Definitions of relapse in trials comparing antipsychotic maintenance with discontinuation or reduction for schizophrenia spectrum disorders: A systematic review

INTRODUCTION: Avoidance of relapse is the main aim of long-term antipsychotic treatment in schizophrenia, yet how 'relapse' is defined in trials is not well-known. METHODS: We conducted a systematic review of definitions of relapse in trials of continuous antipsychotic treatment compared with discontinuation, intermittent treatment or dose reduction for people with schizophrenia spectrum disorders. Trials were identified from previous Cochrane reviews and a new search. The quality of relapse definitions was rated in terms of reliability and clinical relevance and associations between quality of definitions and trial characteristics and outcome were explored. RESULTS: We identified 82 reports of 81 trials which employed 54 different definitions of relapse. There were 33 definitions in the 35 trials published since 1990, with recent trials employing complex definitions often involving alternative criteria. Only ten primary definitions of relapse required the presence of psychotic symptoms in all cases, and only three specified this in combination with a measure of overall severity or functional decline. Only two definitions specified a duration longer than two days. Relapse definitions were rated as showing good reliability in 37 trials, but only seven showed good clinical relevance. Six trials with definitions that were both reliable and clinically relevant were slightly longer, but did not differ from remaining trials in other characteristics or overall or relative risk of relapse. CONCLUSIONS: Antipsychotic trials define relapse in numerous different ways, and few definitions consistently reflect suggested indications of a clinically significant relapse

General Practitioners' and patients' perceptions towards stratified care: a theory informed investigation

Background Stratified primary care involves changing General Practitioners’ (GPs) clinical behaviour in treating patients, away from the current stepped care approach to instead identifying early treatment options that are matched to patients’ risk of persistent disabling pain. This article explores the perspectives of UK-based GPs and patients about a prognostic stratified care model being developed for patients with the five most common primary care musculoskeletal pain presentations. The focus was on views about acceptability, and anticipated barriers and facilitators to the use of stratified care in routine practice. Methods Four focus groups and six semi-structured telephone interviews were conducted with GPs (n = 23), and three focus groups with patients (n = 20). Data were analysed thematically; and identified themes examined in relation to the Theoretical Domains Framework (TDF), which facilitates comprehensive identification of behaviour change determinants. A critical approach was taken in using the TDF, examining the nuanced interrelationships between theoretical domains. Results Four key themes were identified: Acceptability of clinical decision-making guided by stratified care; impact on the therapeutic relationship; embedding a prognostic approach within a biomedical model; and practical issues in using stratified care. Whilst within each theme specific findings are reported, common across themes was the identified relationships between the theoretical domains of knowledge, skills, professional role and identity, environmental context and resources, and goals. Through analysis of these identified relationships it was found that, for GPs and patients to perceive stratified care as being acceptable, it must be seen to enhance GPs’ knowledge and skills, not undermine GPs’ and patients’ respective identities and be integrated within the environmental context of the consultation with minimal disruption. Conclusions Findings highlight the importance of taking into account the context of general practice when intervening to support GPs to make changes to their clinical behaviour. Findings will inform further stages of the research programme; specifically, the intervention format and content of support packages for GPs participating in a future randomised controlled trial (RCT). This study also contributes to the theoretical debate on how best to encourage clinical behaviour change in general practice, and the possible role of the TDF in that process

Experiences of taking neuroleptic medication and impacts on symptoms, sense of self and agency: a systematic review and thematic synthesis of qualitative data

PURPOSE: Neuroleptic (antipsychotic) drugs reduce psychotic symptoms, but how they achieve these effects and how the drugs' effects are experienced by people who take them are less well understood. The present study describes a synthesis of qualitative data about mental and behavioural alterations associated with taking neuroleptics and how these interact with symptoms of psychosis and people's sense of self and agency. METHODS: Nine databases were searched to identify qualitative literature concerning experiences of taking neuroleptic medication. A thematic synthesis was conducted. RESULTS: Neuroleptics were commonly experienced as producing a distinctive state of lethargy, cognitive slowing, emotional blunting and reduced motivation, which impaired functioning but also had beneficial effects on symptoms of psychosis and some other symptoms (e.g. insomnia). For some people, symptom reduction helped restore a sense of normality and autonomy, but others experienced a loss of important aspects of their personality. Across studies, many people adopted a passive stance towards long-term medication, expressing a sense of resignation, endurance or loss of autonomy. CONCLUSIONS: Neuroleptic drugs modify cognition, emotions and motivation. These effects may be associated with reducing the intensity and impact of symptoms, but also affect people's sense of self and agency. Understanding how the effects of neuroleptics are experienced by those who take them is important in developing a more collaborative approach to drug treatment in psychosis and schizophrenia

