Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD).

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children and adolescents with ADHD find it difficult to pay attention and they are hyperactive and impulsive. Methylphenidate is the psychostimulant most often prescribed, but the evidence on benefits and harms is uncertain. This is an update of our comprehensive systematic review on benefits and harms published in 2015. OBJECTIVES: To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases and two trials registers up to March 2022. In addition, we checked reference lists and requested published and unpublished data from manufacturers of methylphenidate. SELECTION CRITERIA: We included all randomised clinical trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. The search was not limited by publication year or language, but trial inclusion required that 75% or more of participants had a normal intellectual quotient (IQ > 70). We assessed two primary outcomes, ADHD symptoms and serious adverse events, and three secondary outcomes, adverse events considered non-serious, general behaviour, and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and risk of bias assessment for each trial. Six review authors including two review authors from the original publication participated in the update in 2022. We used standard Cochrane methodological procedures. Data from parallel-group trials and first-period data from cross-over trials formed the basis of our primary analyses. We undertook separate analyses using end-of-last period data from cross-over trials. We used Trial Sequential Analyses (TSA) to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the GRADE approach. MAIN RESULTS: We included 212 trials (16,302 participants randomised); 55 parallel-group trials (8104 participants randomised), and 156 cross-over trials (8033 participants randomised) as well as one trial with a parallel phase (114 participants randomised) and a cross-over phase (165 participants randomised). The mean age of participants was 9.8 years ranging from 3 to 18 years (two trials from 3 to 21 years). The male-female ratio was 3:1. Most trials were carried out in high-income countries, and 86/212 included trials (41%) were funded or partly funded by the pharmaceutical industry. Methylphenidate treatment duration ranged from 1 to 425 days, with a mean duration of 28.8 days. Trials compared methylphenidate with placebo (200 trials) and with no intervention (12 trials). Only 165/212 trials included usable data on one or more outcomes from 14,271 participants. Of the 212 trials, we assessed 191 at high risk of bias and 21 at low risk of bias. If, however, deblinding of methylphenidate due to typical adverse events is considered, then all 212 trials were at high risk of bias. PRIMARY OUTCOMES: methylphenidate versus placebo or no intervention may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.74, 95% confidence interval (CI) -0.88 to -0.61; I² = 38%; 21 trials; 1728 participants; very low-certainty evidence). This corresponds to a mean difference (MD) of -10.58 (95% CI -12.58 to -8.72) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points). The minimal clinically relevant difference is considered to be a change of 6.6 points on the ADHD-RS. Methylphenidate may not affect serious adverse events (risk ratio (RR) 0.80, 95% CI 0.39 to 1.67; I² = 0%; 26 trials, 3673 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 0.91 (CI 0.31 to 2.68). SECONDARY OUTCOMES: methylphenidate may cause more adverse events considered non-serious versus placebo or no intervention (RR 1.23, 95% CI 1.11 to 1.37; I² = 72%; 35 trials 5342 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 1.22 (CI 1.08 to 1.43). Methylphenidate may improve teacher-rated general behaviour versus placebo (SMD -0.62, 95% CI -0.91 to -0.33; I² = 68%; 7 trials 792 participants; very low-certainty evidence), but may not affect quality of life (SMD 0.40, 95% CI -0.03 to 0.83; I² = 81%; 4 trials, 608 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: The majority of our conclusions from the 2015 version of this review still apply. Our updated meta-analyses suggest that methylphenidate versus placebo or no-intervention may improve teacher-rated ADHD symptoms and general behaviour in children and adolescents with ADHD. There may be no effects on serious adverse events and quality of life. Methylphenidate may be associated with an increased risk of adverse events considered non-serious, such as sleep problems and decreased appetite. However, the certainty of the evidence for all outcomes is very low and therefore the true magnitude of effects remain unclear. Due to the frequency of non-serious adverse events associated with methylphenidate, the blinding of participants and outcome assessors is particularly challenging. To accommodate this challenge, an active placebo should be sought and utilised. It may be difficult to find such a drug, but identifying a substance that could mimic the easily recognised adverse effects of methylphenidate would avert the unblinding that detrimentally affects current randomised trials. Future systematic reviews should investigate the subgroups of patients with ADHD that may benefit most and least from methylphenidate. This could be done with individual participant data to investigate predictors and modifiers like age, comorbidity, and ADHD subtypes.

Antibiotics for secondary prevention of coronary heart disease.

