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Initiating aripiprazole as antipsychotic monotherapy rather than olanzapine, quetiapine, or risperidone, might prevent/delay major adverse cardiovascular events (MACEs) over the long-term in people diagnosed with severe mental illness. Using Clinical Practice Research Datalink data, we emulated a trial of aripiprazole versus olanzapine, quetiapine, and risperidone in 20,404 patients 2005–2014. Primary outcome was five-year MACE risk (composite of hospitalisation for acute myocardial infarction or stroke and cardiovascular death). Here we show that patients initiating aripiprazole had a similar five-year MACE risk as those initiating olanzapine (risk ratio: 1.03, 95% CI, 0.78-1.32), quetiapine (1.02, 95% CI, 0.72-1.32), and risperidone (0.88, 95% CI, 0.67-1.17). Risk was lower among patients initiating and continuing aripiprazole versus risperidone (0.58, 95% CI, 0.39-0.84). For patients at clinical equipoise, antipsychotic selection does not appear to significantly impact risk of the most severe, long-term cardiovascular events. However, further research is needed to replicate our finding of increased risk with continued risperidone use versus aripiprazole. Initiating aripiprazole antipsychotic monotherapy versus olanzapine, quetiapine or risperidone might reduce cardiovascular event risk in severe mental illness. Here, the authors show patients initiating aripiprazole had similar 5-year risk as the comparators, but risk was higher in those continuing risperidone versus aripiprazole

There is limited and conflicting evidence on the comparative cardiometabolic safety and effectiveness of aripiprazole in the management of severe mental illness. We investigated the hypothesis that aripiprazole has a favourable cardiometabolic profile, but similar effectiveness when compared to olanzapine, quetiapine, and risperidone. We conducted an observational emulation of a head-to-head trial of aripiprazole versus olanzapine, quetiapine, and risperidone in UK primary care using data from the Clinical Practice Research Datalink. We included adults diagnosed with severe mental illness (i.e., bipolar disorder, schizophrenia, and other non-organic psychoses) who were prescribed a new antipsychotic between 2005 and 2017, with a 2-year follow-up to 2019. The primary outcome was total cholesterol at 1 year (cardiometabolic safety). The main secondary outcome was psychiatric hospitalisation (effectiveness). Other outcomes included body weight, blood pressure, all-cause discontinuation, and mortality. Analyses adjusted for baseline confounders, including sociodemographics, diagnoses, concomitant medications, and cardiometabolic parameters. We included 26,537 patients (aripiprazole, n = 3,573, olanzapine, n = 8,554, quetiapine, n = 8,289, risperidone, n = 6,121). Median (IQR) age was 53 (42-67) years, 55.4% were female, 82.3% White, and 18.0% were diagnosed with schizophrenia. Patients prescribed aripiprazole had similar total cholesterol levels after 1 year to those prescribed olanzapine (adjusted mean difference [aMD], -0.03, 95% CI, -0.09 to 0.02, p = 0.261), quetiapine (aMD, -0.03, 95% CI, -0.09 to 0.03, p = 0.324), and risperidone (aMD, -0.01, 95% CI, -0.08 to 0.05, p = 0.707). However, there was evidence that patients prescribed aripiprazole had better outcomes on other cardiometabolic parameters, such as body weight and blood pressure, especially compared to olanzapine. After additional adjustment for prior hospitalisation, patients prescribed aripiprazole had similar rates of psychiatric hospitalisation as those prescribed olanzapine (adjusted hazard ratio [aHR], 0.91, 95% CI, 0.82 to 1.01, p = 0.078), quetiapine (aHR, 0.94, 95% CI, 0.85 to 1.04, p = 0.230), or risperidone (aHR, 1.01, 95% CI, 0.91 to 1.12, p = 0.854). Data from our large, powered, diverse, real-world target trial emulation sample, followed over 2 years, suggest that adults diagnosed with severe mental illness prescribed aripiprazole have similar total cholesterol 1 year after first prescription compared to those prescribed olanzapine, quetiapine, and risperidone. However, patients prescribed aripiprazole had better outcomes on some other cardiometabolic parameters, and there was little evidence of differences in effectiveness. Our findings inform a common clinical dilemma and contribute to the evidence base for real-world clinical decision-making on antipsychotic choice for patients diagnosed with severe mental illness.

