The efficacy of real versus sham external Trigeminal Nerve Stimulation (eTNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD) over 4 weeks: a protocol for a multi-centre, double-blind, randomized, parallel-group, phase IIb study (ATTENS).

BACKGROUND: Attention Deficit/Hyperactivity Disorder (ADHD), if severe, is usually treated with stimulant or non-stimulant medication. However, users prefer non-drug treatments due to side effects. Alternative non-medication treatments have so far only shown modest effects. External trigeminal nerve stimulation (eTNS) is a minimal risk, non-invasive neuromodulation device, targeting the trigeminal system. It was approved for ADHD in 2019 by the USA Food and Drug administration (FDA) based on a small proof of concept randomised controlled trial (RCT) in 62 children with ADHD showing improvement of ADHD symptoms after 4 weeks of nightly real versus sham eTNS with minimal side effects. We present here the protocol of a larger confirmatory phase IIb study testing efficacy, longer-term persistency of effects and underlying mechanisms of action. METHODS: A confirmatory, sham-controlled, double-blind, parallel-arm, multi-centre phase IIb RCT of 4 weeks of eTNS in 150 youth with ADHD, recruited in London, Portsmouth, and Southampton, UK. Youth with ADHD will be randomized to either real or sham eTNS, applied nightly for 4 weeks. Primary outcome is the change in the investigator-administered parent rated ADHD rating scale. Secondary outcomes are other clinical and cognitive measures, objective hyperactivity and pupillometry measures, side effects, and maintenance of effects over 6 months. The mechanisms of action will be tested in a subgroup of 56 participants using magnetic resonance imaging (MRI) before and after the 4-week treatment. DISCUSSION: This multi-centre phase IIb RCT will confirm whether eTNS is effective in a larger age range of children and adolescents with ADHD, whether it improves cognition and other clinical measures, whether efficacy persists at 6 months and it will test underlying brain mechanisms. The results will establish whether eTNS is effective and safe as a novel non-pharmacological treatment for ADHD. TRIAL REGISTRATION: ISRCTN82129325 on 02/08/2021, https://doi.org/10.1186/ISRCTN82129325 .

Understanding the Mechanisms of Cognitive Remediation on Recovery in People With Early Psychosis: A Mediation and Moderation Analysis.

BACKGROUND: To provide precision cognitive remediation therapy (CR) for schizophrenia, we need to understand whether the mechanism for improved functioning is via cognition improvements. This mechanism has not been rigorously tested for potential moderator effects. STUDY DESIGN: We used data (n = 377) from a randomized controlled trial using CIRCuiTS, a therapist-supported CR, with participants from first-episode psychosis services. We applied structured equation modeling to test whether: (1) CR hours explain the goal attainment functional outcome (GAS) at posttreatment, (2) global cognitive improvement mediates GAS, and if (3) total symptoms moderate the CR hours to cognitive improvement pathway, and/or negative symptoms moderate the cognition to functioning pathway, testing moderator effects via the mediator or directly on CR hours to functioning path. STUDY RESULTS: CR produced significant functioning benefit for each therapy hour (Coeff = 0.203, 95% CI 0.101-0.304, P < .001). The mediated path from CR hours to cognition and cognition to functioning was small and nonsignificant (Coeff = 0.014, 95% CI = -0.010, 0.037, P = .256). Total symptoms did not moderate the path to cognition (P = .211) or the direct path to outcome (P = .896). However, negative symptoms significantly moderated the effect of cognitive improvements on functioning (P = .015) with high negative symptoms reducing the functional gains of improved cognition. CONCLUSIONS: Although cognitive improvements were correlated with functioning benefit, they did not fully explain the positive effect of increased therapy hours on functioning, suggesting additional CR factors also contribute to therapy benefit. Negative symptoms interfere with the translation of cognitive improvements into functional gains so need consideration.

Olanzapine for young PEople with aNorexia nervosa (OPEN): A protocol for an open-label feasibility study.