BACKGROUND: Coronary heart disease is the leading cause of mortality worldwide with approximately 7.4 million deaths each year. People with established coronary heart disease have a high risk of subsequent cardiovascular events including myocardial infarction, stroke, and cardiovascular death. Antibiotics might prevent such outcomes due to their antibacterial, antiinflammatory, and antioxidative effects. However, a randomised clinical trial and several observational studies have suggested that antibiotics may increase the risk of cardiovascular events and mortality. Furthermore, several non-Cochrane Reviews, that are now outdated, have assessed the effects of antibiotics for coronary heart disease and have shown conflicting results. No previous systematic review using Cochrane methodology has assessed the effects of antibiotics for coronary heart disease. OBJECTIVES: We assessed the benefits and harms of antibiotics compared with placebo or no intervention for the secondary prevention of coronary heart disease. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-EXPANDED, and BIOSIS in December 2019 in order to identify relevant trials. Additionally, we searched TRIP, Google Scholar, and nine trial registries in December 2019. We also contacted 11 pharmaceutical companies and searched the reference lists of included trials, previous systematic reviews, and other types of reviews. SELECTION CRITERIA: Randomised clinical trials assessing the effects of antibiotics versus placebo or no intervention for secondary prevention of coronary heart disease in adult participants (≥18 years). Trials were included irrespective of setting, blinding, publication status, publication year, language, and reporting of our outcomes. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data. Our primary outcomes were all-cause mortality, serious adverse event according to the International Conference on Harmonization - Good Clinical Practice (ICH-GCP), and quality of life. Our secondary outcomes were cardiovascular mortality, myocardial infarction, stroke, and sudden cardiac death. Our primary time point of interest was at maximum follow-up. Additionally, we extracted outcome data at 24±6 months follow-up. We assessed the risks of systematic errors using Cochrane 'Rosk of bias' tool. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes. We calculated absolute risk reduction (ARR) or increase (ARI) and number needed to treat for an additional beneficial outcome (NNTB) or for an additional harmful outcome (NNTH) if the outcome result showed a beneficial or harmful effect, respectively. The certainty of the body of evidence was assessed by GRADE. MAIN RESULTS: We included 38 trials randomising a total of 26,638 participants (mean age 61.6 years), with 23/38 trials reporting data on 26,078 participants that could be meta-analysed. Three trials were at low risk of bias and the 35 remaining trials were at high risk of bias. Trials assessing the effects of macrolides (28 trials; 22,059 participants) and quinolones (two trials; 4162 participants) contributed with the vast majority of the data. Meta-analyses at maximum follow-up showed that antibiotics versus placebo or no intervention seemed to increase the risk of all-cause mortality (RR 1.06; 95% CI 0.99 to 1.13; P = 0.07; I2 = 0%; ARI 0.48%; NNTH 208; 25,774 participants; 20 trials; high certainty of evidence), stroke (RR 1.14; 95% CI 1.00 to 1.29; P = 0.04; I2 = 0%; ARI 0.73%; NNTH 138; 14,774 participants; 9 trials; high certainty of evidence), and probably also cardiovascular mortality (RR 1.11; 95% CI 0.98 to 1.25; P = 0.11; I2= 0%; 4674 participants; 2 trials; moderate certainty of evidence). Little to no difference was observed when assessing the risk of myocardial infarction (RR 0.95; 95% CI 0.88 to 1.03; P = 0.23; I2 = 0%; 25,523 participants; 17 trials; high certainty of evidence). No evidence of a difference was observed when assessing sudden cardiac death (RR 1.08; 95% CI 0.90 to 1.31; P = 0.41; I2 = 0%; 4520 participants; 2 trials; moderate certainty of evidence). Meta-analyses at 24±6 months follow-up showed that antibiotics versus placebo or no intervention increased the risk of all-cause mortality (RR 1.25; 95% CI 1.06 to 1.48; P = 0.007; I2 = 0%; ARI 1.26%; NNTH 79 (95% CI 335 to 42); 9517 participants; 6 trials; high certainty of evidence), cardiovascular mortality (RR 1.50; 95% CI 1.17 to 1.91; P = 0.001; I2 = 0%; ARI 1.12%; NNTH 89 (95% CI 261 to 49); 9044 participants; 5 trials; high certainty of evidence), and probably also sudden cardiac death (RR 1.77; 95% CI 1.28 to 2.44; P = 0.0005; I2 = 0%; ARI 1.9%; NNTH 53 (95% CI 145 to 28); 4520 participants; 2 trials; moderate certainty of evidence). No evidence of a difference was observed when assessing the risk of myocardial infarction (RR 0.95; 95% CI 0.82 to 1.11; P = 0.53; I2 = 43%; 9457 participants; 5 trials; moderate certainty of evidence) and stroke (RR 1.17; 95% CI 0.90 to 1.52; P = 0.24; I2 = 0%; 9457 participants; 5 trials; high certainty of evidence). Meta-analyses of trials at low risk of bias differed from the overall analyses when assessing cardiovascular mortality at maximum follow-up. For all other outcomes, meta-analyses of trials at low risk of bias did not differ from the overall analyses. None of the trials specifically assessed serious adverse event according to ICH-GCP. No data were found on quality of life. AUTHORS' CONCLUSIONS: Our present review indicates that antibiotics (macrolides or quinolones) for secondary prevention of coronary heart disease seem harmful when assessing the risk of all-cause mortality, cardiovascular mortality, and stroke at maximum follow-up and all-cause mortality, cardiovascular mortality, and sudden cardiac death at 24±6 months follow-up. Current evidence does, therefore, not support the clinical use of macrolides and quinolones for the secondary prevention of coronary heart disease. Future trials on the safety of macrolides or quinolones for the secondary prevention in patients with coronary heart disease do not seem ethical. In general, randomised clinical trials assessing the effects of antibiotics, especially macrolides and quinolones, need longer follow-up so that late-occurring adverse events can also be assessed.

Social skills training for attention deficit hyperactivity disorder (ADHD) in children aged 5 to 18 years.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) in children is associated with hyperactivity and impulsivity, attention problems, and difficulties with social interactions. Pharmacological treatment may alleviate the symptoms of ADHD but this rarely solves difficulties with social interactions. Children with ADHD may benefit from interventions designed to improve their social skills. We examined the benefits and harms of social skills training on social skills, emotional competencies, general behaviour, ADHD symptoms, performance in school of children with ADHD, and adverse events. OBJECTIVES: To assess the beneficial and harmful effects of social skills training in children and adolescents with ADHD. SEARCH METHODS: In July 2018, we searched CENTRAL, MEDLINE, Embase, PsycINFO, 4 other databases and two trials registers.We also searched online conference abstracts, and contacted experts in the field for information about unpublished or ongoing randomised clinical trials. We did not limit our searches by language, year of publication, or type or status of publication, and we sought translation of the relevant sections of non-English language articles. SELECTION CRITERIA: Randomised clinical trials investigating social skills training versus either no intervention or waiting-list control, with or without pharmacological treatment of both comparison groups of children and adolescents with ADHD. DATA COLLECTION AND ANALYSIS: We conducted the review in accordance with the Cochrane Handbook for Systematic Reviews of Intervention. We performed the analyses using Review Manager 5 software and Trial Sequential Analysis. We assessed bias according to domains for systematic errors. We assessed the certainty of the evidence with the GRADE approach. MAIN RESULTS: We included 25 randomised clinical trials described in 45 reports. The trials included a total of 2690 participants aged between five and 17 years. In 17 trials, participants were also diagnosed with various comorbidities.The social skills interventions were described as: 1) social skills training, 2) cognitive behavioural therapy, 3) multimodal behavioural/psychosocial therapy, 4) child life and attention skills treatment, 5) life skills training, 6) the "challenging horizon programme", 7) verbal self-instruction, 8) meta-cognitive training, 9) behavioural therapy, 10) behavioural and social skills treatment, and 11) psychosocial treatment. The control interventions were no intervention or waiting list.The duration of the interventions ranged from five weeks to two years. We considered the content of the social skills interventions to be comparable and based on a cognitive-behavioural model. Most of the trials compared child social skills training or parent training combined with medication versus medication alone. Some of the experimental interventions also included teacher consultations.More than half of the trials were at high risk of bias for generation of the allocation sequence and allocation concealment. No trial reported on blinding of participants and personnel. Most of the trials did not report on differences between groups in medication for comorbid disorders. We used all eligible trials in the meta-analyses, but downgraded the certainty of the evidence to low or very low.We found no clinically relevant treatment effect of social skills interventions on the primary outcome measures: teacher-rated social skills at end of treatment (standardised mean difference (SMD) 0.11, 95% confidence interval (CI) 0.00 to 0.22; 11 trials, 1271 participants; I2 = 0%; P = 0.05); teacher-rated emotional competencies at end of treatment (SMD -0.02, 95% CI -0.72 to 0.68; two trials, 129 participants; I2 = 74%; P = 0.96); or on teacher-rated general behaviour (SMD -0.06 (negative value better), 95% CI -0.19 to 0.06; eight trials, 1002 participants; I2 = 0%; P = 0.33). The effect on the primary outcome, teacher-rated social skills at end of treatment, corresponds to a MD of 1.22 points on the social skills rating system (SSRS) scale (95% CI 0.09 to 2.36). The minimal clinical relevant difference (10%) on the SSRS is 10.0 points (range 0 to 102 points on SSRS).We found evidence in favour of social skills training on teacher-rated core ADHD symptoms at end of treatment for all eligible trials (SMD -0.26, 95% CI -0.47 to -0.05; 14 trials, 1379 participants; I2= 69%; P = 0.02), but the finding is questionable due to lack of support from sensitivity analyses, high risk of bias, lack of clinical significance, high heterogeneity, and low certainty.The studies did not report any serious or non-serious adverse events. AUTHORS' CONCLUSIONS: The review suggests that there is little evidence to support or refute social skills training for children and adolescents with ADHD. We may need more trials that are at low risk of bias and a sufficient number of participants to determine the efficacy of social skills training versus no training for ADHD. The evidence base regarding adolescents is especially weak.

Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents - assessment of adverse events in non-randomised studies.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in childhood. The psychostimulant methylphenidate is the most frequently used medication to treat it. Several studies have investigated the benefits of methylphenidate, showing possible favourable effects on ADHD symptoms, but the true magnitude of the effect is unknown. Concerning adverse events associated with the treatment, our systematic review of randomised clinical trials (RCTs) demonstrated no increase in serious adverse events, but a high proportion of participants suffered a range of non-serious adverse events. OBJECTIVES: To assess the adverse events associated with methylphenidate treatment for children and adolescents with ADHD in non-randomised studies. SEARCH METHODS: In January 2016, we searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, 12 other databases and two trials registers. We also checked reference lists and contacted authors and pharmaceutical companies to identify additional studies. SELECTION CRITERIA: We included non-randomised study designs. These comprised comparative and non-comparative cohort studies, patient-control studies, patient reports/series and cross-sectional studies of methylphenidate administered at any dosage or formulation. We also included methylphenidate groups from RCTs assessing methylphenidate versus other interventions for ADHD as well as data from follow-up periods in RCTs. Participants had to have an ADHD diagnosis (from the 3rd to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders or the 9th or 10th edition of theInternational Classification of Diseases, with or without comorbid diagnoses. We required that at least 75% of participants had a normal intellectual capacity (intelligence quotient of more than 70 points) and were aged below 20 years. We excluded studies that used another ADHD drug as a co-intervention. DATA COLLECTION AND ANALYSIS: Fourteen review authors selected studies independently. Two review authors assessed risk of bias independently using the ROBINS-I tool for assessing risk of bias in non-randomised studies of interventions. All review authors extracted data. We defined serious adverse events according to the International Committee of Harmonization as any lethal, life-threatening or life-changing event. We considered all other adverse events to be non-serious adverse events and conducted meta-analyses of data from comparative studies. We calculated meta-analytic estimates of prevalence from non-comparative cohorts studies and synthesised data from patient reports/series qualitatively. We investigated heterogeneity by conducting subgroup analyses, and we also conducted sensitivity analyses. MAIN RESULTS: We included a total of 260 studies: 7 comparative cohort studies, 6 of which compared 968 patients who were exposed to methylphenidate to 166 controls, and 1 which assessed 1224 patients that were exposed or not exposed to methylphenidate during different time periods; 4 patient-control studies (53,192 exposed to methylphenidate and 19,906 controls); 177 non-comparative cohort studies (2,207,751 participants); 2 cross-sectional studies (96 participants) and 70 patient reports/series (206 participants). Participants' ages ranged from 3 years to 20 years. Risk of bias in the included comparative studies ranged from moderate to critical, with most studies showing critical risk of bias. We evaluated all non-comparative studies at critical risk of bias. The GRADE quality rating of the evidence was very low.Primary outcomesIn the comparative studies, methylphenidate increased the risk ratio (RR) of serious adverse events (RR 1.36, 95% confidence interval (CI) 1.17 to 1.57; 2 studies, 72,005 participants); any psychotic disorder (RR 1.36, 95% CI 1.17 to 1.57; 1 study, 71,771 participants); and arrhythmia (RR 1.61, 95% CI 1.48 to 1.74; 1 study, 1224 participants) compared to no intervention.In the non-comparative cohort studies, the proportion of participants on methylphenidate experiencing any serious adverse event was 1.20% (95% CI 0.70% to 2.00%; 50 studies, 162,422 participants). Withdrawal from methylphenidate due to any serious adverse events occurred in 1.20% (95% CI 0.60% to 2.30%; 7 studies, 1173 participants) and adverse events of unknown severity led to withdrawal in 7.30% of participants (95% CI 5.30% to 10.0%; 22 studies, 3708 participants).Secondary outcomesIn the comparative studies, methylphenidate, compared to no intervention, increased the RR of insomnia and sleep problems (RR 2.58, 95% CI 1.24 to 5.34; 3 studies, 425 participants) and decreased appetite (RR 15.06, 95% CI 2.12 to 106.83; 1 study, 335 participants).With non-comparative cohort studies, the proportion of participants on methylphenidate with any non-serious adverse events was 51.2% (95% CI 41.2% to 61.1%; 49 studies, 13,978 participants). These included difficulty falling asleep, 17.9% (95% CI 14.7% to 21.6%; 82 studies, 11,507 participants); headache, 14.4% (95% CI 11.3% to 18.3%; 90 studies, 13,469 participants); abdominal pain, 10.7% (95% CI 8.60% to 13.3%; 79 studies, 11,750 participants); and decreased appetite, 31.1% (95% CI 26.5% to 36.2%; 84 studies, 11,594 participants). Withdrawal of methylphenidate due to non-serious adverse events occurred in 6.20% (95% CI 4.80% to 7.90%; 37 studies, 7142 participants), and 16.2% were withdrawn for unknown reasons (95% CI 13.0% to 19.9%; 57 studies, 8340 participants). AUTHORS' CONCLUSIONS: Our findings suggest that methylphenidate may be associated with a number of serious adverse events as well as a large number of non-serious adverse events in children and adolescents, which often lead to withdrawal of methylphenidate. Our certainty in the evidence is very low, and accordingly, it is not possible to accurately estimate the actual risk of adverse events. It might be higher than reported here.Given the possible association between methylphenidate and the adverse events identified, it may be important to identify people who are most susceptible to adverse events. To do this we must undertake large-scale, high-quality RCTs, along with studies aimed at identifying responders and non-responders.

Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: a Cochrane systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: There is little evidence in the literature on the association between methylphenidate treatment and psychotic symptoms in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). OBJECTIVE: We examine the occurrence of psychotic symptoms during methylphenidate treatment of children and adolescents with ADHD. The data arise from our two Cochrane systematic reviews on methylphenidate, reported elsewhere. METHODS: Electronic databases were searched up to January 2016 (for observational studies) and March 2017 (for randomized trials). We summarized data as risk ratios and pooled prevalences. Trial Sequential Analysis was used to control for random errors. We assessed the risk of bias and the quality of evidence according to Cochrane guidelines. RESULTS: Ten randomized trials (1103 participants), 17 non-randomized studies (76,237 participants) and 12 patient reports or series (18 patients) were identified. In the randomized trials, there was no significant difference in the risk of developing psychotic symptoms [10 of 654 (pooled prevalence, 2.5%) methylphenidate versus 1 of 508 (pooled prevalence, 1.7%) placebo patients; risk ratio, 2.07; 95% confidence interval, 0.58 to 7.35]. Nine of 10 trials had a high risk of bias, and according to the Trial Sequential Analysis, the required information size was not achieved, that is, the meta-analysis was considerably underpowered. There were 873 instances of psychotic symptoms in the non-randomized studies among 55,603 participants (pooled prevalence, 1.2%; 95% confidence interval, 0.7 to 2.4). In the comparative cohort study, methylphenidate significantly increased the risk for any psychotic disorder by 36% (risk ratio, 1.36; 95% confidence interval, 1.17 to 1.57). The overall risk of bias was rated as critical for this study. CONCLUSIONS: Because of sparse data and low quality of evidence, we cannot confirm or refute whether methylphenidate increases the risk of psychotic symptoms in children and adolescents with ADHD. This possible adverse event may affect 1.1% to 2.5%, and physicians, patients and caregivers should be aware of this to ensure proper treatment in case of occurrence during methylphenidate treatment.

