Self-determination theory interventions versus usual care in people with diabetes: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Autonomy-supporting interventions, such as self-determination theory and guided self-determination interventions, may improve self-management and clinical and psychosocial outcomes in people with diabetes. Such interventions have never been systematically reviewed assessing both benefits and harms and concurrently controlling the risks of random errors using trial sequential analysis methodology. This systematic review investigates the benefits and harms of self-determination theory-based interventions compared to usual care in people with diabetes. METHODS: We used the Cochrane methodology. Randomized clinical trials assessing interventions theoretically based on guided self-determination or self-determination theory in any setting were eligible. A comprehensive search (latest search April 2022) was undertaken in CENTRAL, MEDLINE, Embase, LILACS, PsycINFO, SCI-EXPANDED, CINAHL, SSCI, CPCI-S, and CPCI-SSH to identify relevant trials. Two authors independently screened, extracted data, and performed risk-of-bias assessment of included trials using the Cochrane risk-of-bias tool 1.0. Our primary outcomes were quality of life, all-cause mortality, and serious adverse events. Our secondary outcomes were diabetes distress, depressive symptoms, and nonserious adverse events not considered serious. Exploratory outcomes were glycated hemoglobin and motivation (autonomy, controlled, amotivation). Outcomes were assessed at the end of the intervention (primary time point) and at maximum follow-up. The analyses were conducted using Review Manager 5.4 and Trial Sequential Analysis 0.9.5.10. Certainty of the evidence was assessed by GRADE. RESULTS: Our search identified 5578 potentially eligible studies of which 11 randomized trials (6059 participants) were included. All trials were assessed at overall high risk of bias. We found no effect of self-determination theory-based interventions compared with usual care on quality of life (mean difference 0.00 points, 95% CI -4.85, 4.86, I2 = 0%; 225 participants, 3 trials, TSA-adjusted CI -11.83, 11.83), all-cause mortality, serious adverse events, diabetes distress, depressive symptoms, adverse events, glycated hemoglobulin A1c, or motivation (controlled). The certainty of the evidence was low to very low for all outcomes. We found beneficial effect on motivation (autonomous and amotivation; low certainty evidence). CONCLUSIONS: We found no effect of self-determination-based interventions on our primary or secondary outcomes. The evidence was of very low certainty. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020181144.

Adverse events in cognitive behavioral therapy and relaxation training for children and adolescents with obsessive-compulsive disorder: A mixed methods study and analysis plan for the TECTO trial.

Background: Knowledge on adverse events in psychotherapy for youth with OCD is sparse. No official guidelines exist for defining or monitoring adverse events in psychotherapy. Recent recommendations call for more qualitative and quantitative assessment of adverse events in psychotherapy trials. This mixed methods study aims to expand knowledge on adverse events in psychotherapy for youth with OCD. Methods: This is an analysis plan for a convergent mixed methods study within a randomized clinical trial (the TECTO trial). We include at least 128 youth aged 8-17 years with obsessive-compulsive disorder (OCD). Participants are randomized to either family-based cognitive behavioral therapy (FCBT) or family-based psychoeducation and relaxation training (FPRT). Adverse events are monitored quantitatively with the Negative Effects Questionnaire. Furthermore, we assess psychiatric symptoms, global functioning, quality of life, and family factors to investigate predictors for adverse events. We conduct semi-structured qualitative interviews with all youths and their parents on their experience of adverse events in FCBT or FPRT. For the mixed methods analysis, we will merge 1) a qualitative content analysis with descriptive statistics comparing the types, frequencies, and severity of adverse events; 2) a qualitative content analysis of the perceived causes for adverse events with prediction models for adverse events; and 3) a thematic analysis of the participants' treatment evaluation with a correlational analysis of adverse events and OCD severity. Discussion: The in-depth mixed methods analysis can inform 1) safer and more effective psychotherapy for OCD; 2) instruments and guidelines for monitoring adverse events; and 3) patient information on potential adverse events. The main limitation is risk of missing data. Trial registration: ClinicalTrials.gov identifier: NCT03595098. Registered on July 23, 2018.

Prompt closure versus gradual weaning of external ventricular drainage for hydrocephalus following aneurysmal subarachnoid haemorrhage: Protocol for the DRAIN randomised clinical trial.