INTRODUCTION: Antipsychotics are routinely prescribed off-label for anorexia nervosa (AN) despite limited evidence. This article presents a protocol of a study aiming to assess the feasibility of a future definitive trial on olanzapine in young people with AN. METHODS AND ANALYSIS: In an open-label, one-armed feasibility study, 55 patients with AN or atypical AN, aged 12-24, receiving outpatient, inpatient or day-care treatment who are considered for olanzapine treatment will be recruited from NHS sites based in England. Assessments will be conducted at screening, baseline and at 8-, 16 weeks, 6- and 12 months. Primary feasibility parameters will be proportions of patients who agree to take olanzapine and who adhere to treatment and complete study assessments. Qualitative methods will be used to explore acceptability of the intervention and study design. Secondary feasibility parameters will be changes in body mass index, psychopathology, side effects, health-related quality of life, carer burden and proportion of participants who would enrol in a future randomised controlled trial. The study is funded by the National Institute for Health Research via Health Technology Assessment programme. DISCUSSION: Olanzapine for young PEople with aNorexia nervosa will inform a future randomised controlled trial on the efficacy and safety of prescribing olanzapine in young people with AN.

Satisfaction with cognitive remediation therapy: its effects on implementation and outcomes using the cognitive remediation satisfaction scale.

Cognitive Remediation (CR) improves cognition and functioning but is implemented in a variety of ways (independent, group and one-to-one). There is no information on whether service users find these implementation methods acceptable or if their satisfaction influences CR outcomes. We used mixed participatory methods, including focus groups, to co-develop a CR satisfaction scale. This was refined using three psychometric criteria (Cronbach's alpha, item discrimination, test-retest agreement) to select items. Factor analysis explored potential substructures. The refined measure was used in structural equation joint modelling to evaluate whether satisfaction with CR is affected by implementation method and treatment engagement or influences recovery outcome, using data from a randomised controlled trial. Four themes (therapy hours, therapist, treatment effects, computer use) generated a 31-item Cognitive Remediation Satisfaction scale (CRS) that reduced to 18 Likert items, 2 binary and 2 open-ended questions following psychometric assessment. CRS had good internal consistency (Alpha = 0.814), test-retest reliability (r= 0.763), and concurrent validity using the Working Alliance Inventory (r = 0.56). A 2-factor solution divided items into therapy engagement and therapy effects. Satisfaction was not related to implementation method but was significantly associated with CR engagement. Therapy hours were significantly associated with recovery, but there was no direct effect of satisfaction on outcome. Although satisfaction is important to therapy engagement, it has no direct effect on outcome. CR therapy hours directly affect outcome irrespective of which implementation model is used, so measuring satisfaction early might help to identify those who are likely to disengage. The study has mixed methods design.

Cognitive Remediation Works But How Should We Provide It? An Adaptive Randomized Controlled Trial of Delivery Methods Using a Patient Nominated Recovery Outcome in First-Episode Participants.

BACKGROUND AND HYPOTHESIS: Cognitive remediation (CR) benefits cognition and functioning in psychosis but we do not know the optimal level of therapist contact, so we evaluated the potential benefits of different CR modes. STUDY DESIGN: A multi-arm, multi-center, single-blinded, adaptive trial of therapist-supported CR. Participants from 11 NHS early intervention psychosis services were independently randomized to Independent, Group, One-to-One, or Treatment-as-usual (TAU). The primary outcome was functional recovery (Goal Attainment Scale [GAS]) at 15-weeks post randomization. Independent and TAU arms were closed after an interim analysis, and three informative contrasts tested (Group vs One-to-One, Independent vs TAU, Group + One-to-One vs TAU). Health economic analyses considered the cost per Quality Adjusted Life Year (QALY). All analyses used intention-to-treat principles. STUDY RESULTS: We analyzed 377 participants (65 Independent, 134 Group, 112 One-to-One, 66 TAU). GAS did not differ for Group vs One-to-One: Cohen's d: 0.07, -0.25 to 0.40 95% CI, P = .655; Independent vs TAU: Cohen's d: 0.07, -0.41 to 0.55 95% CI, P = .777. GAS and the cognitive score improved for Group + One-to-One vs TAU favoring CR (GAS: Cohen's d: 0.57, 0.19-0.96 95% CI, P = .003; Cognitive score: Cohens d: 0.28, 0.07-0.48 95% CI, P = .008). The QALY costs were £4306 for Group vs TAU and £3170 for One-to-One vs TAU. Adverse events did not differ between treatment methods and no serious adverse events were related to treatment. CONCLUSIONS: Both active therapist methods provided cost-effective treatment benefiting functional recovery in early psychosis and should be adopted within services. Some individuals benefited more than others so needs further investigation. TRIAL REGISTRATION: ISRCTN14678860 https://doi.org/10.1186/ISRCTN14678860Now closed.

Optimized immunosuppression to prevent graft failure in renal transplant recipients with HLA antibodies (OuTSMART): a randomised controlled trial.

