Gastrointestinal adverse events with insulin glargine/lixisenatide fixed-ratio combination versus glucagon-like peptide-1 receptor agonists in people with type 2 diabetes mellitus: A network meta-analysis.

AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the recommended first injectable therapy in type 2 diabetes. However, long-term persistence is suboptimal and partly attributable to gastrointestinal tolerability, particularly during initiation/escalation. Gradual titration of fixed-ratio combination GLP-1 RA/insulin therapies may improve GLP-1 RA gastrointestinal tolerability. We compared gastrointestinal adverse event (AE) rates for iGlarLixi versus GLP-1 RAs during the first 12 weeks of therapy, including a sensitivity analysis with IDegLira. MATERIALS AND METHODS: The PICO framework was used to identify studies from MEDLINE, EMBASE and CENTRAL searches using a proprietary, web-based, standardized tool with single data extraction. Gastrointestinal AEs were modelled using a Bayesian network meta-analysis (NMA), using fixed and random effects for each recommended dose (treatment-specific NMA) and class (drug-class NMA). RESULTS: Treatment-specific NMA included 17 trials (n = 9030; 3665 event-weeks). Nausea rates were significantly lower with iGlarLixi versus exenatide 10 µg twice daily (rate ratio: 0.32; 95% credible interval: 0.15, 0.66), once-daily lixisenatide 20 µg (0.35; 0.24, 0.50) and liraglutide 1.8 mg once daily (0.48; 0.23, 0.98). Rates were numerically, but not statistically, lower versus once-weekly semaglutide 1 mg (0.60; 0.30, 1.23) and dulaglutide 1.5 mg (0.60; 0.29, 1.26), and numerically, but not statistically, higher versus once-weekly exenatide (1.91; 0.91, 4.03). Sensitivity analysis results were similar. In a naïve, pooled analysis, vomiting was lower with iGlarLixi versus other GLP-1 RAs. CONCLUSIONS: During the first 12 weeks of treatment, iGlarLixi was generally associated with less nausea and vomiting than single-agent GLP-1 RAs. Enhanced gastrointestinal tolerability with fixed-ratio combinations may favour treatment persistence.

Efficacy and Safety of Hylan G-F 20 Versus Intra-Articular Corticosteroids in People with Knee Osteoarthritis: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Direct injection of corticosteroids into the joint is a standard treatment for knee osteoarthritis (OA). However, the treatment is somewhat controversial with regard to the benefit of both single and repeated injections; evidence that they are beneficial comes from small studies that show only modest improvements. The aim of this study was to estimate the short- and long-term clinical efficacy and safety of hylan G-F 20 versus intra-articular corticosteroids (IACS) for the treatment of pain in knee OA using Bayesian network meta-analysis. METHODS: Based on a pre-specified protocol, MEDLINE, Embase, and CENTRAL were searched from inception to June 2018 to identify randomized controlled trials. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials was used to assess the included studies. Hylan G-F 20 and IACS were compared using Bayesian network meta-analysis. Efficacy was evaluated at 1, 3, and 6 months, and at the final follow-up for safety outcomes. A pain hierarchy was used to select 1 pain outcome per study. RESULTS: Forty-two trials were included for analysis. The network meta-analysis of pain showed that hylan G-F 20 may be equivalent to IACS in the short-term, but by 6 months the benefit relative to IACS was statistically significant, standardized mean difference (95% credible interval): -0.13 (-0.26, -0.01). There were no statistical differences in adverse events. CONCLUSIONS: Hylan G-F 20 may perform better in relieving pain at 6 months post-injection compared to IACS. Both agents were relatively well tolerated, with no clear differences in safety.

Long-term outcomes of psychological interventions on children and young people's mental health: A systematic review and meta-analysis.

