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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, I 2  = 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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Chronic pain in adults is a frequent clinical symptom with a significant impact on patient well-being. Therefore, sufficient pain management is of utmost importance. While tramadol is a commonly used pain medication, the quality of evidence supporting its use has been questioned considering the observed adverse events. Our objective will be to assess the benefits and harms of tramadol compared with placebo or no intervention for chronic pain., Methods/design: We will conduct a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis to assess the beneficial and harmful effects of tramadol in any dose, formulation, or duration. We will accept placebo or no intervention as control interventions. We will include adult participants with any type of chronic pain, including cancer-related pain. We will systematically search the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, and BIOSIS for relevant literature. We will follow the recommendations by Cochrane and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The risk of systematic errors ('bias') and random errors ('play of chance') will be assessed. The certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach., Discussion: Although tramadol is often being used to manage chronic pain conditions, the beneficial and harmful effects of this intervention are unknown. The present review will systematically assess the current evidence on the benefits and harms of tramadol versus placebo or no intervention to inform clinical practice and future research., Systematic Review Registration: PROSPERO CRD42019140334., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Major depressive disorder causes a great burden on patients and societies. Venlafaxine and mirtazapine are commonly prescribed as second-line treatment for patients with major depressive disorder worldwide. Previous systematic reviews have concluded that venlafaxine and mirtazapine reduce depressive symptoms, but the effects seem small and may not be important to the average patient. Moreover, previous reviews have not systematically assessed the occurrence of adverse events. Therefore, we aim to investigate the risks of adverse events with venlafaxine or mirtazapine versus 'active placebo', placebo, or no intervention for adults with major depressive disorder in two separate systematic reviews., Methods: This is a protocol for two systematic reviews with meta-analysis and Trial Sequential Analysis. The assessments of the effects of venlafaxine or mirtazapine will be reported in two separate reviews. The protocol is reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols, risk of bias will be assessed with the Cochrane risk-of-bias tool version 2, clinical significance will be assessed using our eight-step procedure, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. We will search for published and unpublished trials in major medical databases and trial registers. Two review authors will independently screen the results from the literature searches, extract data, and assess risk of bias. We will include published or unpublished randomised clinical trial comparing venlafaxine or mirtazapine with 'active placebo', placebo, or no intervention for adults with major depressive disorder. The primary outcomes will be suicides or suicide attempts, serious adverse events, and non-serious adverse events. Exploratory outcomes will include depressive symptoms, quality of life, and individual adverse events. If feasible, we will assess the intervention effects using random-effects and fixed-effect meta-analyses., Discussion: Venlafaxine and mirtazapine are frequently used as second-line treatment of major depressive disorder worldwide. There is a need for a thorough systematic review to provide the necessary background for weighing the benefits against the harms. This review will ultimately inform best practice in the treatment of major depressive disorder., Systematic Review Registration: PROSPERO CRD42022315395., (© 2023. The Author(s).)

Background: Deep brain stimulation has been used since the 1980s for neurological disorders and the USA and Europe have now approved it for Parkinson's disease, essential tremor, dystonia, and epilepsy. Previous reviews have assessed the effects of deep brain stimulation on different neurological disorders. These reviews all had methodological limitations., Methods: This is a protocol for a systematic review based on searches of major medical databases (e.g. MEDLINE, EMBASE, CENTRAL) and clinical trial registries. Two review authors will independently extract data and conduct risk of bias assessment. We will include published and unpublished randomised clinical trial comparing deep brain stimulation versus no intervention, usual care, sham stimulation, medical treatment, or resective surgery for Parkinson's disease, essential tremor, dystonia, or epilepsy. The effects of deep brain stimulation will be analysed separately for each of the different diagnoses. Primary outcomes will be all-cause mortality, disease-specific symptoms, and serious adverse events. Secondary outcomes will be quality of life, depressive symptoms, executive functioning, level of functioning, and non-serious adverse events. Data will be analysed using fixed-effect and random-effects meta-analyses and Trial Sequential Analysis. Risk of bias will be assessed with the Cochrane Risk of Bias tool-version 2, an eight-step procedure to assess if the thresholds for clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations (GRADE)., Discussion: Deep brain stimulation is increasingly being used for different neurological diseases, and the effects are unclear based on previous evidence. There is a need for a comprehensive systematic review of the current evidence. This review will provide the necessary background for weighing the benefits against the harms when assessing deep brain stimulation as intervention for individual neurological disorders., Systematic Review Registration: PROSPERO 306,556., (© 2022. The Author(s).)