Background: 3% of kidney transplant recipients return to dialysis annually upon allograft failure. Development of antibodies (Ab) against human leukocyte antigens (HLA) is a validated prognostic biomarker of allograft failure. We tested whether screening for HLA Ab, combined with an intervention to improve adherence and optimization of immunosuppression could prevent allograft failure. Methods: Prospective, open-labelled randomised biomarker-based strategy (hybrid) trial in 13 UK transplant centres [EudraCT (2012-004308-36) and ISRCTN (46157828)]. Patients were randomly allocated (1:1) to unblinded or double-blinded arms and screened every 8 months. Unblinded HLA Ab+ patients were interviewed to encourage medication adherence and had tailored optimisation of Tacrolimus, Mycophenolate mofetil and Prednisolone. The primary outcome was time to graft failure in an intention to treat analysis. The trial had 80% power to detect a hazard ratio of 0.49 in donor specific antibody (DSA)+ patients. Findings: From 11/9/13 to 27/10/16, 5519 were screened for eligibility and 2037 randomised (1028 to unblinded care and 1009 to double blinded care). We identified 198 with DSA and 818 with non-DSA. Development of DSA, but not non-DSA was predictive of graft failure. HRs for graft failure in unblinded DSA+ and non-DSA+ groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54-1.74) respectively, providing no evidence of an intervention effect. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 (1.02, 95% CI: 0.72 to 1.44). The only secondary endpoint reduced in the unblinded arm was biopsy-proven rejection. Interpretation: Intervention to improve adherence and optimize immunosuppression does not delay failure of renal transplants after development of DSA. Whilst DSA predicts increased risk of allograft failure, novel interventions are needed before screening can be used to direct therapy. Funding: The National Institute for Health Research Efficacy and Mechanism Evaluation programme grant (ref 11/100/34).

Effect of Vitamin D Supplementation on Outcomes in People With Early Psychosis: The DFEND Randomized Clinical Trial.

Importance: People with psychotic disorders have an increased risk of vitamin D deficiency, which is evident during first-episode psychosis (FEP) and associated with unfavorable mental and physical health outcomes. Objective: To examine whether vitamin D supplementation contributes to improved clinical outcomes in FEP. Design, Setting, and Participants: This multisite, double-blind, placebo-controlled, parallel-group randomized clinical trial from the UK examined adults 18 to 65 years of age within 3 years of a first presentation with a functional psychotic disorder who had no contraindication to vitamin D supplementation. A total of 2136 patients were assessed for eligibility, 835 were approached, 686 declined participation or were excluded, 149 were randomized, and 104 were followed up at 6 months. The study recruited participants from January 19, 2016, to June 14, 2019, with the final follow-up (after the last dose) completed on December 20, 2019. Interventions: Monthly augmentation with 120 000 IU of cholecalciferol or placebo. Main Outcomes and Measures: The primary outcome measure was total Positive and Negative Syndrome Scale (PANSS) score at 6 months. Secondary outcomes included total PANSS score at 3 months; PANSS positive, negative, and general psychopathology subscale scores at 3 and 6 months; Global Assessment of Function scores (for symptoms and disability); Calgary Depression Scale score, waist circumference, body mass index, and glycated hemoglobin, total cholesterol, C-reactive protein, and vitamin D concentrations at 6 months; and a planned sensitivity analysis in those with insufficient vitamin D levels at baseline. Results: A total of 149 participants (mean [SD] age, 28.1 (8.5) years; 89 [59.7%] male; 65 [43.6%] Black or of other minoritized racial and ethnic group; 84 [56.4%] White [British, Irish, or of other White ethnicity]) were randomized. No differences were observed in the intention-to-treat analysis in the primary outcome, total PANSS score at 6 months (mean difference, 3.57; 95% CI, -1.11 to 8.25; P = .13), or the secondary outcomes at 3 and 6 months (PANSS positive subscore: mean difference, -0.98; 95% CI, -2.23 to 0.27 at 3 months; mean difference, 0.68; 95% CI, -0.69 to 1.99 at 6 months; PANSS negative subscore: mean difference, 0.68; 95% CI, -1.39 to 2.76 at 3 months; mean difference, 1.56; 95% CI, -0.31 to 3.44 at 6 months; and general psychopathology subscore: mean difference, -2.09; 95% CI, -4.36 to 0.18 at 3 months; mean difference, 1.31; 95% CI, -1.42 to 4.05 at 6 months). There also were no significant differences in the Global Assessment of Function symptom score (mean difference, 0.02; 95% CI, -4.60 to 4.94); Global Assessment of Function disability score (mean difference, -0.01; 95% CI, -5.25 to 5.23), or Calgary Depression Scale score (mean difference, -0.39; 95% CI, -2.05 to 1.26) at 6 months. Vitamin D levels were very low in the study group, especially in Black participants and those who identified as another minoritized racial and ethnic group, 57 of 61 (93.4%) of whom had insufficient vitamin D. The treatment was safe and led to a significant increase in 25-hydroxyvitamin D concentrations. Conclusions and Relevance: In this randomized clinical trial, no association was found between vitamin D supplementation and mental health or metabolic outcomes at 6 months. Because so few patients with FEP were vitamin D replete, the results of this study suggest that this group would benefit from active consideration in future population health strategies. Trial Registration: isrctn.org Identifier: ISRCTN12424842.