BACKGROUND: Over 600 RCTs have demonstrated the effectiveness of psychosocial interventions for children and young people's mental health, but little is known about the long-term outcomes. This systematic review sought to establish whether the effects of selective and indicated interventions were sustained at 12 months. METHOD: We conducted a systematic review and meta-analysis focusing on studies reporting medium term outcomes (12 months after end of intervention). FINDINGS: We identified 138 trials with 12-month follow-up data, yielding 165 comparisons, 99 of which also reported outcomes at end of intervention, yielding 117 comparisons. We found evidence of effect relative to control at end of intervention (K = 115, g = 0.39; 95% CI: 0.30-0.47 I2 = 84.19%, N = 13,982) which was maintained at 12 months (K = 165, g = 0.31, CI: 0.25-0.37, I2 = 77.35%, N = 25,652) across a range of diagnostic groups. We explored the impact of potential moderators on outcome, including modality, format and intensity of intervention, selective or indicated intervention, site of delivery, professional/para-professional and fidelity of delivery. We assessed both risk of study bias and publication bias. CONCLUSIONS: Psychosocial interventions provided in a range of settings by professionals and paraprofessionals can deliver lasting benefits. High levels of heterogeneity, moderate to high risk of bias for most studies and evidence of publication bias require caution in interpreting the results. Lack of studies in diagnostic groups such as ADHD and self-harm limit the conclusions that can be drawn. Programmes that increase such interventions' availability are justified by the benefits to children and young people and the decreased likelihood of disorder in adulthood.

High molecular weight Intraarticular hyaluronic acid for the treatment of knee osteoarthritis: a network meta-analysis.

BACKGROUND: The 2013 American Academy of Orthopaedic Surgeons (AAOS) guidelines made strong recommendations against intraarticular hyaluronic acid (IAHA) for patients with knee osteoarthritis (OA), as evidence supporting improvements in pain did not meet the minimal clinically important improvement (MCII) threshold. However, there may be important distinctions based on IAHA molecular weight (MW). Hence our objective was to evaluate the efficacy of IAHAs in knee OA based on molecular weight. METHODS: Randomized controlled trials were searched within MEDLINE, Embase, and CENTRAL and selected based on AAOS criteria. A pain measure hierarchy and longest follow-up were used to select one effect size from each trial. Mean differences between interventions were converted to standardized mean differences (SMDs) and incorporated into a random-effects Bayesian network meta-analysis. High MW (HMW) was defined as ≥6000 kDa, and low MW (LMW) as < 750 kDa. RESULTS: HMW IAHA was associated with a statistically significant and possibly clinically significant improvement in pain (SMD - 0.57 (95% credible interval [Crl]: - 1.04, - 0.11), exceeding the - 0.50 MCII threshold. LMW IAHA had a lesser, non-significant improvement (- 0.23, 95% Crl: - 0.67, 0.20). Back-transforming SMDs to the WOMAC pain scale indicated a 14.65 (95% CI: 13.93, 15.62) point improvement over IA placebo, substantially better than the 8.3 AAOS MCII threshold. CONCLUSIONS: Unlike LMW IAHA, HMW IAHA exceeded the MCII threshold for pain relief, suggesting that improvements can be subjectively perceived by the treated patient. Amalgamation of LMW and HMW may have blurred the benefits of IAHA in the past, leading to negative recommendations. Differentiation according to MW offers refined insight for treatment with IAHA.

The Efficacy and Safety of Piribedil Relative to Pramipexole for the Treatment of Early Parkinson Disease: A Systematic Literature Review and Network Meta-Analysis.

OBJECTIVES: Patients with early Parkinson disease (PD) frequently defer initiation of levodopa treatment to minimize long-term complications. Nonergoline dopamine agonists, such as pramipexole and piribedil, are frequent first-line therapies for early PD patients, yet limited head-to-head randomized controlled trial (RCT) evidence exists for dopamine agonists in this population. We therefore conducted a systematic literature review and network meta-analysis. METHODS: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were systematically searched (until January 7, 2020), identifying RCTs assessing the efficacy of piribedil or pramipexole in early PD. Eligible trial data were incorporated into fixed- and random-effects Bayesian network meta-analyses. RESULTS: No RCTs were identified directly comparing piribedil with pramipexole, but 6 trials provided data for pramipexole versus placebo and 2 compared piribedil versus placebo, facilitating indirect comparisons. Across all time points assessed, no significant differences were found between pramipexole and piribedil for change in the Unified Parkinson's Disease Rating Scale (UPDRS) score from baseline. Piribedil and pramipexole demonstrated superiority relative to placebo for UPDRS II/III change at weeks 22 to 30. No significant differences were noted between the treatments at weeks 20 to 35 for anxiety, constipation, hypotension, nausea, and somnolence. Sensitivity analyses on adjustment for dose titration periods and baseline risk yielded the same pattern of results. CONCLUSIONS: No significant differences were found for pramipexole versus piribedil in the UPDRS II/III scores from baseline in early PD, with similar safety profiles.