Medications to treat psychosis (i.e., antipsychotics) have common and sometimes serious adverse drug reactions and can require several trials before finding a suitable drug and dose. To address this, there is increasing focus on personalizing medicine. Pharmacogenetics investigates how genetic variation influences drug metabolism and response, with recent clinical trials suggesting pharmacogenetic testing can improve remission and reduce adverse drug reactions. Therefore, understanding stakeholder perspectives on acceptability is critical. This pilot study is part of 'GEMS' (Genetics and Environment in Mental Health Study), which investigates pharmacogenetic testing for psychosis. A participant survey, co-created with patients, was completed by 22 patient-participants, and semi-structured interviews were conducted with 11 clinician-participants who had used pharmacogenetic test reports with patients. Both patients and clinicians were generally positive about pharmacogenetics, although clinicians saw this as just one component in the multifactorial process of individualized prescribing. Clinicians and patients both suggested a more user-friendly format of the pharmacogenetic report to enhance patient understanding. Some described the reports as promoting more collaborative care, but this was not universal. Clinicians highlighted both retrospective and prospective value in pharmacogenetics providing more certainty through reducing 'trial-and-error' prescribing. However, accessibility, understanding, and logistics were identified as potential barriers to implementation. Among patients and clinicians who have experienced pharmacogenetic testing to inform antipsychotic prescribing, acceptability is good. There is potential for pharmacogenetics to enhance personalized prescribing, but barriers to widespread implementation remain.

Persistent fatigue is common following acute SARS-CoV-2 infection. Little is known about post-infection fatigue trajectories in children and young people (CYP). This paper reports on a longitudinal analysis of the Children and Young People with Long COVID study. SARS-CoV-2-positive participants, aged 11-to-17-years at enrolment, responding to follow-ups at 3-, 6-, 12-, and 24-months post-infection were included. Fatigue was assessed via the Chalder Fatigue Scale (CFQ; score range: 0-11, with ≥4 indicating clinical case-ness) and by a single-item (no, mild, severe fatigue). Fatigue was described cross-sectionally and examined longitudinally using linear mixed-effects models. Among 943 SARS-CoV-2-positive participants, 581 (61.6%) met CFQ case-ness at least once during follow-up. A higher proportion of ever-cases (vs. never-cases) were female (77.1% vs. 54.4%), older (mean age 15.0 vs. 13.9 years), and met Post-COVID Condition criteria 3-months post-infection (35.6% vs. 7.2%). The proportion of CFQ cases increased from 35.0% at 3-months to 40.2% at 24-months post-infection; 15.9% meet case-ness at all follow-ups. Single-item mild/severe responses showed sensitivity (≥0.728) and specificity (≥0.755) for CFQ case ascertainment. On average, CFQ scores increased by 0.448 points (95% CI, 0.252 to 0.645) over 24-months, but there were subgroup differences (e.g., fatigue increased faster in females than males and improved slightly in those meeting Post-COVID Condition criteria 3-months post-infection while worsening in those not meeting criteria). Persistent fatigue was prominent in CYP up to 24 months after infection. Subgroup differences in scores and trajectories highlight the need for targeted interventions. Single-item assessment is a practical tool for screening significant severe fatigue.

Background Missing data are an inevitable challenge in Randomised Controlled Trials (RCTs), particularly those with Patient Reported Outcome Measures. Methodological guidance suggests that to avoid incorrect conclusions, studies should undertake sensitivity analyses which recognise that data may be ‘missing not at random’ (MNAR). A recommended approach is to elicit expert opinion about the likely outcome differences for those with missing versus observed data. However, few published trials plan and undertake these elicitation exercises, and so lack the external information required for these sensitivity analyses. The aim of this paper is to provide a framework that anticipates and allows for MNAR data in the design and analysis of clinical trials. Methods We developed a framework for performing and using expert elicitation to frame sensitivity analysis in RCTs with missing outcome data. The framework includes the following steps: first defining the scope of the elicitation exercise, second developing the elicitation tool, third eliciting expert opinion about the missing outcomes, fourth evaluating the elicitation results, and fifth analysing the trial data. We provide guidance on key practical challenges that arise when adopting this approach in trials: the criteria for identifying relevant experts, the outcome scale for presenting data to experts, the appropriate representation of expert opinion, and the evaluation of the elicitation results.The framework was developed within the POPPI trial, which investigated whether a preventive, complex psychological intervention, commenced early in ICU, would reduce the development of patient-reported post-traumatic stress disorder symptom severity, and improve health-related quality of life. We illustrate the key aspects of the proposed framework using the POPPI trial. Results For the POPPI trial, 113 experts were identified with potentially suitable knowledge and asked to participate in the elicitation exercise. The 113 experts provided 59 usable elicitation questionnaires. The sensitivity analysis found that the results from the primary analysis were robust to alternative MNAR mechanisms. Conclusions Future studies can adopt this framework to embed expert elicitation within the design of clinical trials. This will provide the information required for MNAR sensitivity analyses that examine the robustness of the trial conclusions to alternative, but realistic assumptions about the missing data.