Quetiapine extended release versus aripiprazole in children and adolescents with first-episode psychosis: the multicentre, double-blind, randomised tolerability and efficacy of antipsychotics (TEA) trial.

BACKGROUND: Head-to-head trials to guide antipsychotic treatment choices for paediatric psychosis are urgently needed because extrapolations from adult studies might not be implementable. In this superiority trial with two-sided significance testing, we aimed to compare the efficacy and safety of quetiapine-extended release (quetiapine-ER) versus aripiprazole in children and adolescents with first-episode psychosis, to determine whether differences between the two treatments were sufficient to guide clinicians in their choice of one drug over the other. METHODS: In this multicentre, double-blind, randomised trial in seven Danish university clinics, we recruited children and adolescents aged 12-17 years with a diagnosis of ICD-10 schizophrenia-spectrum disorder, delusional disorder, or affective-spectrum psychotic disorder, and psychotic symptoms scoring at least 4 on at least one of the following Positive and Negative Syndrome Scale (PANSS) items: P1 (delusions), P2 (conceptual disorganisation), P3 (hallucinations), P5 (grandiosity), P6 (suspiciousness/persecution), and G9 (unusual thought content), and a total PANSS score greater than 60. Patients were randomly assigned (1:1) to 12 weeks of treatment with target doses of 600 mg/day of quetiapine-ER (starting from 50 mg/day) or 20 mg/day of aripiprazole (starting from 2·5 mg/day). The assigned drug was titrated over five levels, with 2 days at each dose, and the final dose achieved on day 9. Randomisation was done using a computer-generated concealed sequence with a block size of 8, and stratified by baseline PANSS positive score (≤20 points or >20 points) and age (12-14 years or 15-17 years). Study drugs were administered in identical capsules, and interventions, assessments, and data analysis were done masked. The primary outcome was PANSS positive score. Key adverse outcomes were bodyweight, homoeostatic model of insulin resistance (HOMA-IR), akathisia, and sedation. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01119014. FINDINGS: Between June 10, 2010, and Jan 29, 2014, 231 participants were assessed for elegibility, of whom 113 were randomly assigned to quetiapine-ER (n=55) or aripiprazole (n=58). PANSS positive score did not differ between groups after 12 weeks (adjusted mean change -5·05 [5·46] for quetiapine-ER, -6·21 [5·42] for aripiprazole; p=0·98), but decreased over time in both groups (p<0·0001). Weight gain was more rapid with quetiapine-ER (p=0·0008), with an adjusted mean weight group difference at week 12 of 3·33 kg (SD 7·23; effect size 0·64; p<0·0001). The HOMA-IR group difference at week 12 favoured aripiprazole (adjusted mean log-transformed group difference 0·259 [SD 0·906]; effect size 0·35; p=0·0060). Akathisia was more common with aripiprazole at week 2 (observed in 34 [60%] of 57 patients; estimated 63·5%) than with quetiapine-ER (15 [30%] of 50; estimated 31·3%; p=0·0021), but not at other timepoints. Sedation proportions did not change significantly over time with either intervention (observed at weeks 2, 4, and 12, respectively, for quetiapine-ER in 43 [83%] of 52, 40 [83%] of 48, and 34 [72%] of 47 patients and for aripiprazole in 49 [89%] of 55, 52 [96%] of 54, and 44 [92%] of 48 patients), and the overall estimated probability combining all timepoints was significantly higher for aripiprazole (97·1%) than for quetiapine-ER (89·2%; p=0·012). In addition to sedation and akathisia, the most common adverse events were tremor (42 [79%] patients in the quetiapine-ER group vs 52 [91%] patients in the aripiprazole group), increased duration of sleep (47 [92%] vs 39 [71%]), orthostatic dizziness (42 [78%] vs 46 [81%]), depression (43 [80%] vs 44 [77%]), tension/inner unrest (37 [69%] vs 50 [88%]), failing memory (41 [76%] vs 44 [77%]), and weight gain (46 [87%] vs 38 [68%]). INTERPRETATION: This first head-to-head comparison of quetiapine-ER versus aripiprazole in early-onset psychosis showed no significant group differences in severity of psychopathology after 12 weeks of treatment. Quetiapine-ER was associated with more metabolic adverse events and aripiprazole with more initial akathisia and, unexpectedly, more sedation. The limited antipsychotic efficacy and high level of adverse events were noticeable. This trial provides novel information for the treatment of early-onset psychosis and highlights the importance of adverse event profiles when choosing among antipsychotics for children and adolescents who often require chronic treatment. FUNDING: The National Research Council for Health and Disease Foundation for Health Promotion, AP Møller Foundation, Rosalie Petersens Foundation, Stevn and Rindom Foundation, Foundation for the Promotion of Medical Science, The Capital Region Psychiatric Research Foundation, Tryg Foundation, Region of Southern Denmark Research Foundation, Danish Psychiatric Research Educational Fund, Psychiatry Foundation, Foundation of 17-12-1981, Psychiatric Research Foundation Region Zealand, Capital Region Strategic Research Foundation, Knud og Dagny Andresens Foundation, Psychiatric Research Foundation of 1967, The Capital Region Research Foundation, Dr Sofus Carl Emil Friis and Hustru Olga Friis Scholarship, Tømrerhandler Johannes Fogs Foundation, Brdr Hartmanns Foundation DKK, Aase and Ejnar Danielsens Foundation, Jacob Madsen and wife Olga Madsens Foundation, CC Klestrup and wife Scholarship, Lundbeck Foundation Scholarship, and Tømrermester Jørgen Holm and wife Elisas Scholarship.

Gastrointestinal adverse events during methylphenidate treatment of children and adolescents with attention deficit hyperactivity disorder: A systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials.