Are systematic review and guideline development tools useful? A Guidelines International Network survey of user preferences.

BACKGROUND: There are now over 140 tools/programs that can assist in developing systematic reviews or clinical practice guidelines (CPGs). It is currently unclear which tools are used by systematic reviewers and CPG developers, which development processes they are used for, and what facilitators or barriers to their use exist. METHODS: To determine which tools are currently being used by systematic reviewers and CPG developers, an online survey was administered during July-August 2017. Guidelines International Network individual and organizational members were invited to participate. Survey questions focused on the nature and frequency of members' use of tools to support systematic review and CPG development. RESULTS: The overall response rate was 34%. The largest number of respondents developed one to five guidelines a year (48%). GRADEpro GDT was the most popular tool (26% of respondents) followed by Dropbox (16%) and RevMan (14%). From the options provided, the reason most respondents (85%) used particular tools was 'to be more efficient'. Most users stated they would use the tool again (95%), and 95% would recommend it to other organizations. However, respondents reported that tool efficiency and facilitators such as data sharing functionality were offset by their availability and cost, issues with structured data fields (that did not allow customization), and other technical and usability factors (e.g., features, workflows). CONCLUSION: The results of this survey provide a focus for discussing improvements in tools to meet the needs of systematic reviewers and CPG developers, and a basis from which to test the efficacy and appropriateness of various tools and platforms across a number of purposes and contexts.

Osteoarthritis, mobility-related comorbidities and mortality: an overview of meta-analyses.

AIMS: The objective of this review was to examine the relationship between osteoarthritis (OA) and mobility-related comorbidities, specifically diabetes mellitus (DM) and cardiovascular disease (CVD). It also investigated the relationship between OA and mortality. METHODS: An overview of meta-analyses was conducted by performing two targeted searches from inception to June 2020. The association between OA and (i) DM or CVD (via PubMed and Embase); and (ii) mortality (via PubMed) was investigated. Meta-analyses were selected if they included studies that examined adults with OA at any site and reported associations between OA and DM, CVD, or mortality. Evidence was synthesized qualitatively. RESULTS: Six meta-analyses met inclusion criteria. One meta-analysis of 20 studies demonstrated a statistically significant association between OA and DM, with pooled odds ratio of 1.41 (95% confidence interval: 1.21, 1.65; n = 1,040,175 patients). One meta-analysis of 15 studies demonstrated significantly increased risk of CVD among OA patients, with a pooled risk ratio of 1.24 (1.12, 1.37, n = 358,944 patients). Stratified by type of CVD, OA was shown to be associated with increased heart failure (HF) and ischemic heart disease (IHD) and reduced transient ischemic attack (TIA). There was no association reported for stroke or myocardial infarction (MI). Three meta-analyses did not find a significant association between OA (any site) and all-cause mortality. However, OA was found to be significantly associated with cardiovascular-related death across two meta-analyses. CONCLUSION: The identified meta-analyses reported significantly increased risk of both DM and CVD (particularly, HF and IHD) among OA patients. It was not possible to confirm consistent directional or causal relationships. OA was found to be associated with increased mortality, but mostly in relation to CVD-related mortality, suggesting that further study is warranted in this area.

Different Types and Acceptability of Psychotherapies for Acute Anxiety Disorders in Children and Adolescents: A Network Meta-analysis.