The association of adverse life events and parental mental health with emotional and behavioral outcomes in young adults with autism spectrum disorder.

People with autism spectrum disorder (ASD) are at increased risk of developing co-occurring mental health difficulties across the lifespan. Exposure to adverse life events and parental mental health difficulties are known risk factors for developing a range of mental health difficulties. This study investigates the association of adverse life events, parental stress and mental health with emotional and behavioral problems in young adults with ASD. One hundred and fifteen young adults with ASD derived from a population-based longitudinal study were assessed at three time-points (12-, 16-, and 23-year) on questionnaire measures of emotional and behavioral problems. Parent-reported exposure to adverse life events and parental stress/mental health were measured at age 23. We used structural equation modeling to investigate the stability of emotional and behavioral problems over time, and the association between adverse life events and parental stress and mental health and emotional and behavioral outcomes at 23-year. Our results indicate that exposure to adverse life events was significantly associated with increased emotional and behavioral problems in young adults with ASD, while controlling for symptoms in childhood and adolescence. Higher reported parental stress and mental health difficulties were associated with a higher frequency of behavioral, but not emotional problems, and did not mediate the impact of adverse life events. These results suggest that child and adolescent emotional and behavioral problems, exposure to life events and parent stress and mental health are independently associated, to differing degrees, with emotional or behavioral outcomes in early adulthood. LAY SUMMARY: People with autism experience high rates of mental health difficulties throughout childhood and into adult life. Adverse life events and parental stress and mental health may contribute to poor mental health in adulthood. We used data at three time points (12-, 16-, and 23-year) to understand how these factors relate to symptoms at 23-year. We found that emotional and behavioral problems in childhood, adverse life events and parent mental health were all associated with increased emotional and behavioral problems in adulthood.

A feasibility randomised controlled trial of a brief early intervention for adolescent depression that targets emotional mental images and memory specificity (IMAGINE).

Brief, evidence-based interventions for adolescent depression are urgently required, particularly for school-settings. Cognitive mechanisms research suggests dysfunctional mental imagery and overgeneral memory could be promising targets to improve mood. This feasibility randomised controlled trial with parallel symptomatic groups (n = 56) compared a novel imagery-based cognitive behavioural intervention (ICBI) to non-directive supportive therapy (NDST) in school settings. Blind assessments (of clinical symptoms and cognitive mechanisms) took place pre-intervention, post-intervention and follow-up three months later. The trial aimed to evaluate the feasibility and acceptability of the methodology and interventions, and estimate the likely range of effects of the intervention on self-reported depression. The pre-defined criteria for proceeding to a definitive RCT were met: full recruitment occurred within eleven months; retention was 89%; ICBI acceptability was above satisfactory; and no harm was indicated. Intention-to-treat analysis found large effects in favour of ICBI (relative to NDST) at post-intervention in reducing depressive symptoms (d = -1.34, 95% CI [-1.87, -0.80]) and improving memory specificity (d = 0.79 [0.35, 1.23]), a key cognitive target. The findings suggest that ICBI may not only improve mood but also strengthen abilities associated with imagining and planning the future, critical skills at this life stage. A fully powered evaluation of ICBI is warranted. Trial Registration: https://www.isrctn.com/; ISRCTN85369879.

A Novel Group Parenting Intervention for Emotional and Behavioral Difficulties in Young Autistic Children: Autism Spectrum Treatment and Resilience (ASTAR): A Randomized Controlled Trial.