BACKGROUND: Aneurysmal subarachnoid haemorrhage (aSAH) is a life-threatening disease caused by rupture of an intracranial aneurysm. A common complication following aSAH is hydrocephalus, for which placement of an external ventricular drain (EVD) is an important first-line treatment. Once the patient is clinically stable, the EVD is either removed or replaced by a ventriculoperitoneal shunt. The optimal strategy for cessation of EVD treatment is, however, unknown. Gradual weaning may increase the risk of EVD-related infection, whereas prompt closure carries a risk of acute hydrocephalus and redundant shunt implantations. We designed a randomised clinical trial comparing the two commonly used strategies for cessation of EVD treatment in patients with aSAH. METHODS: DRAIN is an international multi-centre randomised clinical trial with a parallel group design comparing gradual weaning versus prompt closure of EVD treatment in patients with aSAH. Participants are randomised to either gradual weaning which comprises a multi-step increase of resistance over days, or prompt closure of the EVD. The primary outcome is a composite outcome of VP-shunt implantation, all-cause mortality, or ventriculostomy-related infection. Secondary outcomes are serious adverse events excluding mortality, functional outcome (modified Rankin scale), health-related quality of life (EQ-5D) and Fatigue Severity Scale (FSS). Outcome assessment will be performed 6 months after ictus. Based on the sample size calculation (event proportion 80% in the gradual weaning group, relative risk reduction 20%, type I error 5%, power 80%), 122 patients are needed in each intervention group. Outcome assessment for the primary outcome, statistical analyses and conclusion drawing will be blinded. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03948256.

One-step laparoscopic cholecystectomy with common bile duct exploration and stone extraction versus two-step endoscopic retrograde cholangiography with stone extraction plus laparoscopic cholecystectomy for patients with common bile duct stones: a randomised feasibility and pilot clinical trial-the preGallStep trial.

BACKGROUND: Endoscopic retrograde cholangiography (ERC) with stone extraction and papillotomy with subsequent laparoscopic cholecystectomy-the two-step approach-is the standard treatment of common bile duct stones in many countries. However, ERC is associated with a high risk of complications and more than half of patients require multiple ERCs. Meta-analyses of randomised clinical trials find no major differences of the two-step approach in comparison with laparoscopic cholecystectomy with intraoperative laparoscopic stone clearance-the one-step approach. Currently, there are insufficient data to ascertain superiority. METHODS: The preGallstep trial is an investigator-initiated, multicentre randomised feasibility and pilot clinical trial with blinded outcome assessment. Eligible patients are patients with common bile duct stones (identified by magnetic resonance cholagiopancreatography), age 18 years or above with the possibility to perform both interventions within a reasonable time. We intent to randomise 150 participants allocated 1:1. The experimental intervention is the one-step approach. This consists of laparoscopic common bile duct exploration plus laparoscopic cholecystectomy. The control intervention is the two-step approach which consists of ERC plus sphincterotomy (first step) and subsequent laparoscopic cholecystectomy (second step). Feasibility outcomes include the proportion of eligible patients not wanting to participate, reasons for rejection to participate, difficulties during the informed consent procedure, difficulties with randomisation, difficulties with data management, difficulties with blinding patient charts and forms and difficulties with maintaining blinding for the outcome assessors. The primary pilot outcome is the proportion of participants with at least one postoperative complication according to the Clavien-Dindo score grade II and above until 90 days after randomisation. This outcome will be used for a future sample size calculation of a larger pragmatic trial. Further, a range of clinical explorative outcomes will be assessed. DISCUSSION: As no sample size is estimated in this trial, there is a risk of wrongly assessing the effect on the patient-related outcome. The surgical procedures cannot be blinded. However, blinding will be employed in all other aspects of the trial, including the establishment of a blinded outcome adjudication committee with three independent assessors. Heterogeneity in screening, randomisation, diagnostics, treatment procedures, interventions and follow-up across trial sites may cause challenges in conducting a larger pragmatic trial. To monitor inter-site differences, we have implemented a central data monitoring scheme. TRIAL REGISTRATION: ClinicalTrials.gov identification: NCT04801238 , Registered on 16 March 2021.

Family-based cognitive behavioural therapy versus family-based relaxation therapy for obsessive-compulsive disorder in children and adolescents (the TECTO trial): a statistical analysis plan for the randomised clinical trial.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder which affects up to 3% of children and adolescents. OCD in children and adolescents is generally treated with cognitive behavioural therapy (CBT), which, in more severely affected patients, can be combined with antidepressant medication. The TECTO trial aims to compare the benefits and harms of family-based CBT (FCBT) versus family-based psychoeducation/relaxation training (FPRT) in children and adolescents aged 8 to 17 years. This statistical analysis plan outlines the planned statistical analyses for the TECTO trial. METHODS: The TECTO trial is an investigator-initiated, independently funded, single-centre, parallel-group, superiority randomised clinical trial. Both groups undergo 14 sessions of 75 min each during a period of 16 weeks with either FCBT or FPRT depending on the allocation. Participants are randomised stratified by age and baseline Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) score. The primary outcome is the CY-BOCS score. Secondary outcomes are health-related quality of life assessed using KIDSCREEN-10 and adverse events assessed by the Negative Effects Questionnaire (NEQ). Primary and secondary outcomes are assessed at the end of the intervention. Continuous outcomes will be analysed using linear regression adjusted for the stratification variables and baseline value of the continuous outcome. Dichotomous outcomes will be analysed using logistic regression adjusted for the stratification variables. The statistical analyses will be carried out by two independent blinded statisticians. DISCUSSION: This statistical analysis plan includes a detailed predefined description of how data will be analysed and presented in the main publication before unblinding of study data. Statistical analysis plans limit selective reporting bias. This statistical analysis plan will increase the validity of the final trial results. TRIAL REGISTRATION: ClinicalTrials.gov NCT03595098. July 23, 2018.