Importance: Anxiety disorders are common in children and adolescents, and uncertainty remains regarding the optimal strategy of psychotherapies in this population. Objective: To compare and rank the different types of psychotherapies and the different ways of delivering psychological treatments for anxiety disorders in children and adolescents. Data Sources: PubMed, Cochrane Central Register of Controlled Trials, EMBASE, PsycINFO, Web of Science, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ProQuest Dissertations, LILACS (Literatura Latino Americana em Ciências da Saúde), international trial registers, and US Food and Drug Administration reports were searched from inception to November 30, 2017. Study Selection: Randomized clinical trials that compared any structured psychotherapy with another psychotherapy or a control condition for anxiety disorders in children and adolescents were selected. Data Extraction and Synthesis: Four researchers independently performed data extraction and quality assessment. Pairwise meta-analyses and Bayesian network meta-analysis within the random-effects model were used to synthesize data. Main Outcomes and Measures: Efficacy (change in anxiety symptoms) posttreatment and at follow-up, acceptability (all-cause discontinuation), and quality of life and functional improvement were measured. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. Results: A total of 101 unique trials including 6625 unique participants compared 11 different psychotherapies with 4 specific control conditions. The certainty of evidence was rated as low or very low for most comparisons. For efficacy, most psychotherapies were significantly more effective than the wait list condition posttreatment (standardized mean difference [SMD], -1.43 to -0.61) and at the longest follow-up (SMD, -1.84 to -1.64). However, only group cognitive behavioral therapy (CBT) was significantly more effective than the other psychotherapies and all control conditions posttreatment. For acceptability, bibliotherapy CBT had significantly more all-cause discontinuations than some psychotherapies and control conditions (range of odds ratios, 2.48-9.32). In terms of quality of life and functional improvement, CBT (delivered in different ways) was significantly beneficial compared with psychological placebo and the wait list condition (SMDs, 0.73 to 1.99). Conclusions and Relevance: Group CBT would be the more appropriate choice of psychotherapy for anxiety disorders in children and adolescents, based on these findings. Other types of psychotherapies and different ways of delivering psychological treatment can be alternative options. Further research is needed to explore specific anxiety disorders, disorder-specific psychotherapy, and moderators of treatment effect. Trial Registration: PROSPERO Identifier: CRD42015016283.

Annual Research Review: Digital health interventions for children and young people with mental health problems - a systematic and meta-review.

BACKGROUND: Digital health interventions (DHIs), including computer-assisted therapy, smartphone apps and wearable technologies, are heralded as having enormous potential to improve uptake and accessibility, efficiency, clinical effectiveness and personalisation of mental health interventions. It is generally assumed that DHIs will be preferred by children and young people (CYP) given their ubiquitous digital activity. However, it remains uncertain whether: DHIs for CYP are clinically and cost-effective, CYP prefer DHIs to traditional services, DHIs widen access and how they should be evaluated and adopted by mental health services. This review evaluates the evidence-base for DHIs and considers the key research questions and approaches to evaluation and implementation. METHODS: We conducted a meta-review of scoping, narrative, systematic or meta-analytical reviews investigating the effectiveness of DHIs for mental health problems in CYP. We also updated a systematic review of randomised controlled trials (RCTs) of DHIs for CYP published in the last 3 years. RESULTS: Twenty-one reviews were included in the meta-review. The findings provide some support for the clinical benefit of DHIs, particularly computerised cognitive behavioural therapy (cCBT), for depression and anxiety in adolescents and young adults. The systematic review identified 30 new RCTs evaluating DHIs for attention deficit/hyperactivity disorder (ADHD), autism, anxiety, depression, psychosis, eating disorders and PTSD. The benefits of DHIs in managing ADHD, autism, psychosis and eating disorders are uncertain, and evidence is lacking regarding the cost-effectiveness of DHIs. CONCLUSIONS: Key methodological limitations make it difficult to draw definitive conclusions from existing clinical trials of DHIs. Issues include variable uptake and engagement with DHIs, lack of an agreed typology/taxonomy for DHIs, small sample sizes, lack of blinded outcome assessment, combining different comparators, short-term follow-up and poor specification of the level of human support. Research and practice recommendations are presented that address the key research questions and methodological issues for the evaluation and clinical implementation of DHIs for CYP.

