CLEAR - clozapine in early psychosis: study protocol for a multi-centre, randomised controlled trial of clozapine vs other antipsychotics for young people with treatment resistant schizophrenia in real world settings.

BACKGROUND: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU. METHODS AND DESIGN: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12-24 years old). AIM AND OBJECTIVES: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks. DISCUSSION: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis. TRIAL REGISTRATION: ISRCTN Number: 37176025, IRAS Number: 1004947. TRIAL STATUS: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /.

Enhancing psychological safety in mental health services.

BACKGROUND: Psychological safety-speaking up about ideas and concerns, free from interpersonal risk-are essential to the high-risk environment, such as healthcare settings. Psychologically safe working is particularly important in mental health where recovery-oriented approaches rely on collaborative efforts of interprofessional teams to make complex decisions. Much research focuses on antecedents and outcomes associated with psychological safety, but little focus on the practical steps for how to increase psychological safety across and at different levels of a healthcare organisation. AIMS: We explore how a mental health organisation creates an organisation-wide plan for building the foundations of mental health and how to enhance psychological safety. METHODS: This review encompasses strategies across psychological safety and organisational culture change to increase psychological safety at an individual, team and organisational level. We set out a comprehensive overview of the types of strategies and interventions for increasing the ethos of psychological safety and setting the foundations for delivering an organisation-wide programme on this topic. We also provide a list of key targeted areas in mental health that would maximally benefit from increasing psychological safety-both in clinical and non-clinical settings. CONCLUSIONS: Psychological safety is a crucial determinant of safe and effective patient care in mental health services. This paper provides the key steps and considerations, creating a large-scale programme in psychological safety with a focus on mental health and drawing from the current literature, providing concrete steps for how our current understanding of psychological safety into practice.

An assessment of contamination pickup on ground robotic vehicles for nuclear surveying application.

Ground robotic vehicles are often deployed to inspect areas where radioactive floor contamination is a prominent risk. However, the accuracy of detection could be adversely affected by enhanced radiation signal through self-contamination of the robot occurring over the course of the inspection. In this work, it was hypothesised that a six-legged robot could offer advantages over the more conventional ground robotic devices such as wheeled and tracked rovers. To investigate this, experimental contamination testing and computational Monte Carlo simulation techniques (GEANT4) were employed to understand how radioactive contamination pick-up on three different robotic vehicles would affect their detection accuracy. Two robotic vehicles were selected for comparison with the hexapod robot based on their type of locomotion; a wheeled rover and a tracked rover. With the aid of a non-toxic fluorescent tracer dust, the contamination received by the all three vehicles when traversing a contaminated area was initially compared through physical inspection using high definition cameras. The parametric results from these tests where used in the computational study carried out in GEANT4. A cadmium zinc telluride detector was simulated at heights ranging from 10 to 50 cm above each contaminated vehicle, as if it were mounted on a plinth. Assuming a uniform activity of 60 Bq cm-2on all contaminated surfaces, the results suggested that due to the hexapod's small ground-contacting surface area and geometry, radiation detection rates using an uncollimated detector are likely to be overestimated by between only 0.07%-0.12%, compared with 3.95%-8.43% and 1.75%-14.53% for the wheeled and tracked robot alternatives, respectively.

Real-time active suppression of directional acoustic wave components in tubular acoustic systems.

Acoustic pulse reflectometry is a method of non-destructive testing used for locating and characterising features and defects in gas-filled objects such as tubes, pipes, and ducts. A sound wave is emitted into the waveguide and travels in the axial direction until it is partially or fully reflected at changes in cross-section. The recorded reflection sequence is analysed to reveal time-of-flight, amplitude, and reflection shape. Analysis of reflection sequences is problematic due to the presence of multiple repeated echoes. The principal contribution is the introduction and demonstration of a method of actively suppressing unwanted echoes by modifying the signal emitted by the speaker in real-time. Unlike previous work, the proposed system accounts for inter-transducer attenuation and does not require re-calibration for each test object. The proposed real-time active absorbing termination is implemented using a programmable embedded controller and shown to function effectively. A quantitative evaluation of available wave separation techniques is provided using a known metric for quantifying the performance of absorbing terminations is introduced.

Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission.

Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.

Speed of facial affect intensity recognition as an endophenotype of first-episode psychosis and associated limbic-cortical grey matter systems.

BACKGROUND: Psychotic disorders are highly heritable such that the unaffected relatives of patients may manifest characteristics, or endophenotypes, that are more closely related to risk genes than the overt clinical condition. Facial affect processing is dependent on a distributed cortico-limbic network that is disrupted in psychosis. This study assessed facial affect processing and related brain structure as a candidate endophenotype of first-episode psychosis (FEP). METHOD: Three samples comprising 30 FEP patients, 30 of their first-degree relatives and 31 unrelated healthy controls underwent assessment of facial affect processing and structural magnetic resonance imaging (sMRI) data. Multivariate analysis (partial least squares, PLS) was used to identify a grey matter (GM) system in which anatomical variation was associated with variation in facial affect processing speed. RESULTS: The groups did not differ in their accuracy of facial affect intensity rating but differed significantly in speed of response, with controls responding faster than relatives, who responded faster than patients. Within the control group, variation in speed of affect processing was significantly associated with variation of GM density in amygdala, lateral temporal cortex, frontal cortex and cerebellum. However, this association between cortico-limbic GM density and speed of facial affect processing was absent in patients and their relatives. CONCLUSIONS: Speed of facial affect processing presents as a candidate endophenotype of FEP. The normal association between speed of facial affect processing and cortico-limbic GM variation was disrupted in FEP patients and their relatives.

Administrative incidence of psychosis assessed in an early intervention service in England: first epidemiological evidence from a diverse, rural and urban setting.

BACKGROUND: Early Intervention in Psychosis Services (EIS) for young people in England experiencing first-episode psychosis (FEP) were commissioned in 2002, based on an expected incidence of 15 cases per 100 000 person-years, as reported by schizophrenia epidemiology in highly urban settings. Unconfirmed reports from EIS thereafter have suggested higher than anticipated rates. The aim of this study was to compare the observed with the expected incidence and delineate the clinical epidemiology of FEP using epidemiologically complete data from the CAMEO EIS, over a 6-year period in Cambridgeshire, for a mixed rural-urban population. METHOD: A population-based study of FEP (ICD-10, F10-39) in people aged 17-35 years referred between 2002 and 2007; the denominator was estimated from mid-year census statistics. Sociodemographic variation was explored by Poisson regression. Crude and directly standardized rates (for age, sex and ethnicity) were compared with pre-EIS rates from two major epidemiological FEP studies conducted in urban English settings. RESULTS: A total of 285 cases met FEP diagnoses in CAMEO, yielding a crude incidence of 50 per 100 000 person-years [95% confidence interval (CI) 44.5-56.2]. Age- and sex-adjusted rates were raised for people from black ethnic groups compared with the white British [incidence rate ratio (IRR) 2.1, 95% CI 1.1-3.8]. Rates in our EIS were comparable with pre-EIS rates observed in more urban areas after age, sex and ethnicity standardization. CONCLUSIONS: Our findings suggest that the incidence observed in EIS is far higher than originally anticipated and is comparable to rates observed in more urban settings prior to the advent of EIS. Sociodemographic variation due to ethnicity and other factors extend beyond urban populations. Our results have implications for psychosis aetiology and service planning.

Behavioural and neurocognitive responses to sad facial affect are attenuated in patients with mania.

BACKGROUND: The processing of facial emotion involves a distributed network of limbic and paralimbic brain structures. Many of these regions are also implicated in the pathophysiology of mood disorders. Behavioural data indicate that depressed subjects show a state-related positive recognition bias for faces displaying negative emotions. There are sparse data to suggest there may be an analogous, state-related negative recognition bias for negative emotions in mania. We used functional magnetic resonance imaging (fMRI) to investigate the behavioural and neurocognitive correlates of happy and sad facial affect recognition in patients with mania. METHOD: Functional MRI and an explicit facial affect recognition task were used in a case-control design to measure brain activation and associated behavioural response to variable intensity of sad and happy facial expressions in 10 patients with bipolar I mania and 12 healthy comparison subjects. RESULTS: The patients with mania had attenuated subjective rating of the intensity of sad facial expressions, and associated attenuation of activation in the subgenual anterior cingulate and bilateral amygdala, with increased activation in the posterior cingulate and posterior insula. No behavioural or neurocognitive abnormalities were found in response to presentation of happy facial expressions. CONCLUSIONS: Patients with mania showed a specific, mood-congruent, negative bias in sad facial affect recognition, which was associated with an abnormal profile of brain activation in paralimbic regions implicated in affect recognition and mood disorders. Functional imaging of facial emotion recognition may be a useful probe of cortical and subcortical abnormalities in mood disorders.