Loop diuretics in adult intensive care patients with fluid overload: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

BACKGROUND: Fluid overload is a risk factor for organ dysfunction and death in intensive care unit (ICU) patients, but no guidelines exist for its management. We systematically reviewed benefits and harms of a single loop diuretic, the predominant treatment used for fluid overload in these patients. METHODS: We conducted a systematic review with meta-analysis and Trial Sequential Analysis (TSA) of a single loop diuretic vs. other interventions reported in randomised clinical trials, adhering to our published protocol, the Cochrane Handbook, and PRISMA statement. We assessed the risks of bias with the ROB2-tool and certainty of evidence with GRADE. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42020184799). RESULTS: We included 10 trials (804 participants), all at overall high risk of bias. For loop diuretics vs. placebo/no intervention, we found no difference in all-cause mortality (relative risk (RR) 0.72, 95% confidence interval (CI) 0.49-1.06; 4 trials; 359 participants; I2 = 0%; TSA-adjusted CI 0.15-3.48; very low certainty of evidence). Fewer serious adverse events were registered in the group treated with loop diuretics (RR 0.81, 95% CI 0.66-0.99; 6 trials; 476 participants; I2 = 0%; very low certainty of evidence), though contested by TSA (TSA-adjusted CI 0.55-1.20). CONCLUSIONS: The evidence is very uncertain about the effect of loop diuretics on mortality and serious adverse events in adult ICU patients with fluid overload. Loop diuretics may reduce the occurrence of these outcomes, but large randomised placebo-controlled trials at low risk of bias are needed.

Family-based cognitive behavioural therapy versus family-based relaxation therapy for obsessive-compulsive disorder in children and adolescents: protocol for a randomised clinical trial (the TECTO trial).

BACKGROUND: Cognitive behavioural therapy (CBT) is the recommended first-line treatment for children and adolescents with obsessive-compulsive disorder (OCD), but evidence concerning treatment-specific benefits and harms compared with other interventions is limited. Furthermore, high risk-of-bias in most trials prevent firm conclusions regarding the efficacy of CBT. We investigate the benefits and harms of family-based CBT (FCBT) versus family-based psychoeducation and relaxation training (FPRT) in youth with OCD in a trial designed to reduce risk-of-bias. METHODS: This is an investigator-initiated, independently funded, single-centre, parallel group superiority randomised clinical trial (RCT). Outcome assessors, data managers, statisticians, and conclusion drawers are blinded. From child and adolescent mental health services we include patients aged 8-17 years with a primary OCD diagnosis and an entry score of ≥16 on the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). We exclude patients with comorbid illness contraindicating trial participation; intelligence quotient < 70; or treatment with CBT, PRT, antidepressant or antipsychotic medication within the last 6 months prior to trial entry. Participants are randomised 1:1 to the experimental intervention (FCBT) versus the control intervention (FPRT) each consisting of 14 75-min sessions. All therapists deliver both interventions. Follow-up assessments occur in week 4, 8 and 16 (end-of-treatment). The primary outcome is OCD symptom severity assessed with CY-BOCS at end-of-trial. Secondary outcomes are quality-of-life and adverse events. Based on sample size estimation, a minimum of 128 participants (64 in each intervention group) are included. DISCUSSION: In our trial design we aim to reduce risk-of-bias, enhance generalisability, and broaden the outcome measures by: 1) conducting an investigator-initiated, independently funded RCT; 2) blinding investigators; 3) investigating a representative sample of OCD patients; 3) using an active control intervention (FPRT) to tease apart general and specific therapy effects; 4) using equal dosing of interventions and therapist supervision in both intervention groups; 5) having therapists perform both interventions decided by randomisation; 6) rating fidelity of both interventions; 7) assessing a broad range of benefits and harms with repeated measures. The primary study limitations are the risk of missing data and the inability to blind participants and therapists to the intervention. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03595098, registered July 23, 2018.

Internet based intervention (Emotion Regulation Individual Therapy for Adolescents) as add-on to treatment as usual versus treatment as usual for non-suicidal self-injury in adolescent outpatients: The TEENS randomised feasibility trial.