Quantity and Quality of Homework Compliance: A Meta-Analysis of Relations With Outcome in Cognitive Behavior Therapy.

Homework assignments have been shown to produce both causal and correlational effects in prior meta-analytic reviews of cognitive behavior therapy (CBT), but this research area has been characterized by a focus on the amount of compliance (i.e., quantity), and little is known about the role of skill acquisition (i.e., quality). A landmark study by Neimeyer and Feixas (1990) showed stronger homework-outcome relations when quality was assessed, but previous reviews have not considered whether the same pattern is evident across studies. Seventeen studies of CBT (N = 2,312 clients) published following calls for research on homework quality were included in the current meta-analysis. In the present review, homework compliance relations were demonstrated when outcome was assessed at posttreatment (quality Hedges' g = 0.78, 95% Confidence Interval [CI] = 0.03 to 1.53, k = 3, n = 417; quantity g = 0.79, 95% CI = 0.57 to 1.02, k = 15, n = 1537) and at follow-up (quality g = 1.07, 95% CI = 0.06 to 2.08, k = 3, n = 417; quantity g = 0.51, 95% CI = 0.28 to 0.74, k = 7, n = 1291). All effect sizes were different from 0, ps < .05. Differences that were obtained in homework-outcome relations among sources of compliance data (client, therapist, objective) were tentative due to overlapping CIs, but suggest a potential moderating effect. If confirmed by further research, the present findings would suggest that trial methods capable of assessing both quantity and quality have been an important omission in research on homework-outcome relations in CBT.

The skills and experience of GRADE methodologists can be assessed with a simple tool.

OBJECTIVES: To suggest approaches for guideline developers on how to assess a methodologist's expertise with Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods and tasks and to provide a set of minimum skills and experience required to perform specific tasks related to guideline development using GRADE. STUDY DESIGN AND SETTING: We used an iterative and consensus-based process involving individuals with in-depth experience with GRADE. We considered four main tasks: (1) development of key questions; (2) assessment of the certainty of effect estimates; (3) development of recommendations; and (4) teaching GRADE. RESULTS: There are three basic approaches to determine a methodologist's skill set. First, self-report of knowledge, skills, and experience with a standardized "GRADE curriculum vitae (CV)" focused on each of the GRADE-related tasks; second, demonstration of skills using worked examples; third, a formal evaluation using a written or oral test. We suggest that the GRADE CV is likely to be useful and feasible to implement. We also suggest minimum training including attendance at one or more full-day workshops and familiarity with the main GRADE publications and the GRADE handbook. CONCLUSIONS: The selection of a GRADE methodologist must be a thoughtful, reasoned decision, informed by the criteria suggested in this article and tailored to the specific project. Our suggested approaches need further pilot testing and validation.

Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis.

BACKGROUND: Major depressive disorder is one of the most common mental disorders in children and adolescents. However, whether to use pharmacological interventions in this population and which drug should be preferred are still matters of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for major depressive disorder in young people. METHODS: We did a network meta-analysis to identify both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents. We included trials of amitriptyline, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, imipramine, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, and venlafaxine. Trials recruiting participants with treatment-resistant depression, treatment duration of less than 4 weeks, or an overall sample size of less than ten patients were excluded. We extracted the relevant information from the published reports with a predefined data extraction sheet, and assessed the risk of bias with the Cochrane risk of bias tool. The primary outcomes were efficacy (change in depressive symptoms) and tolerability (discontinuations due to adverse events). We did pair-wise meta-analyses using the random-effects model and then did a random-effects network meta-analysis within a Bayesian framework. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42015016023. FINDINGS: We deemed 34 trials eligible, including 5260 participants and 14 antidepressant treatments. The quality of evidence was rated as very low in most comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo (standardised mean difference -0·51, 95% credible interval [CrI] -0·99 to -0·03). In terms of tolerability, fluoxetine was also better than duloxetine (odds ratio [OR] 0·31, 95% CrI 0·13 to 0·95) and imipramine (0·23, 0·04 to 0·78). Patients given imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than did those given placebo (5·49, 1·96 to 20·86; 3·19, 1·01 to 18·70; and 2·80, 1·20 to 9·42, respectively). In terms of heterogeneity, the global I(2) values were 33·21% for efficacy and 0% for tolerability. INTERPRETATION: When considering the risk-benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated. FUNDING: National Basic Research Program of China (973 Program).