OBJECTIVES: To study in more depth the relationship between type, dose, or duration of methylphenidate offered to children and adolescents with attention deficit hyperactivity disorder and their risks of gastrointestinal adverse events based on our Cochrane systematic review. METHODS AND FINDINGS: We use data from our review including 185 randomised clinical trials. Randomised parallel-group trials and cross-over trials reporting gastrointestinal adverse events associated with methylphenidate were included. Data were extracted and quality assessed according to Cochrane guidelines. Data were summarised as risk ratios (RR) with 95% confidence intervals (CI) using the inverse variance method. Bias risks were assessed according to domains. Trial Sequential Analysis (TSA) was used to control random errors. Eighteen parallel group trials and 43 cross-over trials reported gastrointestinal adverse events. All trials were at high risk of bias. In parallel group trials, methylphenidate decreased appetite (RR 3.66, 95% CI 2.56 to 5.23) and weight (RR 3.89, 95% CI 1.43 to 10.59). In cross-over trials, methylphenidate increased abdominal pain (RR 1.61, 95% CI 1.27 to 2.04). We found no significant differences in the risk according to type, dose, or duration of administration. The required information size was achieved in three out of four outcomes. CONCLUSION: Methylphenidate increases the risks of decreased appetite, weight loss, and abdominal pain in children and adolescents with attention deficit hyperactivity disorder. No differences in the risks of gastrointestinal adverse events according to type, dose, or duration of administration were found.

Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD).

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children with ADHD find it difficult to pay attention, they are hyperactive and impulsive.Methylphenidate is the drug most often prescribed to treat children and adolescents with ADHD but, despite its widespread use, this is the first comprehensive systematic review of its benefits and harms. OBJECTIVES: To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. SEARCH METHODS: In February 2015 we searched six databases (CENTRAL, Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, Conference Proceedings Citations Index), and two trials registers. We checked for additional trials in the reference lists of relevant reviews and included trials. We contacted the pharmaceutical companies that manufacture methylphenidate to request published and unpublished data. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. At least 75% of participants needed to have an intellectual quotient of at least 70 (i.e. normal intellectual functioning). Outcomes assessed included ADHD symptoms, serious adverse events, non-serious adverse events, general behaviour and quality of life. DATA COLLECTION AND ANALYSIS: Seventeen review authors participated in data extraction and risk of bias assessment, and two review authors independently performed all tasks. We used standard methodological procedures expected within Cochrane. Data from parallel-group trials and first period data from cross-over trials formed the basis of our primary analyses; separate analyses were undertaken using post-cross-over data from cross-over trials. We used Trial Sequential Analyses to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach for high risk of bias, imprecision, indirectness, heterogeneity and publication bias. MAIN RESULTS: The studies.We included 38 parallel-group trials (5111 participants randomised) and 147 cross-over trials (7134 participants randomised). Participants included individuals of both sexes, at a boys-to-girls ratio of 5:1, and participants' ages ranged from 3 to 18 years across most studies (in two studies ages ranged from 3 to 21 years). The average age across all studies was 9.7 years. Most participants were from high-income countries.The duration of methylphenidate treatment ranged from 1 to 425 days, with an average duration of 75 days. Methylphenidate was compared to placebo (175 trials) or no intervention (10 trials). Risk of Bias.All 185 trials were assessed to be at high risk of bias. Primary outcomes. Methylphenidate may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.77, 95% confidence interval (CI) -0.90 to -0.64; 19 trials, 1698 participants; very low-quality evidence). This corresponds to a mean difference (MD) of -9.6 points (95% CI -13.75 to -6.38) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points; DuPaul 1991a). A change of 6.6 points on the ADHD-RS is considered clinically to represent the minimal relevant difference. There was no evidence that methylphenidate was associated with an increase in serious (e.g. life threatening) adverse events (risk ratio (RR) 0.98, 95% CI 0.44 to 2.22; 9 trials, 1532 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 0.91 (CI 0.02 to 33.2). SECONDARY OUTCOMES: Among those prescribed methylphenidate, 526 per 1000 (range 448 to 615) experienced non-serious adverse events, compared with 408 per 1000 in the control group. This equates to a 29% increase in the overall risk of any non-serious adverse events (RR 1.29, 95% CI 1.10 to 1.51; 21 trials, 3132 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 1.29 (CI 1.06 to 1.56). The most common non-serious adverse events were sleep problems and decreased appetite. Children in the methylphenidate group were at 60% greater risk for trouble sleeping/sleep problems (RR 1.60, 95% CI 1.15 to 2.23; 13 trials, 2416 participants), and 266% greater risk for decreased appetite (RR 3.66, 95% CI 2.56 to 5.23; 16 trials, 2962 participants) than children in the control group.Teacher-rated general behaviour seemed to improve with methylphenidate (SMD -0.87, 95% CI -1.04 to -0.71; 5 trials, 668 participants; very low-quality evidence).A change of seven points on the Child Health Questionnaire (CHQ; range 0 to 100 points; Landgraf 1998) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a MD of 8.0 points (95% CI 5.49 to 10.46) on the CHQ, which suggests that methylphenidate may improve parent-reported quality of life (SMD 0.61, 95% CI 0.42 to 0.80; 3 trials, 514 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: The results of meta-analyses suggest that methylphenidate may improve teacher-reported ADHD symptoms, teacher-reported general behaviour, and parent-reported quality of life among children and adolescents diagnosed with ADHD. However, the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects. Within the short follow-up periods typical of the included trials, there is some evidence that methylphenidate is associated with increased risk of non-serious adverse events, such as sleep problems and decreased appetite, but no evidence that it increases risk of serious adverse events.Better designed trials are needed to assess the benefits of methylphenidate. Given the frequency of non-serious adverse events associated with methylphenidate, the particular difficulties for blinding of participants and outcome assessors point to the advantage of large, 'nocebo tablet' controlled trials. These use a placebo-like substance that causes adverse events in the control arm that are comparable to those associated with methylphenidate. However, for ethical reasons, such trials should first be conducted with adults, who can give their informed consent.Future trials should publish depersonalised individual participant data and report all outcomes, including adverse events. This will enable researchers conducting systematic reviews to assess differences between intervention effects according to age, sex, comorbidity, type of ADHD and dose. Finally, the findings highlight the urgent need for large RCTs of non-pharmacological treatments.

Methylphenidate for attention-deficit/hyperactivity disorder in children and adolescents: Cochrane systematic review with meta-analyses and trial sequential analyses of randomised clinical trials.