Background: Non-suicidal self-injury (NSSI) is common in adolescents receiving psychiatric treatment and is a significant risk factor for suicidal behavior. There are few randomised clinical trials assessing interventions for NSSI in youth, and knowledge about internet-delivered interventions is limited. Objective: We assessed the feasibility of Internet based Emotion Regulation Individual Therapy for Adolescents (ERITA) in psychiatric outpatients aged 13-17 years who engaged in NSSI. Method: A randomised clinical feasibility trial with a parallel group design. Non-suicidal self-injury engaging patients were recruited from Child and Adolescent Mental Health Outpatient Services in the Capital Region of Denmark from May to October 2020. ERITA was provided as add-on to treatment as usual (TAU). ERITA is a therapist-guided, internet-based program of emotion regulation and skills training involving a parent. The control intervention was TAU. Feasibility outcomes were the proportion who completed follow-up interviews at end of intervention; proportion of eligible patients who participated in the trial; proportion of participants completing ERITA. We further investigated relevant exploratory outcomes, including adverse risk-related events. Results: We included 30 adolescent participants, 15 in each group (ERITA vs. Treatment as usual). 90% (95% CI, 72%-97%) of the participants completed post-treatment interviews; 54% (95% CI, 40%-67%) of the eligible participants were included and randomised; and 87% (95% CI, 58%-98%) of the participants completed at least six out of 11 ERITA modules. We identified no difference for the primary exploratory clinical outcome of NSSI between the two groups. Conclusion: There are few randomised clinical trials assessing interventions for NSSI in youth, and knowledge about internet-delivered interventions is limited. Based on our results we conclude that a large-scale trial seems feasible and warranted.

Comprehensive cardiac rehabilitation for patients following infective endocarditis: results of the randomized CopenHeartIE trial.

AIMS: Infective endocarditis is a complex and highly mortal disease requiring lengthy treatment. Physical and mental deconditioning is common. Nonetheless, rehabilitation is virtually unexplored in this population. The aim of this trial was therefore to investigate the effects of cardiac rehabilitation in patients following endocarditis. METHODS AND RESULTS: In a randomized trial, adults with left-sided or cardiac device endocarditis were randomized 1:1 to 12 weeks of physical exercise training and five psycho-educational consultations (cardiac rehabilitation) vs. usual care without rehabilitation (control). Primary outcome was mental health measured by SF-36 Mental Component Summary (MCS) at 6 months. Secondary outcome was physical capacity measured by peak oxygen uptake (VO2) at 4 months. Exploratory outcomes were investigated. Low inclusion rate resulted in trial termination before reaching the target sample size. A total of 117 participants (mean age: 60 years, 81% male) were randomized to cardiac rehabilitation (n = 58) or to control (n = 59). Mental health and physical capacity at baseline were generally poor (MCS: 38.9-42.2 points, VO2 peak: 16.1-16.6 mL/kg/min). Cardiac rehabilitation compared with control showed no effect on mental health (MCS: 44.6 points vs. 48.8 points, P = 0.41) or physical capacity (VO2 peak: 19.9 mL/kg/min vs. 18.0 mL/kg/min, P = 0.09). Effects favouring the intervention were identified in exploratory outcomes including general fatigue (P = 0.005), and physical capacity as maximal power (W) (P = 0.005). Adherence to the intervention was 28%. CONCLUSIONS: Results indicate no effect of cardiac rehabilitation in patients following endocarditis; however, lack of statistical power and poor adherence render findings inconclusive. Valuable insight into patients' capabilities and safety was gained, and further investigations into rehabilitation needs and modes of delivery in this high-need population should be a future priority. REGISTRATION: The trial is registered at ClinicalTrials.gov, NCT01512615.

Guided self-determination intervention versus attention control for people with type 2 diabetes in outpatient clinics: a protocol for a randomised clinical trial.