Practitioner Review: Treatments for Tourette syndrome in children and young people - a systematic review.

BACKGROUND: Tourette syndrome (TS) and chronic tic disorder (CTD) affect 1-2% of children and young people, but the most effective treatment is unclear. To establish the current evidence base, we conducted a systematic review of interventions for children and young people. METHODS: Databases were searched from inception to 1 October 2014 for placebo-controlled trials of pharmacological, behavioural, physical or alternative interventions for tics in children and young people with TS or CTD. Certainty in the evidence was assessed with the GRADE approach. RESULTS: Forty trials were included [pharmacological (32), behavioural (5), physical (2), dietary (1)]. For tics/global score there was evidence favouring the intervention from four trials of α2-adrenergic receptor agonists [clonidine and guanfacine, standardised mean difference (SMD) = -0.71; 95% CI -1.03, -0.40; N = 164] and two trials of habit reversal training (HRT)/comprehensive behavioural intervention (CBIT) (SMD = -0.64; 95% CI -0.99, -0.29; N = 133). Certainty in the effect estimates was moderate. A post hoc analysis combining oral clonidine/guanfacine trials with a clonidine patch trial continued to demonstrate benefit (SMD = -0.54; 95% CI -0.92, -0.16), but statistical heterogeneity was high. Evidence from four trials suggested that antipsychotic drugs improved tic scores (SMD = -0.74; 95% CI -1.08, -0.40; N = 76), but certainty in the effect estimate was low. The evidence for other interventions was categorised as low or very low quality, or showed no conclusive benefit. CONCLUSIONS: When medication is considered appropriate for the treatment of tics, the balance of clinical benefits to harm favours α2-adrenergic receptor agonists (clonidine and guanfacine) as first-line agents. Antipsychotics are likely to be useful but carry the risk of harm and so should be reserved for when α2-adrenergic receptor agonists are either ineffective or poorly tolerated. There is evidence that HRT/CBIT is effective, but there is no evidence for HRT/CBIT alone relative to combining medication and HRT/CBIT. There is currently no evidence to suggest that the physical and dietary interventions reviewed are sufficiently effective and safe to be considered as treatments.

Epidemiology of Mental Health Attendances at Emergency Departments: Systematic Review and Meta-Analysis.

BACKGROUND: The characteristics of Emergency Department (ED) attendances due to mental or behavioural health disorders need to be described to enable appropriate development of services. We aimed to describe the epidemiology of mental health-related ED attendances within health care systems free at the point of access, including clinical reason for presentation, previous service use, and patient sociodemographic characteristics. METHOD: Systematic review and meta-analysis of observational studies describing ED attendances by patients with common mental health conditions. FINDINGS: 18 studies from seven countries met eligibility criteria. Patients attending due to mental or behavioural health disorders accounted for 4% of ED attendances; a third were due to self-harm or suicidal ideation. 58.1% of attendees had a history of psychiatric illness and up to 58% were admitted. The majority of studies were single site and of low quality so results must be interpreted cautiously. CONCLUSIONS: Prevalence studies of mental health-related ED attendances are required to enable the development of services to meet specific needs.

NICE v. SIGN on psychosis and schizophrenia: same roots, similar guidelines, different interpretations.

A recent editorial claimed that the 2014 National Institute for Health and Care Excellence (NICE) guideline on psychosis and schizophrenia, unlike its equivalent 2013 Scottish Intercollegiate Guidelines Network (SIGN) guideline, is biased towards psychosocial treatments and against drug treatments. In this paper we underline that the NICE and SIGN guidelines recommend similar interventions, but that the NICE guideline has more rigorous methodology. Our analysis suggests that the authors of the editorial appear to have succumbed to bias themselves.

Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis.