BackgroundMetformin is a pharmacological candidate to mitigate second-generation antipsychotic (SGA)-induced weight gain in patients diagnosed with severe mental illnesses (SMI).ObjectiveTo determine the incidence, prevalence and demographic patterns of metformin co-prescription among patients diagnosed with SMI initiating SGAs. To estimate the impact of metformin co-prescription on weight over 2 years post-SGA initiation.MethodsA cohort study of patients diagnosed with SMI initiating aripiprazole, olanzapine, quetiapine or risperidone in 2005–2019 using primary care data from Clinical Practice Research Datalink. We estimated cumulative incidence and period prevalences of co-prescription and explored prescribing differences by demographic and clinical factors. We compared weight change among patients prescribed an SGA-only versus an SGA plus metformin, accounting for confounders using linear regression.FindingsAmong 26 537 patients initiating SGAs, 4652 were ever prescribed metformin and 21 885 were not. The two-year incidence of first metformin prescription was 3.3%. The SGA plus metformin group were more ethnically diverse, had greater social deprivation, more comorbidities and higher baseline weight (mean 90.4 vs 76.8 kg). By 2 years post-SGA initiation, mean weight in the SGA-only group had changed by +4.16% (95% CI −1.26 to +9.58) compared with −0.65% (95% CI −4.26 to +2.96) in the SGA plus metformin group. After confounder adjustment, the 2-year mean difference in weight with metformin co-prescription was −1.48 kg (95% CI −4.03 to 1.07) among females and −1.84 kg (95% CI −4.67 to 0.98) among males.ConclusionMetformin is infrequently co-prescribed, despite apparent efficacy and guidelines.Clinical implicationsPrimary and secondary care collaboration should be strengthened and barriers to co-prescribing addressed.

ObjectiveTo assess family satisfaction with intensive care units (ICUs) in the UK using the Family Satisfaction in the Intensive Care Unit 24-item (FS-ICU-24) questionnaire, and to investigate how characteristics of patients and their family members impact on family satisfaction.DesignProspective cohort study nested within a national clinical audit database.SettingStratified, random sample of 20 adult general ICUs participating in the Intensive Care National Audit & Research Centre Case Mix Programme.ParticipantsFamily members of patients staying at least 24 hours in ICU were recruited between May 2013 and June 2014.InterventionsConsenting family members were sent a postal questionnaire 3 weeks after the patient died or was discharged from ICU. Up to four family members were recruited per patient.Main outcome measuresFamily satisfaction was measured using the FS-ICU-24 questionnaire.Main resultsA total of 12 346 family members of 6380 patients were recruited and 7173 (58%) family members of 4615 patients returned a completed questionnaire. Overall and domain-specific family satisfaction scores were high (mean overall family satisfaction 80, satisfaction with care 83, satisfaction with information 76 and satisfaction with decision-making 73 out of 100) but varied significantly across adult general ICUs studied and by whether the patient survived ICU. For family members of ICU survivors, characteristics of both the family member (age, ethnicity, relationship to patient (next-of-kin and/or lived with patient) and visit frequency) and the patient (acute severity of illness and receipt of invasive mechanical ventilation) were significant determinants of family satisfaction, whereas, for family members of ICU non-survivors, only patient characteristics (age, acute severity of illness and duration of stay) were significant.ConclusionsOverall family satisfaction in UK adult general ICUs was high but varied significantly. Adjustment for differences in family member/patient characteristics is important to avoid falsely identifying ICUs as statistical outliers.Trial registration number ISRCTN47363549

