid thinking were specifically related to paranoia but not deservedness.
This study provides evidence for the role of negative cognition, metacognition and negative affect in the development of paranoid beliefs, which has implications for psychological interventions and our understanding of psychosis.
For people with psychosis, contact with informal caregivers is an important source of social support, associated with recovery, and with better outcomes following individual cognitive therapy (CBTp). In this study, we tested whether increased flexibility in delusional thinking, an established predictor of positive outcome following CBTp, was a possible mechanism underlying this effect.
219 participants with delusions (mean age 38 years; 71% male; 75% White) were grouped according to the presence of a caregiver (37% with a caregiver) and caregiver level of expressed emotion (High/Low EE, 64% Low). Delusional belief flexibility was compared between groups, controlling for interpersonal functioning, severity of psychotic symptoms, and other hypothesised outcome predictors.
Participants with caregivers were nearly three times more likely than those without to show flexibility (OR = 2.7, 95% CI 1.5 to 5.0, p = 0.001), and five times more likely if the caregiving relationship was Low EE (OR = 5.0, 95% CI 2.0–13.0, p = 0.001). ORs remained consistent irrespective of controlling for interpersonal functioning and other predictors of outcome.
This is the first evidence that having supportive caregiving relationships is associated with a specific cognitive attribute in people with psychosis, suggesting a potential cognitive mechanism by which outcomes following CBTp, and perhaps more generally, are improved by social support.
Background: Research suggests that core schemas are important in both the development and maintenance of psychosis. Aims: The aim of the study was to investigate and compare core schemas in four groups along the continuum of psychosis and examine the relationships between schemas and positive psychotic symptomatology. Method: A measure of core schemas was distributed to 20 individuals experiencing first-episode psychosis (FEP), 113 individuals with “at risk mental states” (ARMS), 28 participants forming a help-seeking clinical group (HSC), and 30 non-help-seeking individuals who endorse some psychotic-like experiences (NH). Results: The clinical groups scored significantly higher than the NH group for negative beliefs about self and about others. No significant effects of group on positive beliefs about others were found. For positive beliefs about the self, the NH group scored significantly higher than the clinical groups. Furthermore, negative beliefs about self and others were related to positive psychotic symptomatology and to distress related to those experiences. Conclusions: Negative evaluations of the self and others appear to be characteristic of the appraisals of people seeking help for psychosis and psychosis-like experiences. The results support the literature that suggests that self-esteem should be a target for intervention. Future research would benefit from including comparison groups of people experiencing chronic psychosis and people who do not have any psychotic-like experiences.
Internalised stigma in young people meeting criteria for at-risk mental states (ARMS) has been highlighted as an important issue, and it has been suggested that provision of cognitive therapy may increase such stigma.
To investigate the effects of cognitive therapy on internalised stigma using a secondary analysis of data from the EDIE-2 trial.
Participants meeting criteria for ARMS were recruited as part of a multisite randomised controlled trial of cognitive therapy for prevention and amelioration of psychosis. Participants were assessed at baseline and at 6, 12, 18 and 24 months using measures of psychotic experiences, symptoms and internalised stigma.
Negative appraisals of experiences were significantly reduced in the group assigned to cognitive therapy (estimated difference at 12 months was −1.36 (95% Cl −2.69 to −0.02), P = 0.047). There was no difference in social acceptability of experiences (estimated difference at 12 months was 0.46, 95% Cl −0.05 to 0.98, P = 0.079).
These findings suggest that, rather than increasing internalised stigma, cognitive therapy decreases negative appraisals of unusual experiences in young people at risk of psychosis; as such, it is a non-stigmatising intervention for this population.
Interventions to reduce treatment delay in first-episode psychosis have met with mixed results. Systematic reviews highlight the need for greater understanding of delays within the care pathway if successful strategies are to be developed.
To document the care-pathway components of duration of untreated psychosis (DUP) and their link with delays in accessing specialised early intervention services (EIS). To model the likely impact on efforts to reduce DUP of targeted changes in the care pathway.
Data for 343 individuals from the Birmingham, UK, lead site of the National EDEN cohort study were analysed.
A third of the cohort had a DUP exceeding 6 months. The greatest contribution to DUP for the whole cohort came from delays within mental health services, followed by help-seeking delays. It was found that delay in reaching EIS was strongly correlated with longer DUP.
Community education and awareness campaigns to reduce DUP may be constrained by later delays within mental health services, especially access to EIS. Our methodology, based on analysis of care pathways, will have international application when devising strategies to reduce DUP.