BACKGROUND: Tourette syndrome (TS) is a neurodevelopmental condition characterised by chronic motor and vocal tics affecting up to 1% of school-age children and young people and is associated with significant distress and psychosocial impairment. OBJECTIVE: To conduct a systematic review of the benefits and risks of pharmacological, behavioural and physical interventions for tics in children and young people with TS (part 1) and to explore the experience of treatment and services from the perspective of young people with TS and their parents (part 2). DATA SOURCES: For the systematic reviews (parts 1 and 2), mainstream bibliographic databases, The Cochrane Library, education, social care and grey literature databases were searched using subject headings and text words for tic* and Tourette* from database inception to January 2013. REVIEW/RESEARCH METHODS: For part 1, randomised controlled trials and controlled before-and-after studies of pharmacological, behavioural or physical interventions in children or young people (aged < 18 years) with TS or chronic tic disorder were included. Mixed studies and studies in adults were considered as supporting evidence. Risk of bias associated with each study was evaluated using the Cochrane tool. When there was sufficient data, random-effects meta-analysis was used to synthesize the evidence and the quality of evidence for each outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. For part 2, qualitative studies and survey literature conducted in populations of children/young people with TS or their carers or in health professionals with experience of treating TS were included in the qualitative review. Results were synthesized narratively. In addition, a national parent/carer survey was conducted via the Tourettes Action website. Participants included parents of children and young people with TS aged under 18 years. Participants (young people with TS aged 10-17 years) for the in-depth interviews were recruited via a national survey and specialist Tourettes clinics in the UK. RESULTS: For part 1, 70 studies were included in the quantitative systematic review. The evidence suggested that for treating tics in children and young people with TS, antipsychotic drugs [standardised mean difference (SMD) -0.74, 95% confidence interval (CI) -1.08 to -0.41; n = 75] and noradrenergic agents [clonidine (Dixarit(®), Boehringer Ingelheim) and guanfacine: SMD -0.72, 95% CI -1.03 to -0.40; n = 164] are effective in the short term. There was little difference among antipsychotics in terms of benefits, but adverse effect profiles do differ. Habit reversal training (HRT)/comprehensive behavioural intervention for tics (CBIT) was also shown to be effective (SMD -0.64, 95% CI -0.99 to -0.29; n = 133). For part 2, 295 parents/carers of children and young people with TS contributed useable survey data. Forty young people with TS participated in in-depth interviews. Four studies were in the qualitative review. Key themes were difficulties in accessing specialist care and behavioural interventions, delay in diagnosis, importance of anxiety and emotional symptoms, lack of provision of information to schools and inadequate information regarding medication and adverse effects. LIMITATIONS: The number and quality of clinical trials is low and this downgrades the strength of the evidence and conclusions. CONCLUSIONS: Antipsychotics, noradrenergic agents and HRT/CBIT are effective in reducing tics in children and young people with TS. The balance of benefits and harms favours the most commonly used medications: risperidone (Risperdal(®), Janssen), clonidine and aripiprazole (Abilify(®), Otsuka). Larger and better-conducted trials addressing important clinical uncertainties are required. Further research is needed into widening access to behavioural interventions through use of technology including mobile applications ('apps') and video consultation. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002059. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The Use of Bayesian Networks to Assess the Quality of Evidence from Research Synthesis: 2. Inter-Rater Reliability and Comparison with Standard GRADE Assessment.

BACKGROUND: The grades of recommendation, assessment, development and evaluation (GRADE) approach is widely implemented in systematic reviews, health technology assessment and guideline development organisations throughout the world. We have previously reported on the development of the Semi-Automated Quality Assessment Tool (SAQAT), which enables a semi-automated validity assessment based on GRADE criteria. The main advantage to our approach is the potential to improve inter-rater agreement of GRADE assessments particularly when used by less experienced researchers, because such judgements can be complex and challenging to apply without training. This is the first study examining the inter-rater agreement of the SAQAT. METHODS: We conducted two studies to compare: a) the inter-rater agreement of two researchers using the SAQAT independently on 28 meta-analyses and b) the inter-rater agreement between a researcher using the SAQAT (who had no experience of using GRADE) and an experienced member of the GRADE working group conducting a standard GRADE assessment on 15 meta-analyses. RESULTS: There was substantial agreement between independent researchers using the Quality Assessment Tool for all domains (for example, overall GRADE rating: weighted kappa 0.79; 95% CI 0.65 to 0.93). Comparison between the SAQAT and a standard GRADE assessment suggested that inconsistency was parameterised too conservatively by the SAQAT. Therefore the tool was amended. Following amendment we found fair-to-moderate agreement between the standard GRADE assessment and the SAQAT (for example, overall GRADE rating: weighted kappa 0.35; 95% CI 0.09 to 0.87). CONCLUSIONS: Despite a need for further research, the SAQAT may aid consistent application of GRADE, particularly by less experienced researchers.