OBJECTIVE: To examine the feasibility and preliminary efficacy of a group behavioral parenting intervention for emotional and behavioral problems (EBPs) in young autistic children. METHOD: This was a feasibility pilot randomized controlled trial comparing a 12-week group behavioral parenting intervention (Predictive Parenting) to an attention control (Psychoeducation). Parents of 62 autistic children 4 to 8 years of age were randomized to Predictive Parenting (n = 31) or Psychoeducation (n = 31). The primary outcome was a blinded observational measure of child behaviors that challenge. Secondary outcomes were observed child compliance and parenting behaviors; parent- and teacher-reported child EBPs; self-reported parenting practices, stress, self-efficacy, and well-being. Cost-effectiveness was also explored. RESULTS: Recruitment, retention, completion of measures, treatment fidelity, and parental satisfaction were high for both interventions. There was no group difference in primary outcome: mean log of rate 0.18 lower (d, 90% CI = -0.44 to 0.08) in Predictive Parenting. Differences in rates of child compliance (0.44, 90% CI = 0.11 to 0.77), facilitative parenting (0.63, 90% CI = 0.33 to 0.92) and parent-defined target symptom change (-0.59, 90% CI -0.17 to -1.00) favored Predictive Parenting. There were no differences on other measures. Predictive Parenting was more expensive than Psychoeducation, with a low probability of being more cost-effective. CONCLUSION: Feasibility was demonstrated. There was no evidence from this pilot trial that Predictive Parenting resulted in reductions in child EBPs beyond those seen following Psychoeducation; in addition, the effect size was small, and it was more expensive. However, it showed superiority for child compliance and facilitative parenting with moderate effect sizes. Future, definitive studies should evaluate whether augmented or extended intervention would lead to larger improvements. CLINICAL TRIAL REGISTRATION INFORMATION: Autism Spectrum Treatment and Resilience (ASTAR); https://www.isrctn.com/; 91411078.

The role of C-reactive protein as a prognostic marker in COVID-19.

BACKGROUND: C-reactive protein (CRP) is a non-specific acute phase reactant elevated in infection or inflammation. Higher levels indicate more severe infection and have been used as an indicator of COVID-19 disease severity. However, the evidence for CRP as a prognostic marker is yet to be determined. The aim of this study is to examine the CRP response in patients hospitalized with COVID-19 and to determine the utility of CRP on admission for predicting inpatient mortality. METHODS: Data were collected between 27 February and 10 June 2020, incorporating two cohorts: the COPE (COVID-19 in Older People) study of 1564 adult patients with a diagnosis of COVID-19 admitted to 11 hospital sites (test cohort) and a later validation cohort of 271 patients. Admission CRP was investigated, and finite mixture models were fit to assess the likely underlying distribution. Further, different prognostic thresholds of CRP were analysed in a time-to-mortality Cox regression to determine a cut-off. Bootstrapping was used to compare model performance [Harrell's C statistic and Akaike information criterion (AIC)]. RESULTS: The test and validation cohort distribution of CRP was not affected by age, and mixture models indicated a bimodal distribution. A threshold cut-off of CRP ≥40 mg/L performed well to predict mortality (and performed similarly to treating CRP as a linear variable). CONCLUSIONS: The distributional characteristics of CRP indicated an optimal cut-off of ≥40 mg/L was associated with mortality. This threshold may assist clinicians in using CRP as an early trigger for enhanced observation, treatment decisions and advanced care planning.

Trajectories of emotional and behavioral problems from childhood to early adult life.

LAY ABSTRACT: Although mental health problems are common in autism, relatively little is known about their stability and the factors that influence their persistence or change over the life-course. To address this, we use data from the Special Needs and Autism Project (SNAP) cohort studied at three time-points from 12 to 23 years. Using the parent-reported Strengths and Difficulties Questionnaire (SDQ) domains of conduct, emotional, and ADHD symptoms, we evaluated the role of child, family, and contextual characteristics on these three trajectories. Symptoms decreased significantly over time for all three domains, but many participants still scored above the published disorder cutoffs. Individuals showed high levels of persistence. Higher initial adaptive function and language levels predicted a greater decline in conduct and ADHD symptoms. In contrast, higher language functioning was associated with higher levels of emotional symptoms, as was lower levels of autism symptom severity and higher parental education. Those with higher neighborhood deprivation had higher initial conduct problems but a steeper decline over time. Our findings highlight that it may be possible to accurately predict mental health trajectories over this time period, which could help parents and carers in planning and help professionals target resources more efficiently.

Effect of Optimized Immunosuppression (Including Rituximab) on Anti-Donor Alloresponses in Patients With Chronically Rejecting Renal Allografts.