Intrauterine factors important for cognitive development, such as birth weight, chorionicity and umbilical cord characteristics were investigated. A total of 663 twin pairs completed the Wechsler Intelligence Scale for Children-Revised and scores were available for Performance, Verbal and Total Intelligence Quotient (IQ). The intrauterine factors examined were birth weight, placental weight and morphology, cord knots, cord length and cord insertion. IQ scores for the varying levels of the intrauterine markers adjusting for gender and gestational age were calculated. The heritability of IQ and the association between IQ and intrauterine environment were examined. Twins with lower birth weight and cord knots had lower IQ scores. The aetiology of IQ is largely distinct from that of birth weight and cord knots, and non-shared environment may influence the observed relationships.
There is evidence that patients with schizophrenia benefit from standard cognitive behaviour therapy (CBT) only if active techniques are used (‘full therapy’). By contrast, attending sessions but not proceeding beyond engagement and assessment strategies (‘partial therapy’), or simply not attending sessions (‘no therapy’), is not associated with better outcomes. The factors leading to full therapy are unknown. We hypothesized that patients' initial ideas about the nature and extent of their problems would predict use of CBT. A match between patients' views of their problems and the principles underlying treatment would lead to better outcomes.
Ninety-two patients with a recent relapse of psychosis completed the Illness Perception Questionnaire (IPQ) before receiving CBT. We examined whether their illness perceptions predicted the take-up of therapy.
Patients who did not attend sessions believed their problems would not last as long as those who attended them. Those who attended sessions but did not proceed to full therapy had a lower sense of control over their problems and a more biological view of their causes. Patients who took up full therapy were more likely to attribute the cause of their problems to their personality and state of mind. The take-up of therapy was predicted neither by levels of psychiatric symptoms nor by insight.
People with psychosis who have psychologically orientated views of their problems, including the potential to gain control over them, may be more likely to engage fully and do well with standard CBT for psychosis, irrespective of the severity of their problems.
Meta-analyses show that cognitive behaviour therapy for psychosis (CBT-P) improves distressing positive symptoms. However, it is a complex intervention involving a range of techniques. No previous study has assessed the delivery of the different elements of treatment and their effect on outcome. Our aim was to assess the differential effect of type of treatment delivered on the effectiveness of CBT-P, using novel statistical methodology.
The Psychological Prevention of Relapse in Psychosis (PRP) trial was a multi-centre randomized controlled trial (RCT) that compared CBT-P with treatment as usual (TAU). Therapy was manualized, and detailed evaluations of therapy delivery and client engagement were made. Follow-up assessments were made at 12 and 24 months. In a planned analysis, we applied principal stratification (involving structural equation modelling with finite mixtures) to estimate intention-to-treat (ITT) effects for subgroups of participants, defined by qualitative and quantitative differences in receipt of therapy, while maintaining the constraints of randomization.
Consistent delivery of full therapy, including specific cognitive and behavioural techniques, was associated with clinically and statistically significant increases in months in remission, and decreases in psychotic and affective symptoms. Delivery of partial therapy involving engagement and assessment was not effective.
Our analyses suggest that CBT-P is of significant benefit on multiple outcomes to patients able to engage in the full range of therapy procedures. The novel statistical methods illustrated in this report have general application to the evaluation of heterogeneity in the effects of treatment.
To ascertain how new funding arrangements, introduced in New Zealand's 2001 Primary Health Care (PHC) Strategy, have impacted on the expansion of nurses’ role in general practice.
Nurses are central to the new policy that was designed to improve the health status of New Zealanders and reduce inequalities in health. Nurses were to be a crucial part of the PHC team, expanding their current roles to provide increased access to appropriate services. This paper investigates how the new funding arrangements, introduced as part of the policy, have impacted on the expansion of nurses’ roles and consequently the realisation of the policy goals.
Semi-structured interviews were undertaken with 128 key stakeholders five years after the introduction of the PHC Strategy, and surveys were completed by practice nurses, general practitioners and practice managers in purposively selected practices within the 20 participating Primary Health Organisations.
There has been substantial growth in the development of nursing roles for some nurses in general practice; however, this expansion has not been universal and one of the main reasons for this is the way funding devolves at the practice level. One of the consequences of the policymakers not taking into account the business model of the majority of general practices, is the resulting overarching goal of the strategy not being realised, and inequalities in health status remaining.