Comparative efficacy and acceptability of psychotherapies for acute anxiety disorders in children and adolescents: study protocol for a network meta-analysis.

INTRODUCTION: Anxiety disorders are associated with significant public health burden in young individuals. Cognitive-behavioural therapy (CBT) is the most commonly used psychotherapy for anxiety disorders in children and adolescents, but previous reviews were hindered by a limited number of trials with direct comparisons between different psychotherapies and their deliveries. Consequently, the main aim of this research was to investigate the comparative efficacy and acceptability of various types and deliveries of psychotherapies for anxiety disorders in children and adolescents. METHODS AND ANALYSIS: We will systematically search PubMed, EMBASE, Cochrane, Web of Science, PsycINFO, CINAHL, ProQuest Dissertations and LiLACS for randomised controlled trials, regardless of whether participants received blinding or not, published from 1 January 1966 to 30 January 2015 (updated to 1 July 2015), that compared any psychotherapy with either a control condition or an active comparator with different types and/or different delivery formats for the acute treatment of anxiety disorders in children and adolescents. Data extraction, risk of bias and quality assessments will be independently extracted by two reviewers. The primary outcome for efficacy will be mean overall change scores in anxiety symptoms (self-rated or assessor-rated) from baseline to post-treatment between two groups. The acceptability of treatment will be measured as the proportion of patients who discontinued treatment during the acute phase of treatment. We will assess efficacy, based on the standardised mean difference (SMD), and acceptability, based on the OR, using a random-effects network meta-analysis within a Bayesian framework. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. ETHICS AND DISSEMINATION: No ethical issues are foreseen. The results will be published in a peer-reviewed journal and will be disseminated electronically and in print. The meta-analysis may be updated to inform and guide management of anxiety in children and adolescents. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015016283.

Comparative efficacy and tolerability of first-generation and newer-generation antidepressant medications for depressive disorders in children and adolescents: study protocol for a systematic review and network meta-analysis.

INTRODUCTION: Depressive disorders are among the most common psychiatric disorders in children and adolescents, and have adverse effects on their psychosocial functioning. Questions concerning the efficacy and safety of antidepressant medications in the treatment of depression in children and adolescents, led us to integrate the direct and indirect evidence using network meta-analysis to create hierarchies of these drugs. METHODS AND ANALYSIS: Seven databases with PubMed, EMBASE, the Cochrane Library, Web of Science, CINAHL, LiLACS and PsycINFO will be searched from 1966 to December 2013 (updated to May, 2015). There are no restrictions on language or type of publication. Randomised clinical trials assessing first-generation and newer-generation antidepressant medications against active comparator or placebo as acute treatment for depressive disorders in children and adolescents (under 18 years of age) will be included. The primary outcome for efficacy will be mean improvement in depressive symptoms, as measured by the mean change score of a depression rating scale from baseline to post-treatment. The tolerability of treatment will be defined as side effect discontinuation, as defined by the proportion of patients who discontinued treatment due to adverse events during the trial. We will also assess the secondary outcome for efficacy (response rate), acceptability (all-cause discontinuation) and suicide-related outcomes. We will perform the Bayesian network meta-analyses for all relative outcome measures. Subgroup analyses and sensitivity analyses will be conducted to assess the robustness of the findings. DISSEMINATION: The network meta-analysis will provide useful information on antidepressant treatment for child and adolescent depression. The results will be disseminated through peer-reviewed publication or conference presentations. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015016023.