STUDY QUESTION: Is methylphenidate beneficial or harmful for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents? METHODS: Electronic databases were searched up to February 2015 for parallel and crossover randomised clinical trials comparing methylphenidate with placebo or no intervention in children and adolescents with ADHD. Meta-analyses and trial sequential analyses (TSA) were conducted. Quality was assessed using GRADE. Teachers, parents, and observers rated ADHD symptoms and general behaviour. STUDY ANSWER AND LIMITATIONS: The analyses included 38 parallel group trials (n=5111, median treatment duration 49 days) and 147 crossover trials (n=7134, 14 days). The average age across all studies was 9.7 years. The analysis suggested a beneficial effect of methylphenidate on teacher rated symptoms in 19 parallel group trials (standardised mean difference (SMD) -0.77, n=1698), corresponding to a mean difference of -9.6 points on the ADHD rating scale. There was no evidence that methylphenidate was associated with an increase in serious adverse events (risk ratio 0.98, nine trials, n=1532; TSA adjusted intervention effect RR 0.91). Methylphenidate was associated with an increased risk of non-serious adverse events (1.29, 21 trials, n=3132; TSA adjusted RR 1.29). Teacher rated general behaviour seemed to improve with methylphenidate (SMD -0.87, five trials, n=668) A change of 7 points on the child health questionnaire (CHQ) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a mean difference of 8.0 points on the CHQ (range 0-100 points), which suggests that methylphenidate may improve parent reported quality of life (SMD 0.61, three trials, n=514). 96.8% of trials were considered high risk of bias trials according to the Cochrane guidelines. All outcomes were assessed very low quality according to GRADE. WHAT THIS STUDY ADDS: The results suggest that among children and adolescents with a diagnosis of ADHD, methylphenidate may improve teacher reported symptoms of ADHD and general behaviour and parent reported quality of life. However, given the risk of bias in the included studies, and the very low quality of outcomes, the magnitude of the effects is uncertain. Methylphenidate is associated with an increased risk of non-serious but not serious adverse events. FUNDING, COMPETING INTERESTS, DATA SHARING: Region Zealand Research Foundation and Copenhagen Trial Unit. Competing interests are given in the full paper on bmj.com. Full data are available in the version of this review published in The Cochrane Library.

Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10years in the CLARICOR randomised, blinded clinical trial.

BACKGROUND: The CLARICOR trial reported that clarithromycin compared with placebo increased all-cause mortality in patients with stable coronary heart disease. This study investigates the effects of clarithromycin versus placebo during 10years follow up. METHODS: The CLARICOR trial is a randomised, placebo-controlled trial including 4373 patients with stable coronary heart disease. The interventions were 2weeks of clarithromycin 500mg a day versus placebo. 10year follow up was performed through Danish public registers and analysed with Cox regression. RESULTS: Clarithromycin increased all-cause mortality (hazard ratio (HR): 1.10, 95% confidence interval (CI): 1.00-1.21) and cerebrovascular disease during 10years (HR: 1.19, 95% CI: 1.02-1.38). The increased mortality and morbidity were restricted to patients not on statin at entry (HR: 1.16, 95% CI: 1.04-1.31, and HR: 1.25, 95% CI: 1.03-1.50). The assumption of constant HR during the 10years was violated for cardiovascular death (P=0.01) and cardiovascular death outside hospital (P<0.0005). Analyses of the effects over time showed that clarithromycin increased cardiovascular mortality during the first three years (HR: 1.42, 95% CI: 1.09-1.84) due to increased cardiovascular mortality outside hospital in patients not on statin (HR: 2.36, 95% CI: 1.60-3.50). During the last 4years, cardiovascular death outside hospital was lower in the clarithromycin group (HR: 0.64, 95% CI: 0.46-0.88). CONCLUSION: Clarithromycin increased mortality due to cardiovascular death outside hospital and cerebrovascular morbidity in patients with stable coronary heart disease who were not on statin. The increased cardiovascular mortality was years later compensated, likely through frailty attrition.

Attachment Competences in Children With ADHD During the Social-Skills Training and Attachment (SOSTRA) Randomized Clinical Trial.

OBJECTIVE: To investigate the effects of social-skills training and a parental training program on children with ADHD as measured by the children's attachment competences. METHOD: The SOSTRA trial is a randomized, parallel-group, outcome-assessor-blinded, superiority trial evaluating 8 weeks social-skills training and parental training plus standard treatment versus standard treatment alone for 8- to 12-year old children with ADHD. RESULTS: There were no significant differences in attachment competences at 6 months between the experimental (n = 25) and the control (n = 22) groups (odds ratio = 1.06, 95% confidence interval = [0.31, 3.58], p = .91). In total, 17 children (36%) changed their entry status, 1 (2%) from secure to insecure attachment, while 16 (34%) changed from insecure to secure attachment. CONCLUSION: The experimental treatment does not seem to affect attachment competences compared with standard treatment alone. Children in the SOSTRA trial improved their attachment competences significantly at 6-month follow-up.

Osteoprotegerin independently predicts mortality in patients with stable coronary artery disease: the CLARICOR trial.

OBJECTIVES: To elucidate the prognostic power of serum osteoprotegerin (OPG) in patients with stable coronary artery disease (CAD). METHODS: Serum OPG levels were measured in the CLARICOR trial cohort of 4063 patients with stable CAD on blood samples drawn at randomization. The follow-up was 2.6 years for detailed cardiovascular events and 6 years for all-cause mortality. RESULTS: OPG levels were significantly increased in non-survivors (21%) compared to survivors (median [quartiles] 2092 ng/L [1636; 2800] compared to 1695 ng/L [1322; 2193, p < 0.0001]). The 2.6-year follow-up showed that OPG adds to the prediction of both cardiovascular and all-cause mortality in combination with clinical risk factors (HR [one log10 unit increase] 6.1 [95% CI 2.4-15.6, p = 0.0001]) and HR 6.5 [95% CI 3.4-12.5, p < 0.0001], respectively). Similar, in the 6-year follow-up, OPG was found to be a strong predictor for all-cause mortality. Importantly, OPG remained an independent predictor of mortality even after adjustment for both clinical and conventional cardiovascular risk markers (HR 2.5 [95% CI 1.6-3.9, p < 0.0001]). CONCLUSIONS: Serum OPG has a long-lasting independent predictive power as to all-cause mortality and cardiovascular death in patients with stable CAD.

Quetiapine versus aripiprazole in children and adolescents with psychosis--protocol for the randomised, blinded clinical Tolerability and Efficacy of Antipsychotics (TEA) trial.

BACKGROUND: The evidence for choices between antipsychotics for children and adolescents with schizophrenia and other psychotic disorders is limited. The main objective of the Tolerability and Efficacy of Antipsychotics (TEA) trial is to compare the benefits and harms of quetiapine versus aripiprazole in children and adolescents with psychosis in order to inform rational, effective and safe treatment selections. METHODS/DESIGN: The TEA trial is a Danish investigator-initiated, independently funded, multi-centre, randomised, blinded clinical trial. Based on sample size estimation, 112 patients aged 12-17 years with psychosis, antipsychotic-naïve or treated for a limited period are, 1:1 randomised to a 12- week, double-blind intervention with quetiapine versus aripiprazole. Effects on psychopathology, cognition, health-related quality of life, and adverse events are assessed 2, 4, and 12 weeks after randomisation. The primary outcome is change in the positive symptom score of the Positive and Negative Syndrome Scale. The recruitment period is 2010-2014. DISCUSSION: Antipsychotics are currently the only available pharmacologic treatments for psychotic disorders. However, information about head-to-head differences in efficacy and tolerability of antipsychotics are scarce in children and adolescents. The TEA trial aims at expanding the evidence base for the use of antipsychotics in early onset psychosis in order to inform more rational treatment decisions in this vulnerable population. Here, we account for the trial design, address methodological challenges, and discuss the estimation of sample size. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01119014.

The SafeBoosC phase II randomised clinical trial: a treatment guideline for targeted near-infrared-derived cerebral tissue oxygenation versus standard treatment in extremely preterm infants.