INTRODUCTION: In the management of type 2 diabetes, autonomy-supporting interventions may be a prerequisite to achieving more long-term improvement. Preliminary evidence has shown that the guided self-determination (GSD) method might have an effect on haemoglobin A1c and diabetes distress in people with type 1 diabetes. Previous trials were at risk of uncertainty. Thus, the objective is to investigate the benefits and harms of a GSD intervention versus an attention control group intervention in adults with type 2 diabetes. METHODS AND ANALYSIS: This trial protocol is guided by the The Standard Protocol Items: Recommendations for International Trials Statement. We describe the protocol for a pragmatic randomised, dual-centre, parallel-group, superiority clinical trial testing a GSD intervention versus an attention control for people with type 2 diabetes in outpatient clinics. The participants (n=224) will be recruited from two diverse regions of Denmark. The experimental stepped-care intervention will consist of three to five GSD sessions lasting up to 1 hour with a trained GSD facilitator. The sessions will be conducted face to face, by video conference or over the telephone. The attention controls will receive three to five sessions lasting up to an hour with a communication-trained healthcare professional provided face to-face, by video conference, or over the telephone. Participants will be included if they have type 2 diabetes,>18 years old, are not pregnant. Participants will be assessed before randomisation, at 5-month, and 12-month follow-up, the latter being the primary. The primary outcome is diabetes distress. Secondary outcomes are quality of life, depressive symptoms and non-serious adverse events. Exploratory outcomes are haemoglobin A1c, motivation and serious adverse events. Data will be collected using REDCap and analysed using Stata V.16. ETHICS AND DISSEMINATION: The trial will be conducted in compliance with the protocol, the Helsinki Declaration in its latest form, International Harmonisation of Good Clinical Practice guidelines and the applicable regulatory requirement(s). The trial has been approved by the Danish Data Protection Agency (P-2020-864). The Ethics Committee of the Capital Region of Denmark reviewed the trial protocol, but exempted the trial protocol from full review (H-20003638). The results of the trial will be presented at the outpatient clinics treating people with type 2 diabetes, at national and international conferences as well as to associations for people with diabetes and their relatives. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT04601311.

Ketamine for critically ill patients with severe acute brain injury: Protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials.

INTRODUCTION: Intensive care for patients with severe acute brain injury aims both to treat the immediate consequences of the injury and to prevent and treat secondary brain injury to ensure a good functional outcome. Sedation may be used to facilitate mechanical ventilation, for treating agitation, and for controlling intracranial pressure. Ketamine is an N-methyl-D-aspartate receptor antagonist with sedative, analgesic, and potentially neuroprotective properties. We describe a protocol for a systematic review of randomised clinical trials assessing the beneficial and harmful effects of ketamine for patients with severe acute brain injury. METHODS AND ANALYSIS: We will systematically search international databases for randomised clinical trials, including CENTRAL, MEDLINE, Embase, and trial registries. Two authors will independently review and select trials for inclusion, and extract data. We will compare ketamine by any regimen versus placebo, no intervention, or other sedatives or analgesics for patients with severe acute brain injury. The primary outcomes will be functional outcome at maximal follow up, quality of life, and serious adverse events. We will also assess secondary and exploratory outcomes. The extracted data will be analysed using Review Manager and Trials Sequential Analysis. Evidence certainty will be graded using GRADE. ETHICS AND DISSEMINATION: The results of the systematic review will be disseminated through peer-reviewed publication. With the review, we hope to inform future randomised clinical trials and improve clinical practice. PROSPERO NO: CRD42021210447.

A screening method to spot biomarkers that may warn of serious events in a chronic disease - illustrated by cardiological CLARICOR trial data.

OBJECTIVES: To develop a crude screening method for detecting biomarkers which frequently exhibit a rise (or fall) in level prior to a serious event (e.g. a stroke) in patients with a chronic disease, signalling that the biomarker may have an alarm-raising or prognostic potential. The subsequent assessment of the marker's clinical utility requires costly, difficult longitudinal studies. Therefore, initial screening of candidate-biomarkers is desirable. METHODS: The method exploits a cohort of patients with biomarkers measured at entry and with recording of first serious event during follow-up. Copying those individual records onto a common timeline where a specific event occurs on the same day (Day 0) for all patients, the baseline biomarker level, when plotted against the patient's entry time on the revised timeline, will have a positive (negative) regression slope if biomarker levels generally rise (decline) the closer one gets to the event. As an example, we study 1,958 placebo-treated patients with stable coronary artery disease followed for nine years in the CLARICOR trial (NCT00121550), examining 11 newer biomarkers. RESULTS: Rising average serum levels of cardiac troponin T and of N-terminal pro-B-type natriuretic peptide were seen prior to a fatal cardiovascular outcome. C-reactive protein rose prior to non-cardiovascular death. Glomerular filtration rate, seven lipoproteins, and nine newer cardiological biomarkers did not show convincing changes. CONCLUSIONS: For early detection of biomarkers with an alarm-raising potential in chronic diseases, we proposed the described easy procedure. Using only baseline biomarker values and clinical course of participants with coronary heart disease, we identified the same cardiovascular biomarkers as those previously found containing prognostic information using longitudinal or survival analysis.

An Internet-based emotion regulation intervention versus no intervention for non-suicidal self-injury in adolescents: a statistical analysis plan for a feasibility randomised clinical trial.