RituxiCAN-C4 combined an open-labeled randomized controlled trial (RCT) in 7 UK centers to assess whether rituximab could stabilize kidney function in patients with chronic rejection, with an exploratory analysis of how B cell-depletion influenced T cell anti-donor responses relative to outcome. Between January 2007 and March 2015, 59 recruits were enrolled after screening, 23 of whom consented to the embedded RCT. Recruitment was halted when in a pre-specified per protocol interim analysis, the RCT was discovered to be significantly underpowered. This report therefore focuses on the exploratory analysis, in which we confirmed that when B cells promoted CD4+ anti-donor IFNγ production assessed by ELISPOT, this associated with inferior clinical outcome; these patterns were inhibited by optimized immunosuppression but not rituximab. B cell suppression of IFNγ production, which associated with number of transitional B cells and correlated with slower declines in kidney function was abolished by rituximab, which depleted transitional B cells for prolonged periods. We conclude that in this patient population, optimized immunosuppression but not rituximab promotes anti-donor alloresponses associated with favorable outcomes. Clinical Trial Registration: Registered with EudraCT (2006-002330-38) and www.ClinicalTrials.gov, identifier: NCT00476164.

Vitamin D supplementation compared to placebo in people with First Episode psychosis - Neuroprotection Design (DFEND): a protocol for a randomised, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: People experiencing their first episode of psychosis are often deficient in vitamin D. Observational studies have reported an association between low vitamin D concentrations and poorer subsequent health outcomes in psychosis. A vitamin D deficiency in neonates and children has been linked to a later increased risk of schizophrenia and psychotic-like experiences. This trial aims to examine the effect of high-dose vitamin D supplementation on outcomes in early psychosis. We hypothesise that vitamin D supplementation will be associated with better mental health outcomes. METHODS/DESIGN: The DFEND study is a multicentre double-blind placebo-controlled parallel-group trial of vitamin D supplementation in people with early psychosis. Patients with an ICD-10 diagnosis of functional psychosis will be randomised in a 1:1 ratio to receive either 120,000 IU/month of vitamin D (cholecalciferol) or a matched placebo for 6 months. The primary outcome is the total Positive and Negative Syndrome Scale (PANSS) score at the 6-month follow-up for all patients. Secondary outcomes include assessment of mood (Calgary Depression Scale), general function (Global Assessment of Functioning), cardiovascular risk (body mass index, waist circumference, C-reactive protein, cholesterol and HbA1c) and vitamin D levels at the 6-month follow-up. Additionally, 3- and 6-month total PANSS scores will be analysed for those with inadequate vitamin D levels at the baseline. DISCUSSION: The DFEND study is the first trial to examine whether vitamin D supplementation in early psychosis is associated with better mental health outcomes. The findings of this study may help to resolve the clinical equipoise regarding the benefits and cost-effectiveness of routine vitamin D supplementation in people with psychosis. TRIAL REGISTRATION: ISRCTN, ISRCTN12424842. Registered on 25 February 2015.

Cost-Effectiveness of Combination Disease-Modifying Antirheumatic Drugs Versus Tumor Necrosis Factor Inhibitors in Active Rheumatoid Arthritis: A Pragmatic, Randomized, Multicenter Trial.

OBJECTIVE: To determine whether intensive combinations of conventional synthetic disease-modifying antirheumatic drugs (csDMARDS) achieve similar clinical benefits more cheaply than high-cost biologics such as tumor necrosis factor inhibitors (TNFi) in patients with active rheumatoid arthritis (RA) whose illness has failed to respond to methotrexate and another DMARD. METHODS: We used within-trial cost-effectiveness and cost-utility analyses from health and social care and 2 societal perspectives. Participants were recruited into an open-label, 12-month, pragmatic, randomized, multicenter, 2-arm, noninferiority trial in 24 rheumatology clinics in England and Wales. Costs were linked with the Health Assessment Questionnaire (HAQ; primary outcome) and quality-adjusted life years derived from 2 measures (Short-Form 36 health survey and EuroQol 5-domain 3-level instrument). RESULTS: In total, 205 participants were recruited, 104 in the csDMARD arm and 101 in the TNFi arm. Participants in the csDMARD arm with poor response at 6 months were offered TNFi; 46 participants (44%) switched. Relevant cost and outcome data were available for 93% of participants at 6-month follow-up and for 91-92% of participants at 12-month follow-up. The csDMARD arm had significantly lower total costs from all perspectives (6-month health and social care adjusted mean difference -£3,615 [95% confidence interval (95% CI) -4,104, -3,182]; 12-month health and social care adjusted mean difference -£1,930 [95% CI -2,599, -1,301]). The HAQ score showed benefit to the csDMARD arm at 12 months (-0.16 [95% CI -0.32, -0.01]); other outcomes/follow-ups showed no differences. CONCLUSION: Starting treatment with csDMARDs, rather than TNFi, achieves similar outcomes at significantly lower costs. Patients with active RA and who meet the National Institute for Health and Care Excellence criteria for expensive biologics can be treated with combinations of intensive csDMARDs in a cost-effective manner.