Cooper pairing near charged black holes

We show that a quartic contact interaction between charged fermions can lead to Cooper pairing and a superconducting instability in the background of a charged asymptotically Anti-de Sitter black hole. For a massless fermion we obtain the zero mode analytically and compute the dependence of the critical temperature T_c on the charge of the fermion. The instability we find occurs at charges above a critical value, where the fermion dispersion relation near the Fermi surface is linear. The critical temperature goes to zero as the marginal Fermi liquid is approached, together with the density of states at the Fermi surface. Besides the charge, the critical temperature is controlled by a four point function of a fermionic operator in the dual strongly coupled field theory.Comment: 1+33 pages, 4 figure

Visceral hyperalgesia induced by forebrain-specific suppression of native Kv7/KCNQ/M-current in mice

<p>Abstract</p> <p>Background</p> <p>Dysfunction of brain-gut interaction is thought to underlie visceral hypersensitivity which causes unexplained abdominal pain syndromes. However, the mechanism by which alteration of brain function in the brain-gut axis influences the perception of visceral pain remains largely elusive. In this study we investigated whether altered brain activity can generate visceral hyperalgesia.</p> <p>Results</p> <p>Using a forebrain specific αCaMKII promoter, we established a line of transgenic (Tg) mice expressing a dominant-negative pore mutant of the Kv7.2/KCNQ2 channel which suppresses native KCNQ/M-current and enhances forebrain neuronal excitability. Brain slice recording of hippocampal pyramidal neurons from these Tg mice confirmed the presence of hyperexcitable properties with increased firing. Behavioral evaluation of Tg mice exhibited increased sensitivity to visceral pain induced by intraperitoneal (i.p.) injection of either acetic acid or magnesium sulfate, and intracolon capsaicin stimulation, but not cutaneous sensation for thermal or inflammatory pain. Immunohistological staining showed increased c-Fos expression in the somatosensory SII cortex and insular cortex of Tg mice that were injected intraperitoneally with acetic acid. To mimic the effect of cortical hyperexcitability on visceral hyperalgesia, we injected KCNQ/M channel blocker XE991 into the lateral ventricle of wild type (WT) mice. Intracerebroventricular injection of XE991 resulted in increased writhes of WT mice induced by acetic acid, and this effect was reversed by co-injection of the channel opener retigabine.</p> <p>Conclusions</p> <p>Our findings provide evidence that forebrain hyperexcitability confers visceral hyperalgesia, and suppression of central hyperexcitability by activation of KCNQ/M-channel function may provide a therapeutic potential for treatment of abdominal pain syndromes.</p

Stratified primary care versus non-stratified care for musculoskeletal pain: findings from the STarT MSK feasibility and pilot cluster randomized controlled trial

Background: Musculoskeletal (MSK) pain from the five most common presentations to primary care (back, neck, shoulder, knee or multi-site pain), where the majority of patients are managed, is a costly global health challenge. At present, first-line decisionmaking is based on clinical reasoning and stratified models of care have only been tested in patients with low back pain. We therefore, examined the feasibility of; a) a future definitive cluster randomised controlled trial (RCT), and b) General Practitioners (GPs) providing stratified care at the point-of-consultation for these five most common MSK pain presentations. Methods: The design was a pragmatic pilot, two parallel-arm (stratified versus nonstratified care), cluster RCT and the setting was 8 UK GP practices (4 intervention, 4 control) with randomisation (stratified by practice size) and blinding of trial statistician and outcome data-collectors. Participants were adult consulters with MSK pain without indicators of serious pathologies, urgent medical needs, or vulnerabilities. Potential participant records were tagged and individuals sent postal invitations using a GP point-of-consultation electronic medical record (EMR) template. The intervention was supported by the EMR template housing the Keele STarT MSK Tool (to stratify into low, medium and high-risk prognostic subgroups of persistent pain and disability) and recommended matched treatment options. Feasibility outcomes included exploration of recruitment and follow-up rates, selection bias, and GP intervention fidelity. To capture recommended outcomes including pain and function, participants completed an initial questionnaire, brief monthly questionnaire (postal or SMS), and 6-month follow-up questionnaire. An anonymised EMR audit described GP decision-making. Results: GPs screened 3063 patients (intervention=1591, control=1472), completed the EMR template with 1237 eligible patients (intervention=513, control=724) and 524 participants (42%) consented to data collection (intervention=231, control=293). Recruitment took 28 weeks (target 12 weeks) with >90% follow-up retention (target >75%). We detected no selection bias of concern and no harms identified. GP stratification tool fidelity failed to achieve a-priori success criteria, whilst fidelity to the matched treatments achieved “complete success”. Conclusions: A future definitive cluster RCT of stratified care for MSK pain is feasible and is underway, following key amendments including a clinician-completed version of the stratification tool and refinements to recommended matched treatments

Risk-based stratified primary care for common musculoskeletal pain presentations: qualitative findings from the STarT MSK cluster randomised controlled trial.