BACKGROUND: Non-suicidal self-injury (NSSI) has a lifetime prevalence of 17% in adolescents in the general population and up to 74% in adolescents with psychiatric disorders. NSSI is one of the most important predictors of later suicidal behaviour and death by suicide. The TEENS feasibility trial was initiated to assess the feasibility and safety of Internet-based Emotion Regulation Individual Therapy for Adolescents (ERITA) as an add-on to treatment as usual in 13-17-year-old patients with NSSI referred to the Child and Adolescent Mental Health Services. METHODS: The TEENS feasibility trial is a randomised clinical trial with a parallel-group design. The trial intervention is an 11-week online therapy which is tested as an add-on to treatment as usual versus treatment as usual. The primary feasibility outcomes are the fraction of participants who (1) completed 12 weeks of follow-up interview or assessment, (2) consented to inclusion and randomisation out of all eligible participants, and (3) were compliant with the experimental intervention, assessed as completion of at least six out of eleven modules in the programme. Since this is a feasibility trial, we did not predefine a required sample size. The exploratory clinical outcome, the frequency of NSSI episodes, assessed using Deliberate Self-Harm Inventory - Youth version (DSHI-Y), at the end of intervention, is planned to be the future primary outcome in a larger pragmatic definitive randomised clinical trial. After completion of the feasibility trial, blinded data will be analysed by two independent statisticians blinded to the intervention, where 'A' and 'B' refer to the two groups. A third party will compare these reports, and discrepancies will be discussed. The statistical report with the analyses chosen for the manuscript is being tracked using a version control system, and both statistical reports will be published as a supplementary material. Based on the final statistical report, two blinded conclusions will be drawn by the steering group. DISCUSSION: We present a pre-defined statistical analysis plan for the TEENS feasibility trial, which limits bias, p-hacking, data-driven interpretations. This statistical analysis plan is accompanied by a pre-programmed version-controlled statistical report with simulated data, which increases transparency and reproducibility. TRIAL REGISTRATION: ClinicalTrials.gov NCT04243603 . Registered on 28 January 2020.

Exercise-based cardiac rehabilitation for adults after heart valve surgery.

BACKGROUND: The impact of exercise-based cardiac rehabilitation (CR) following heart valve surgery is uncertain. We conducted an update of this systematic review and a meta-analysis to assess randomised controlled trial evidence for the use of exercise-based CR following heart valve surgery. OBJECTIVES: To assess the benefits and harms of exercise-based CR compared with no exercise training in adults following heart valve surgery or repair, including both percutaneous and surgical procedures. We considered CR programmes consisting of exercise training with or without another intervention (such as an intervention with a psycho-educational component). SEARCH METHODS: We searched the Cochrane Central Register of Clinical Trials (CENTRAL), in the Cochrane Library; MEDLINE (Ovid); Embase (Ovid); the Cumulative Index to Nursing and Allied Health Literature (CINAHL; EBSCO); PsycINFO (Ovid); Latin American Caribbean Health Sciences Literature (LILACS; Bireme); and Conference Proceedings Citation Index-Science (CPCI-S) on the Web of Science (Clarivate Analytics) on 10 January 2020. We searched for ongoing trials from ClinicalTrials.gov, Clinical-trials.com, and the World Health Organization International Clinical Trials Registry Platform on 15 May 2020. SELECTION CRITERIA: We included randomised controlled trials that compared exercise-based CR interventions with no exercise training. Trial participants comprised adults aged 18 years or older who had undergone heart valve surgery for heart valve disease (from any cause) and had received heart valve replacement or heart valve repair. Both percutaneous and surgical procedures were included. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. We assessed the risk of systematic errors ('bias') by evaluating risk domains using the 'Risk of bias' (RoB2) tool. We assessed clinical and statistical heterogeneity. We performed meta-analyses using both fixed-effect and random-effects models. We used the GRADE approach to assess the quality of evidence for primary outcomes (all-cause mortality, all-cause hospitalisation, and health-related quality of life). MAIN RESULTS: We included six trials with a total of 364 participants who have had open or percutaneous heart valve surgery. For this updated review, we identified four additional trials (216 participants). One trial had an overall low risk of bias, and we classified the remaining five trials as having some concerns. Follow-up ranged across included trials from 3 to 24 months. Based on data at longest follow-up, a total of nine participants died: 4 CR versus 5 control (relative risk (RR) 0.83, 95% confidence interval (CI) 0.26 to 2.68; 2 trials, 131 participants; GRADE quality of evidence very low). No trials reported on cardiovascular mortality. One trial reported one cardiac-related hospitalisation in the CR group and none in the control group (RR 2.72, 95% CI 0.11 to 65.56; 1 trial, 122 participants; GRADE quality of evidence very low). We are uncertain about health-related quality of life at completion of the intervention in CR compared to control (Short Form (SF)-12/36 mental component: mean difference (MD) 1.28, 95% CI -1.60 to 4.16; 2 trials, 150 participants; GRADE quality of evidence very low; and SF-12/36 physical component: MD 2.99, 95% CI -5.24 to 11.21; 2 trials, 150 participants; GRADE quality of evidence very low), or at longest follow-up (SF-12/36 mental component: MD -1.45, 95% CI -4.70 to 1.80; 2 trials, 139 participants; GRADE quality of evidence very low; and SF-12/36 physical component: MD -0.87, 95% CI -3.57 to 1.83; 2 trials, 139 participants; GRADE quality of evidence very low).  AUTHORS' CONCLUSIONS: Due to lack of evidence and the very low quality of available evidence, this updated review is uncertain about the impact of exercise-CR in this population in terms of mortality, hospitalisation, and health-related quality of life. High-quality (low risk of bias) evidence on the impact of CR is needed to inform clinical guidelines and routine practice.