IntroductionEven though respiratory support is a common intervention in paediatric critical care, there is no randomised controlled trial (RCT) evidence regarding the effectiveness of two commonly used modes of non-invasive respiratory support (NRS), continuous positive airway pressure (CPAP) and high-flow nasal cannula therapy (HFNC). FIRST-line support for assistance in breathing in children is a master protocol of two pragmatic non-inferiority RCTs to evaluate the clinical and cost-effectiveness of HFNC (compared with CPAP) as the first-line mode of support in critically ill children.Methods and analysisWe will recruit participants over a 30-month period at 25 UK paediatric critical care units (paediatric intensive care units/high-dependency units). Patients are eligible if admitted/accepted for admission, aged >36 weeks corrected gestational age and <16 years, and assessed by the treating clinician to require NRS for an acute illness (step-up RCT) or within 72 hours of extubation following a period of invasive ventilation (step-down RCT). Due to the emergency nature of the treatment, written informed consent will be deferred to after randomisation. Randomisation will occur 1:1 to CPAP or HFNC, stratified by site and age (<12 vs ≥12 months). The primary outcome is time to liberation from respiratory support for a continuous period of 48 hours. A total sample size of 600 patients in each RCT will provide 90% power with a type I error rate of 2.5% (one sided) to exclude the prespecified non-inferiority margin of HR of 0.75. Primary analyses will be undertaken separately in each RCT in both the intention-to-treat and per-protocol populations.Ethics and disseminationThis master protocol received favourable ethical opinion from National Health Service East of England—Cambridge South Research Ethics Committee (reference: 19/EE/0185) and approval from the Health Research Authority (reference: 260536). Results will be disseminated via publications in peer-reviewed medical journals and presentations at national and international conferences.Trial registration number ISRCTN60048867

Background The FIRST-ABC trial comprises of two pragmatic, multicentre, parallel groups, non-inferiority randomised clinical trials designed to evaluate the clinical non-inferiority of first-line use of high flow nasal cannula (HFNC) to continuous positive airway pressure (CPAP) in critically ill children who require non-invasive respiratory support (NRS). Objectives To describe the pre-specified statistical and health economic analysis for the FIRST-ABC trial before completion of patient recruitment and data collection. Methods The statistical analysis plan was designed by the chief investigators and statisticians. We define the primary and secondary outcomes, summarise methods for data collection and safety monitoring, and present a detailed description of the planned statistical and health economic analysis. Results The primary clinical outcome is time to liberation from respiratory support. The primary effect estimate will be the adjusted hazard ratio, reported with a 95% confidence interval. As a sensitivity analysis, the primary analysis will be repeated using time to start weaning of NRS. Subgroup analyses will be performed to test for interactions between the effect of allocated treatment group and pre-specified baseline covariates. The health economic analysis will follow the intention-to-treat principle and report the mean (95% confidence interval) incremental costs, quality-adjusted life years (QALYs) and cost-effectiveness up to 6 months. All analyses will be performed separately for each of the two trials, and any results will not be combined. Conclusion The FIRST-ABC trial will assess the non-inferiority of HFNC compared to CPAP in two parallel trials with shared infrastructure (step-up RCT and step-down RCT). We have developed a pre-specified statistical and health economics analysis plan for the FIRST-ABC study before trial completion to minimise analytical bias. Trial registration ISRCTN ISRCTN60048867 . Registered on 19 June 2019.

PurposeWhile most children and young people (CYP) recover from COVID-19, some develop ‘post-COVID-19 condition’ (PCC), affecting their health and well-being. We explored (1) whether distinct persistent PCC symptom subgroups exist in CYP and whether these subgroups remain stable up to 24 months postinfection; (2) whether impairments differ across subgroups and (3) how CYP with persistent PCC describe the evolving impact of the pandemic/lockdowns on their health and experiences up to 24 months postinfection.MethodsA cohort of CYP across England was recruited in 2020–2021 (the children and young people with Long COVID study). A subsample of 68 CYP meeting the PCC Delphi research definition at 3, 6, 12 and 24 months post-PCR-confirmed infection was analysed. Latent class analysis identified symptom subgroups (objective 1); associations with impairments (measured via EuroQol Five Dimensions Youth) were examined (objective 2). Free-text responses from six CYP at all four follow-up points (n=24) were thematically analysed to capture evolving experiences (objective 3).ResultsIncluded CYP were older (72.1% were 15–17 years), female (82.4%) and white (80.9%). Two symptom groups emerged: a frequent symptom subgroup (median: 6.5–9 symptoms over time, mainly shortness of breath and tiredness); and a less frequent symptom subgroup (median: 4–5 symptoms, mostly tiredness). Generally, no association was found between symptom subgroups and impairments. Qualitative analysis indicated feelings of anxiety, respiratory problems and concerns around relaxation of lockdown restrictions persisted over follow-up. School-related worries were transient.DiscussionEven CYP with persistent PCC characterised by fewer symptoms experience long-term anxiety and impact, emphasising even few symptoms can be debilitating and underscoring the need for personalised PCC management for CYP.