Process monitoring of an industrial fed-batch fermentation.

Market demand places great emphasis in industry on product quality. Consequently, process monitoring and control have become important aspects of systems engineering. In this article we detail the results of a 2-year study focusing on the development of a condition monitoring system for a fed-batch fermentation system operated by Biochemie Gmbh in Austria. We also demonstrate the suitability and limitations of current state of the art technologies in this field and suggest novel modifications and configurations to improve their suitability for application to a fed-batch fermentation system.

The functional anatomy of auditory hallucinations in schizophrenia.

We used continuous whole brain functional magnetic resonance imaging (fMRI) with a 3-T magnet to map the cerebral activation associated with auditory hallucinations in four subjects with schizophrenia. The subjects experienced episodes of hallucination whilst in the scanner so that periods of hallucination could be compared with periods of rest in the same individuals. Group analysis demonstrated shared areas of activation in right and left superior temporal gyri, left inferior parietal cortex and left middle frontal gyrus. When the data were examined on an individual basis, the temporal cortex and prefrontal cortex areas were activated during episodes of hallucination in all four subjects. These findings support the theory that auditory hallucination reflects abnormal activation of normal auditory pathways.

A novel sustained-release formulation of ibuprofen provides effective once-daily therapy in the treatment of rheumatoid arthritis and osteoarthritis.

The efficacy and safety of a novel sustained-release formulation of ibuprofen given once-daily was compared with conventional-release ibuprofen tablets 400 mg given four times daily, in a single-blind, parallel-group study. This study was conducted at 84 general practice centres throughout the UK among patients with osteoarthritis or rheumatoid arthritis. An unequal randomisation in the ratio of 4:1 was carried out, with 463 patients who received sustained-release and 115 who received conventional-release ibuprofen providing evaluable data. In this study sustained-release ibuprofen was shown to be a more effective alternative to conventional ibuprofen therapy for the treatment of arthritic diseases in general practice, offering the convenience of once-daily dosing and the associated potential benefit of improved patient compliance.

The relation of acyl transfer to the overall reaction of thiolase I from porcine heart.

Thiolase I (long chain 3-ketoacyl-CoA-specific) from porcine heart has been characterized kinetically. In the direction of acetoacetyl-CoA cleavage, a variety of thiols including CoASH show the same Vmax at saturating concentrations of acetoacetyl-CoA. At a constant overall velocity of acetoacetyl-CoA disappearance, one of the two acetyl groups from acetoacetyl-CoA will partition between CoASH and 2-mercaptoethanol at increasing 2-mercaptoethanol concentrations. These observations suggest rate-determining formation of an acetyl enzyme intermediate in the direction of acetoacetyl-CoA cleavage. In the direction of acetoacetyl-CoA formation from two molecules of acetyl-CoA, the Vmax of acetoacetyl-CoA formation is identical with the Vmax for an acetyl-CoA in equilibrium CoA isotope exchange reaction and the Vmax for an enzyme-catalyzed acetyl transfer reaction between acetyl-CoA and 2-mercaptoethanol. This suggests that in the direction of acetoacetyl-CoA synthesis, the acetyl transfer half-reaction is rate-limiting. The acetyl intermediate has been isolated and characterized. The equilibrium constant for acetyl enzyme formation from acetyl-CoA and free enzyme is 1 +/- 0.5 X 10(-2). The rate constant for spontaneous hydrolysis of the acetyl enzyme (2.6 X 10(-4) s-1) is a factor of 400 faster than the rate constant for acetyl-CoA hydrolysis under comparable conditions. The acetyl enzyme is thermodynamically and kinetically destabilized compared to acetyl-CoA.