An internet-based emotion regulation intervention versus no intervention for nonsuicidal self-injury in adolescents: study protocol for a feasibility trial.

BACKGROUND: Non-suicidal self-injury (NSSI) has gained increased attention in recent years due to increased prevalence, especially among adolescents. Evidence-based interventions for NSSI are sparse. Emotion regulation individual therapy for adolescents (ERITA) is an online intervention that needs investigation. Non-randomised studies suggest ERITA improves emotion regulations skills and reduces NSSI frequency. Before conducting a large pragmatic randomised clinical trial, we aim to investigate the feasibility of ERITA in Denmark. METHODS: A randomised, parallel group feasibility trial comparing ERITA as add on to treatment as usual versus treatment as usual in 30 adolescents age 13-17 years with recurrent NSSI referred to outpatient clinics in The Child and Adolescent Mental Health Services in the Capital Region of Denmark. Feasibility outcomes are (1) completion of follow-up, (2) the fraction of eligible participants who consent to inclusion and randomisation and (3) compliance with the intervention. Clinical outcomes such as self-injury frequency and the ability to regulate emotions will be investigated exploratorily. DISCUSSION: Internet-based interventions are assumed to be appealing to adolescents by being easily accessible and easy to navigate by tech natives. Disclosure of self-injury behaviour may be facilitated by an online intervention. The evidence for self-injury specific treatment needs to be extended but prior to a large clinical trial, the feasibility of methods and procedures must be assessed. TRIAL REGISTRATION: ClinicalTrials.Gov Identifier: NCT04243603 .

Self-determination theory interventions versus usual care in people with diabetes: a protocol for a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Existing self-management and behavioural interventions for diabetes vary widely in their content, and their sustained long-term effectiveness is uncertain. Autonomy supporting interventions may be a prerequisite to achieve 'real life' patient engagement and more long-term improvement through shared decision-making and collaborative goal setting. Autonomy supportive interventions aim to promote that the person with diabetes' motivation is autonomous meaning that the person strives for goals they themselves truly believe in and value. This is the goal of self-determination theory and guided self-determination interventions. Self-determination theory has been reviewed but without assessing both benefits and harms and accounting for the risk of random errors using trial sequential analysis. The guided self-determination has not yet been systematically reviewed. The aim of this protocol is to investigate the benefits and harms of self-determination theory-based interventions versus usual care in adults with diabetes. METHODS/DESIGN: We will conduct the systematic review following The Cochrane Collaboration guidelines. This protocol is reported according to the PRISMA checklist. A comprehensive search will be undertaken in the CENTRAL, MEDLINE, EMBASE, LILACS, PsycINFO, SCI-EXPANDED, CINAHL, SSCI, CPCI-S and CPCI-SSH to identify relevant trials. We will include randomised clinical trials assessing interventions theoretically based on guided self-determination or self-determination theory provided face-to-face or digitally by any healthcare professional in any setting. The primary outcomes will be quality of life, mortality, and serious adverse events. The secondary will be diabetes distress, depressive symptoms and adverse events not considered serious. Exploratory outcomes will be glycated haemoglobin and motivation. Outcomes will be assessed at the end of the intervention and at maximum follow-up. The analyses will be performed using Stata version 16 and trial sequential analysis. Two authors will independently screen, extract data from and perform risk of bias assessment of included studies using the Cochrane risk of bias tool. Certainty of the evidence will be assessed by GRADE. DISCUSSION: Self-determination theory interventions aim to promote a more autonomous patient engagement and are commonly used. It is therefore needed to evaluate the benefit and harms according to existing trials. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020181144.

Early specialised palliative care: interventions, symptoms, problems.