UNLABELLED: Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rStO2) reflects venous oxygen saturation. If cerebral metabolism is stable, rStO2 can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the burden of hypo- and hyperoxia can be reduced by the combined use of close monitoring of the cerebral rStO2 and a treatment guideline to correct deviations in rStO2 outside a predefined target range. AIMS: To describe the rationale for and content of this treatment guideline. METHODS: Review of the literature and assessment of the quality of evidence and the grade of recommendation for each of the interventions. RESULTS AND CONCLUSIONS: A clinical intervention algorithm based on the main determinants of cerebral perfusion-oxygenation changes during the first hours after birth was generated. The treatment guideline is presented to assist neonatologists in making decisions in relation to cerebral oximetry readings in preterm infants within the SafeBoosC phase II randomised clinical trial. The evidence grades were relatively low and the guideline cannot be recommended outside a research setting.

Selenium supplementation for patients with Graves' hyperthyroidism (the GRASS trial): study protocol for a randomized controlled trial.

BACKGROUND: Graves' hyperthyroidism is an autoimmune disease causing hyperfunction of the thyroid gland. The concentration of selenium is high in the thyroid gland and two important groups of enzymes within the thyroid are selenoproteins, that is, they depend on selenium. Selenium may have beneficial effects on autoimmune hypothyroidism and on Graves' orbitopathy, but the effects of selenium on Graves' hyperthyroidism is unknown.We hypothesize that adjuvant selenium may be beneficial in the treatment of Graves' hyperthyroidism. The objective is to investigate if selenium supplementation plus standard treatment with anti-thyroid drugs versus standard treatment with anti-thyroid drugs will lead to a decrease in anti-thyroid drug treatment failure (that is, failure to remain euthyroid, without further treatment, one year after cessation of anti-thyroid drug treatment), faster and longer lasting remission (that is, anti-thyroid drug treatment success), and improved quality of life in patients with Graves' hyperthyroidism. METHODS AND DESIGN: The trial is an investigator-initiated, randomised, blinded, multicentre clinical trial. Inclusion criteria are: age 18 years or older; diagnosis of active Graves' hyperthyroidism within the last two months; and informed consent. Exclusion criteria are major co-morbidity; previous radioactive iodine treatment; ongoing anti-thyroid drug treatment for more than two months; treatment with immunomodulatory drugs; known allergy towards the components in the selenium and placebo pills; pregnancy or breast-feeding; and intake of selenium supplementation above 70 µg per day. We plan to include 492 participants, randomised (1:1) to two tablets of 100 µg selenium once daily for the 24 to 30 months intervention period versus two identical placebo tablets once daily.The primary outcome is the proportion of participants with anti-thyroid drug treatment failure (see above) at the end of the intervention period (24 to 30 months). Secondary outcomes are: thyroid-specific quality of life during the first year after randomisation; level of thyroid stimulating hormone-receptor antibodies at 18 months after randomisation and at the end of the intervention period (24 to 30 months); hyperthyroid symptoms during the first year after randomisation; eye symptoms during the first year after randomisation, and at the end of the intervention period (24 to 30 months); adverse reactions during the intervention period; and serious adverse events during the intervention period. DISCUSSION: It was of great importance to the initiators of this trial, that the results would be directly applicable to daily clinical practice. Therefore, it was designed as a pragmatic trial: the patients follow their usual treatment at their usual hospitals. In order to still collect high quality data on the clinical course and quality of life, an elaborate trial management system was designed to keep track of patient input, need for trial personnel input and action, and to collect data from medical chart systems. Meticulous follow-up on missing responses to the QoL measurements has been incorporated into the system, to minimise missing quality of life data. Monitoring of adverse reactions and events is achieved by thorough instruction of the participants, surveillance of patient-reported outcomes, and integration with national databases regarding hospitalizations. A very long intervention period was necessary, since patients are not considered in remission until one year after stopping anti-thyroid drugs. Usually, patients are treated for 12 to 18 months with anti-thyroid drugs, yielding a total intervention period of 24 to 30 months. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01611896.

A phase II randomized clinical trial on cerebral near-infrared spectroscopy plus a treatment guideline versus treatment as usual for extremely preterm infants during the first three days of life (SafeBoosC): study protocol for a randomized controlled trial.

BACKGROUND: Every year in Europe about 25,000 infants are born extremely preterm. These infants have a 20% mortality rate, and 25% of survivors have severe long-term cerebral impairment. Preventative measures are key to reduce mortality and morbidity in an extremely preterm population. The primary objective of the SafeBoosC phase II trial is to examine if it is possible to stabilize the cerebral oxygenation of extremely preterm infants during the first 72 hours of life through the application of cerebral near-infrared spectroscopy (NIRS) oximetry and implementation of an clinical treatment guideline based on intervention thresholds of cerebral regional tissue saturation rStO2. METHODS/DESIGN: SafeBoosC is a randomized, blinded, multinational, phase II clinical trial. The inclusion criteria are: neonates born more than 12 weeks preterm; decision to conduct full life support; parental informed consent; and possibility to place the cerebral NIRS oximeter within 3 hours after birth. The infants will be randomized into one of two groups. Both groups will have a cerebral oximeter monitoring device placed within three hours of birth. In the experimental group, the cerebral oxygenation reading will supplement the standard treatment using a predefined treatment guideline. In the control group, the cerebral oxygenation reading will not be visible and the infant will be treated according to the local standards. The primary outcome is the multiplication of the duration and magnitude of rStO2 values outside the target ranges of 55% to 85%, that is, the 'burden of hypoxia and hyperoxia' expressed in '%hours'. To detect a 50% difference between the experimental and control group in %hours, 166 infants in total must be randomized. Secondary outcomes are mortality at term date, cerebral ultrasound score, and interburst intervals on an amplitude-integrated electroencephalogram at 64 hours of life and explorative outcomes include neurodevelopmental outcome at 2 years corrected age, magnetic resonance imaging at term, blood biomarkers at 6 and 64 hours after birth, and adverse events. DISCUSSION: Cerebral oximetry guided interventions have the potential to improve neurodevelopmental outcome in extremely preterm infants. It is a logical first step to test if it is possible to reduce the burden of hypoxia and hyperoxia. TRIAL REGISTRATION: ClinicalTrial.gov, NCT01590316.