Trajectories in Symptoms of Autism and Cognitive Ability in Autism From Childhood to Adult Life: Findings From a Longitudinal Epidemiological Cohort.

OBJECTIVE: For the first time, we use a longitudinal population-based autism cohort to chart the trajectories of cognition and autism symptoms from childhood to early adulthood and identify features that predict the level of function and change with development. METHOD: Latent growth curve models were fitted to data from the Special Needs and Autism Project cohort at three time points: 12, 16, and 23 years. Outcome measures were IQ and parent-reported Social Responsiveness Scale autism symptoms. Of the 158 participants with an autism spectrum disorder at 12 years, 126 (80%) were reassessed at 23 years. Child, family, and contextual characteristics obtained at 12 years predicted intercept and slope of the trajectories. RESULTS: Both trajectories showed considerable variability. IQ increased significantly by a mean of 7.48 points from 12 to 23 years, whereas autism symptoms remained unchanged. In multivariate analysis, full-scale IQ was predicted by initial language level and school type (mainstream/specialist). Participants with a history of early language regression showed significantly greater IQ gains. Autism symptoms were predicted by Social Communication Questionnaire scores (lifetime version) and emotional and behavioral problems. Participants attending mainstream schools showed significantly fewer autism disorder symptoms at 23 years than those in specialist settings; this finding was robust to propensity score analysis for confounding. CONCLUSION: Our findings suggest continued cognitive increments for many people with autism across the adolescent period, but a lack of improvement in autism symptoms. Our finding of school influences on autism symptoms requires replication in other cohorts and settings before drawing any implications for mechanisms or policy.

Clinical-learning versus machine-learning for transdiagnostic prediction of psychosis onset in individuals at-risk.

Predicting the onset of psychosis in individuals at-risk is based on robust prognostic model building methods including a priori clinical knowledge (also termed clinical-learning) to preselect predictors or machine-learning methods to select predictors automatically. To date, there is no empirical research comparing the prognostic accuracy of these two methods for the prediction of psychosis onset. In a first experiment, no improved performance was observed when machine-learning methods (LASSO and RIDGE) were applied-using the same predictors-to an individualised, transdiagnostic, clinically based, risk calculator previously developed on the basis of clinical-learning (predictors: age, gender, age by gender, ethnicity, ICD-10 diagnostic spectrum), and externally validated twice. In a second experiment, two refined versions of the published model which expanded the granularity of the ICD-10 diagnosis were introduced: ICD-10 diagnostic categories and ICD-10 diagnostic subdivisions. Although these refined versions showed an increase in apparent performance, their external performance was similar to the original model. In a third experiment, the three refined models were analysed under machine-learning and clinical-learning with a variable event per variable ratio (EPV). The best performing model under low EPVs was obtained through machine-learning approaches. The development of prognostic models on the basis of a priori clinical knowledge, large samples and adequate events per variable is a robust clinical prediction method to forecast psychosis onset in patients at-risk, and is comparable to machine-learning methods, which are more difficult to interpret and implement. Machine-learning methods should be preferred for high dimensional data when no a priori knowledge is available.

Update to the study protocol, including statistical analysis plan, for the multicentre, randomised controlled OuTSMART trial: a combined screening/treatment programme to prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies.