BACKGROUND: Few studies have investigated the content of interventions provided in early specialised palliative care (SPC). OBJECTIVES: To characterise the content of interventions delivered in early SPC in the Danish Palliative Care Trial (DanPaCT), a multicentre trial with six participating sites. METHODS: A retrospective qualitative and quantitative study coding all new interventions initiated by the palliative teams and documented in the medical records during the 8-week study period of DanPaCT. Interventions were categorised according to (a) symptom/problem prompting the intervention, (b) type of intervention and (c) professional(s) providing the intervention. RESULTS: In total, 145 patients were randomised to the SPC teams. According to the medical records, patients received a median of 3.5 (range 0-22) new interventions in the 8-week intervention-period from the palliative teams. For 24 (18%) of the patients there was no documented interventions in the medical records. The most frequent symptom/problems treated were pain, (100 interventions; 20% of interventions given) and impaired physical function (62; 13% of interventions given). The most frequent type of intervention was pharmacological (232; 42% of interventions given). CONCLUSIONS: This is one of the first studies to meticulously investigate the content of interventions documented in the medical records for patients receiving early SPC. Diverse symptoms were treated with many different interventions. However, a relatively low number of interventions were documented. This may explain the lack of effect in DanPaCT but also questions whether all interventions were adequately documented TRIAL REGISTRATION NUMBER: NCT01348048.

Psychotherapy versus treatment as usual and other control interventions in children and adolescents with overweight and obesity: a protocol for systematic review with meta-analysis and Trial Sequential Analysis.

INTRODUCTION: The prevalence of children with overweight and obesity is increasing worldwide. Multicomponent interventions incorporating diet, physical activity and behavioural change have shown limited improvement to body mass index (BMI). However, the impact of psychotherapy is poorly explored. This systematic review aims to assess the effects of psychotherapeutic approaches for children with all degrees of overweight. METHODS AND ANALYSIS: We will include randomised clinical trials involving children and adolescents between 0 and 18 years with overweight and obesity, irrespective of publication type, year, status or language up to April 2020. Psychotherapy will be compared with no intervention; wait list control; treatment as usual; sham psychotherapy or pharmaceutical placebo. The following databases will be searched: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, MEDLINE, Embase, PsycINFO, PubMed, Web of Science, CINAHL and LILACS. Primary outcomes will be BMI z-score, quality of life measured by a validated scale and proportion of patients with serious adverse events. Secondary outcomes will be body weight, self-esteem, anxiety, depression and proportion of patients with non-serious adverse events. Exploratory outcomes will be body fat, muscle mass and serious adverse events. Study inclusion, data extraction and bias risk assessments will be conducted independently by at least two authors. We will assess risk of bias according to Cochrane guidelines and the Cochrane Effective Practice and Organisation of Care guidance. We will use meta-analysis and control risks of random errors with Trial Sequential Analysis. The quality of the evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation Tool. The systematic review will be reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane guidelines. ETHICS AND DISSEMINATION: As individual patient data will not be included, we do not require ethics approval. This review will be published in a peer review journal. PROSPERO REGISTRATION NUMBER: CRD42018086458.

Early head-up mobilisation versus standard care for patients with severe acquired brain injury: A systematic review with meta-analysis and Trial Sequential Analysis.

BACKGROUND: There is increasing focus on earlier rehabilitation in patients with traumatic or hypoxic brain injury or stroke. This systematic review evaluates the benefits and harms of early head-up mobilisation versus standard care in patients with severe acquired brain injury. METHODS: We searched Medline, CENTRAL, EMBASE, four other databases and 13 selected clinical trial registries until April 2020. Eligible randomised clinical trials compared early head-up mobilisation versus standard care in patients with severe acquired brain injury and were analysed conducting random- and fixed-effects meta-analyses and Trial Sequential Analysis (TSA). Certainty of evidence was assessed by GRADE. MAIN RESULTS: We identified four randomised clinical trials (total n = 385 patients) with severe acquired brain injury (stroke 86% and traumatic brain injury 13%). Two trials were at low risk and two at high risk of bias. We found no evidence of a difference between early mobilisation vs. standard care on mortality or poor functional outcome at end of the intervention (relative risk (RR) 1.19, 95% CI 0.93 to 1.53; I2 0%; very low certainty) or at maximal follow-up (RR 1.03, 95% CI 0.89 to 1.21; I2 0%; very low certainty). We found evidence against an effect on quality of life at maximal follow-up. The proportion of patients with at least one serious adverse event did not differ at end of intervention or at maximal follow-up. For most comparisons, TSA suggested that further trials are needed. CONCLUSIONS: We found no evidence of a difference between early mobilisation versus standard care for patients with severe acquired brain injury. Early mobilisation appeared not to exert a major impact on quality of life. This systematic review highlights the insufficient evidence in patients with severe brain injury, and no firm conclusions can be drawn from these data. TRIAL REGISTRATION: Protocol uploaded to PROSPERO: April 2018 (revised October 2018, CRD42018088790).