Social skills training for Attention Deficit Hyperactivity Disorder (ADHD) in children aged 5 to 18 years.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) in children is associated with hyperactivity and impulsitivity, attention problems, and difficulties with social interactions. Pharmacological treatment may alleviate symptoms of ADHD but seldom solves difficulties with social interactions. Social skills training may benefit ADHD children in their social interactions. We examined the effects of social skills training on children's social competences, general behaviour, ADHD symptoms, and performance in school. OBJECTIVES: To assess the effects of social skills training in children and adolescents with ADHD. SEARCH METHODS: We searched the following electronic databases: CENTRAL (2011, Issue1), MEDLINE (1948 to March 2011), EMBASE (1980 to March 2011), ERIC (1966 to March 2011 ), AMED (1985 to June 2011), PsycINFO (1806 to March 2011), CINAHL (1980 to March 2011), and Sociological Abstracts (1952 to March 2011). We also searched the metaRegister of Controlled Trials on 15 October 2010. We did not apply any language or date restrictions to the searches. We searched online conference abstracts and contacted 176 experts in the field for possible information about unpublished or ongoing RCTs. SELECTION CRITERIA: Randomised trials investigating social skills training for children with ADHD as a stand alone treatment or as an adjunct to pharmacological treatment. DATA COLLECTION AND ANALYSIS: We conducted the review according to the Cochrane Handbook for Systematic Reviews of Intervention. Two authors (OJS, MS) extracted data independently using an appropriate data collection form. We performed the analyses using Review Manager 5 software. MAIN RESULTS: We included 11 randomised trials described in 26 records (all full text articles) in the review. The trials included a total of 747 participants. All participants were between five and 12 years of age. No trials assessed adolescents. In 10 of the trials the participants suffered from different comorbidities.The duration of the interventions ranged from eight to 10 weeks (eight trials) up to two years. The types of social skills interventions were named social skills training, cognitive behavioural intervention, multimodal behavioural/psychosocial therapy, behavioural therapy/treatment, behavioural and social skills treatment, and psychosocial treatment. The content of the social skills interventions were comparable and based on a cognitive behavioural model. Most of the trials compared child social skills training and parent training plus medication versus medication alone. Some of the experimental interventions also included teacher consultations.More than half of the trials were at high risk of bias regarding generation of the allocation sequence and allocation concealment. No trial reported blinding of participants and personnel and most of the trials had no reports regarding differences between groups in collateral medication for comorbid disorders. Overall, the trials had high risk of bias due to systematic errors. Even so, as recommended by the Cochrane Handbook of Systematic Reviews of Interventions, we used all eligible trials in the meta-analysis, but the results are downgraded to low quality evidence.There were no statistically significant treatment effects either on social skills competences (positive value = better for the intervention group) (SMD 0.16; 95% CI -0.04 to 0.36; 5 trials, n = 392), on the teacher-rated general behaviour (negative value = better for the intervention group) (SMD 0.00; 95% CI -0.21 to 0.21; 3 trials, n = 358), or on the ADHD symptoms (negative value = better for the intervention group) (SMD -0.02; 95% CI -0.19 to 0.16; 6 trials, n = 515).No serious or non-serious adverse events were reported. AUTHORS' CONCLUSIONS: The review suggests that there is little evidence to support or refute social skills training for adolescents with ADHD. There is need for more trials, with low risk of bias and with a sufficient number of participants, investigating the efficacy of social skills training versus no training for both children and adolescents.

Randomised social-skills training and parental training plus standard treatment versus standard treatment of children with attention deficit hyperactivity disorder - the SOSTRA trial protocol.

BACKGROUND: Children with attention deficit hyperactivity disorder (ADHD) are hyperactive and impulsive, cannot maintain attention, and have difficulties with social interactions. Medical treatment may alleviate symptoms of ADHD, but seldom solves difficulties with social interactions. Social-skills training may benefit ADHD children in their social interactions. We want to examine the effects of social-skills training on difficulties related to the children's ADHD symptoms and social interactions. METHODS/DESIGN: The design is randomised two-armed, parallel group, assessor-blinded trial. Children aged 8-12 years with a diagnosis of ADHD are randomised to social-skills training and parental training plus standard treatment versus standard treatment alone. A sample size calculation estimated that at least 52 children must be included to show a 4-point difference in the primary outcome on the Conners 3rd Edition subscale for 'hyperactivity-impulsivity' between the intervention group and the control group. The outcomes will be assessed 3 and 6 months after randomisation. The primary outcome measure is ADHD symptoms. The secondary outcome is social skills. Tertiary outcomes include the relationship between social skills and symptoms of ADHD, the ability to form attachment, and parents' ADHD symptoms. DISCUSSION: We hope that the results from this trial will show that the social-skills training together with medication may have a greater general effect on ADHD symptoms and social and emotional competencies than medication alone. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT00937469.

Lipid synthesis and secretion in HepG2 cells is not affected by ACTH.

Apolipoprotein B (apoB) containing lipoproteins, i.e. VLDL, LDL and Lp(a), are consequently lowered by ACTH treatment in humans. This is also seen as reduced plasma apoB by 20-30% and total cholesterol by 30-40%, mostly accounted for by a decrease in LDL-cholesterol. Studies in hepatic cell line (HepG2) cells showed that apoB mRNA expression is reduced in response to ACTH incubation and is followed by a reduced apoB secretion, which may hypothesize that ACTH lowering apoB containing lipoproteins in humans may be mediated by the inhibition of hepatic apoB synthesis. This was recently confirmed in vivo in a human postprandial study, where ACTH reduced transient apoB48 elevation from the small intestine, however, the exogenic lipid turnover seemed unimpaired. In the present study we investigated if lipid synthesis and/or secretion in HepG2 cells were also affected by pharmacological levels of ACTH to accompany the reduced apoB output. HepG2 cells were incubated with radiolabelled precursors ([14C]acetate and [3H]glycerol) either before or during ACTH stimuli. Cellular and secreted lipids were extracted with chloroform:methanol and separated by the thin layer chromatography (TLC), and [14C]labelled cholesterol and cholesteryl ester and [3H]labelled triglycerides and phospholipids were quantitated by the liquid scintillation counting. It demonstrated that ACTH administration did not result in any significant change in neither synthesis nor secretion of the studied lipids, this regardless of presence or absence of oleic acid, which is known to stabilize apoB and enhance apoB production. The present study suggests that ACTH lowers plasma lipids in humans mainly mediated by the inhibition of apoB synthesis and did not via the reduced lipid synthesis.

ACTH reduces the rise in ApoB-48 levels after fat intake.

It has been repeatedly demonstrated that ACTH administration lowers plasma lipid concentrations in man. The present study was designed to test the hypothesis, based on observations of decreased apolipoprotein B (ApoB) synthesis and secretion in vitro, that ACTH administration inhibits the postprandial output of ApoB in man. Therefore, we studied the response to a fat-rich meal supplemented with Vitamin A in eight healthy volunteers, who underwent this test without premedication, after 4 days administration of ACTH, and after 4 days administration of a glucocorticoid (betamethasone). As expected, fasting plasma levels of low-density lipoproteins (LDL)-cholesterol (-25%) and ApoB (-17%) decreased after ACTH, but not after betamethasone administration. Also, the elevation of plasma ApoB-48 in response to fat intake (to twice the basal levels) was markedly reduced after ACTH administration. However, the postprandial rise in plasma triglycerides and retinyl palmitate was unimpaired, suggesting that ACTH administration induced the secretion of fewer but larger chylomicrons. The effect of betamethasone on the postprandial response was similar but less pronounced. This study confirms earlier reports on the lipid-lowering effects of ACTH and supports our theory, based on in vitro studies, that the lipid-lowering effects of ACTH administration in man involves an inhibition of ApoB production.