BACKGROUND: The STarT MSK cluster randomised controlled trial (RCT) investigated the clinical- and cost-effectiveness of risk-based stratified primary care versus usual care for patients with back, neck, shoulder, knee or multi-site pain. Trial quantitative results showed risk-based stratified care was not superior to usual care for patients' clinical outcomes, but the intervention led to some changes in GP clinical decision-making. This paper reports a linked qualitative study exploring how risk-based stratified care was perceived and used in the trial, from the perspectives of clinicians and patients. METHODS: Semi-structured interviews were conducted with 27 patients, and focus groups and interviews with 20 clinicians (GPs and physiotherapists) in the intervention arm of the trial. Data were analysed thematically and findings explored using Normalisation Process Theory (NPT) and the COM-B model. MAIN FINDINGS: Risk-based stratified care (subgrouping and matching treatments) was found to have 'coherence' (i.e. made sense) to several clinicians and patients, in that it was well-integrated in practice, and supported clinical decision-making. However, for some GPs stratified care was less 'meaningful', as the risk-stratification tool did not fit with usual ways of consulting and added to already time-pressured consultations. GPs reported giving more patients written information/advice due to easier access to electronic information leaflets through the trial template and were motivated to refer patients to physiotherapy as they believed the trial resulted in faster physiotherapy access (although this was not the case). Patients and clinicians reported that risk-based stratified care influenced conversations in the consultation, prompting greater attention to psychosocial factors, and facilitating negotiation of treatment options. Physiotherapists saw benefits in receiving information about patients' risk subgroup on referral forms. CONCLUSION: These findings provide context for interpreting some of the trial outcomes, particularly in relation to changes in clinical decision-making when risk-based stratified care was used. Findings also indicate potential reasons for lack of GP engagement with risk-based stratified care. Positive outcomes were identified that were not captured in the quantitative data, specifically that risk-based stratified care positively influenced some GP-patient conversations and facilitated negotiation of treatment options. TRIAL REGISTRATION: ISRCTN15366334 (26/04/2016)

Integrating clinician support with intervention design as part of a programme testing stratified care for musculoskeletal pain in general practice.

BACKGROUND: Stratified care involves subgrouping patients based on key characteristics, e.g. prognostic risk, and matching these subgroups to early treatment options. The STarT-MSK programme developed and tested a new stratified primary care intervention for patients with common musculoskeletal (MSK) conditions in general practice. Stratified care involves changing General Practitioners' (GPs) behaviour, away from the current 'stepped' care approach to identifying early treatment options matched to patients' risk of persistent pain. Changing healthcare practice is challenging, and to aid the successful delivery of stratified care, education and support for GPs was required. This paper details the iterative development of a clinician support package throughout the lifespan of the programme, to support GPs in delivering the stratified care intervention. We argue that clinician support is a crucial aspect of the intervention itself, which is often overlooked. METHODS: Qualitative research with patients and GPs identified barriers and facilitators to the adoption of stratified care, which were mapped onto the Theoretical Domains Framework (TDF). Identified domains were 'translated' into an educational paradigm, and an initial version of the support package developed. This was further refined following a feasibility and pilot RCT, and a finalised support package was developed for the main RCT. RESULTS: The clinician support package comprised face-to-face sessions combining adult-learning principles with behaviour change theory in a multimethod approach, which included group discussion, simulated consultations, patient vignettes and model consultation videos. Structured support for GPs was crucial to facilitate fidelity and, ultimately, a successful trial. Clinician support is a two-way process- the study team can learn from and adapt to specific local factors and issues not previously identified. The support from senior clinicians was required to ensure 'buy in'. Monitoring of GP performance, provision of regular feedback and remedial support are important aspects of effective clinician support. CONCLUSION: Designing effective clinician support from the onset of trial intervention design, in an evidence-based, theory-informed manner, is crucial to encourage active engagement and intervention fidelity within the trial, enabling the delivery of a robust and reliable proof-of-principle trial. We offer practical recommendations for future general practice interventions

Growth of a cohort of very low birth weight infants in Johannesburg, South Africa

<p>Abstract</p> <p>Background</p> <p>Little is known about the growth of VLBW infants in South Africa. The aim of this study was to assess the growth of a cohort of VLBW infants in Johannesburg.</p> <p>Methods</p> <p>A secondary analysis of a prospective cohort was conducted on 139 VLBW infants (birth weight ≤1500 g) admitted to Charlotte Maxeke Johannesburg Academic Hospital. Growth measurements were obtained from patient files and compared with the World Health Organization Child Growth Standards (WHO-CGS) and with a previous cohort of South African VLBW infants. The sample size per analysis ranged from 11 to 81 infants.</p> <p>Results</p> <p>Comparison with the WHO-CGS showed initial poor growth followed by gradual catch up growth with mean Z scores of 0.0 at 20 months postmenstrual age for weight, -0.8 at 20 months postmenstrual age for length and 0.0 at 3 months postmenstrual age for head circumference. Growth was comparable with that of a previous cohort of South African VLBW infants in all parameters.</p> <p>Conclusions</p> <p>Initial poor growth in the study sample was followed by gradual catch up growth but with persistent deficits in length for age at 20 months postmenstrual age relative to healthy term infants.</p