BACKGROUND: Chronic rejection is the single biggest cause of premature kidney graft failure. HLA antibodies (Ab) are an established prognostic biomarker for premature graft failure so there is a need to test whether treatment decisions based on the presence of the biomarker can alter prognosis. The Optimised TacrolimuS and MMF for HLA Antibodies after Renal Transplantation (OuTSMART) trial combines two elements. Firstly, testing whether a routine screening programme for HLA Ab in all kidney transplant recipients is useful by comparing blinding versus unblinding of HLA Ab status. Secondly, for those found to be HLA Ab+, testing whether the introduction of a standard optimisation treatment protocol can reduce graft failure rates. METHODS: OuTSMART is a prospective, open-labelled, randomised biomarker-based strategy (hybrid) trial, with two arms stratified by biomarker (HLA Ab) status. The primary outcome was amended from graft failure rates at 3 years to time to graft failure to increase power and require fewer participants to be recruited. Length of follow-up subsequently is variable, with all participants followed up for at least 43 months up to a maximum of 89 months. The primary outcome will be analysed using Cox regression adjusting for stratification factors. Analyses will be according to the intention-to-treat using all participants as randomised. Outcomes will be analysed comparing standard care versus biomarker-led care groups within the HLA Ab+ participants (including those who become HLA Ab+ through re-screening) as well as between HLA-Ab-unblinded and HLA-Ab-blinded groups using all participants. DISCUSSION: Changes to the primary outcome permit recruitment of fewer participants to achieve the same statistical power. Pre-stating the statistical analysis plan guards against changes to the analysis methods at the point of analysis that might otherwise introduce bias through knowledge of the data. Any deviations from the analysis plan will be justified in the final report. TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN46157828 . Registered on 26 March 2013; EudraCT 2012-004308-36 . Registered on 10 December 2012.

Effect of lifestyle, medication and ethnicity on cardiometabolic risk in the year following the first episode of psychosis: prospective cohort study.

BACKGROUND: The first episode of psychosis is a critical period in the emergence of cardiometabolic risk. AIMS: We set out to explore the influence of individual and lifestyle factors on cardiometabolic outcomes in early psychosis. METHOD: This was a prospective cohort study of 293 UK adults presenting with first-episode psychosis investigating the influence of sociodemographics, lifestyle (physical activity, sedentary behaviour, nutrition, smoking, alcohol, substance use) and medication on cardiometabolic outcomes over the following 12 months. RESULTS: Rates of obesity and glucose dysregulation rose from 17.8% and 12%, respectively, at baseline to 23.7% and 23.7% at 1 year. Little change was seen over time in the 76.8% tobacco smoking rate or the quarter who were sedentary for over 10 h daily. We found no association between lifestyle at baseline or type of antipsychotic medication prescribed with either baseline or 1-year cardiometabolic outcomes. Median haemoglobin A1c (HbA1c) rose by 3.3 mmol/mol in participants from Black and minority ethnic (BME) groups, with little change observed in their White counterparts. At 12 months, one-third of those with BME heritage exceeded the threshold for prediabetes (HbA1c >39 mmol/mol). CONCLUSIONS: Unhealthy lifestyle choices are prevalent in early psychosis and cardiometabolic risk worsens over the next year, creating an important window for prevention. We found no evidence, however, that preventative strategies should be preferentially directed based on lifestyle habits. Further work is needed to determine whether clinical strategies should allow for differential patterns of emergence of cardiometabolic risk in people of different ethnicities.

A novel group parenting intervention to reduce emotional and behavioural difficulties in young autistic children: protocol for the Autism Spectrum Treatment and Resilience pilot randomised controlled trial.

INTRODUCTION: The majority of young autistic children display impairing emotional and behavioural difficulties that contribute to family stress. There is some evidence that behavioural parenting interventions are effective for reducing behavioural difficulties in autistic children, with less evidence assessing change in emotional difficulties. Previous trials have tended to use unblinded parent-report measures as primary outcomes and many do not employ an active control, limiting the conclusions that can be drawn. METHODS AND ANALYSIS: The Autism Spectrum Treatment and Resilience study is a pilot randomised controlled trial (RCT) testing the specific effect of a 12-week group parenting intervention (Predictive Parenting) on primary and secondary outcomes, in comparison to an attention control condition consisting of psychoeducation parent groups. Following a feasibility study to test research procedures and the interventions, the pilot RCT participants include 60 parents of autistic children aged 4-8 years who are randomised to Predictive Parenting versus the attention control. Measures are administered at baseline and post intervention to assess group differences in child and parent outcomes, costs and service use and adverse events. The primary outcome is an objective measure of child behaviours that challenge during interactions with their parent and a researcher. The trial aims to provide data on recruitment, retention, completion of measures and acceptability of the intervention and research protocol, in addition to providing a preliminary indication of potential efficacy and establishing an effect size that could be used to power a larger-scale efficacy trial. We will also provide preliminary estimates of the cost-effectiveness of the interventions. ETHICS AND DISSEMINATION: Ethical approval was granted from NHS Camden and Kings Cross Research Ethics Committee (ref: 16/LO/1769) along with NHS R&D approval from South London and Maudsley, Guy's and St Thomas', and Croydon Health Services NHS Trusts. The findings will be disseminated through publication in peer-reviewed journals and presentations at conferences. TRIAL REGISTRATION NUMBER: ISRCTN91411078.