Background: Early onset fetal growth restriction secondary to placental insufficiency can lead to severe maternal and neonatal morbidity and mortality. Pre-clinical studies and a few small randomised clinical trials have suggested that phosphodiesterase type 5 (PDE-5) inhibitors may have protective effects against placental insufficiency in this context; however, robust evidence is lacking. The STRIDER Consortium conducted four randomised trials to investigate the use of a PDE-5 inhibitor, sildenafil, for the treatment of early onset fetal growth restriction. We present a protocol for the pre-planned systematic review with individual participant data meta-analysis, aggregate meta-analysis, and trial sequential analysis of these and other eligible trials. The main objective of this study will be to evaluate the effects of PDE-5 inhibitors on neonatal morbidity compared with placebo or no intervention among pregnancies with fetal growth restriction., Methods: We will search the following electronic databases with no language or date restrictions: OVID MEDLINE, OVID EMBASE, the Cochrane Controlled Register of Trials (CENTRAL), and the clinical trial registers Clinicaltrials.gov and World Health Organisation International Clinical Trials Registry Platform (ICTRP). We will identify randomised trials of PDE-5 inhibitors in singleton pregnancies with growth restriction. Two reviewers will independently screen all citations, full-text articles, and abstract data. Our primary outcome will be infant survival without evidence of serious adverse neonatal outcome. Secondary outcomes will include gestational age at birth and birth weight z-scores. We will assess bias using the Cochrane Risk of Bias 2 tool. We will conduct aggregate meta-analysis using fixed and random effects models, Trial Sequential Analysis, and individual participant data meta-analysis using one- and two-stage approaches. The certainty of evidence will be assessed with GRADE., Discussion: This pre-defined protocol will minimise bias during analysis and interpretation of results, toward the goal of providing robust evidence regarding the use of PDE-5 inhibitors for the treatment of early onset fetal growth restriction., Systematic Review Registration: PROSPERO (CRD42017069688)., (© 2021. The Author(s).)

Background: Major depressive disorder is a common psychiatric disorder causing great burden on patients and societies. Tricyclic antidepressants are frequently used worldwide to treat patients with major depressive disorder. It has repeatedly been shown that tricyclic antidepressants reduce depressive symptoms with a statistically significant effect, but the effect is small and of questionable clinical importance. Moreover, the beneficial and harmful effects of all types of tricyclic antidepressants have not previously been systematically assessed. Therefore, we aim to investigate the beneficial and harmful effects of tricyclic antidepressants versus 'active placebo', placebo or no intervention for adults with major depressive disorder., Methods: This is a protocol for a systematic review with meta-analysis that will be reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols, bias will be assessed with the Cochrane Risk of Bias tool-version 2, our eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, Trial Sequential Analysis will be conducted to control random errors and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. To identify relevant trials, we will search both for published and unpublished trials in major medical databases and trial registers, such as CENTRAL, MEDLINE, EMBASE and ClinicalTrials.gov from their inception to 12 May 2021. Clinical study reports will be applied for from regulatory authorities and pharmaceutical companies. Two review authors will independently screen the results from the literature searches, extract data and perform risk of bias assessment. We will include any published or unpublished randomised clinical trial comparing tricyclic antidepressants with 'active placebo', placebo or no intervention for adults with major depressive disorder. The following interventions will be assessed: amineptine, amitriptyline, amoxapine, butriptyline, cianopramine, clomipramine, desipramine, demexiptiline, dibenzepin, dosulepin, dothiepin, doxepin, imipramine, iprindole, lofepramine, maprotiline, melitracen, metapramine, nortriptyline, noxiptiline, opipramol, protriptyline, tianeptine, trimipramine and quinupramine. Primary outcomes will be depressive symptoms, serious adverse events and quality of life. Secondary outcomes will be suicide or suicide-attempts and non-serious adverse events. If feasible, we will assess the intervention effects using random-effects and fixed-effect meta-analyses., Discussion: Tricyclic antidepressants are recommended by clinical guidelines and frequently used worldwide in the treatment of major depressive disorder. There is a need for a thorough systematic review to provide the necessary background for weighing the benefits against the harms. This review will ultimately inform best practice in the treatment of major depressive disorder., Systematic Review Registration: PROSPERO CRD42021226161 ., (© 2021. The Author(s).)

Background: Major depression significantly impairs quality of life, increases the risk of suicide, and poses tremendous economic burden on individuals and societies. Duloxetine, a serotonin norepinephrine reuptake inhibitor, is a widely prescribed antidepressant. The effects of duloxetine have, however, not been sufficiently assessed in earlier systematic reviews and meta-analyses., Methods/design: A systematic review will be performed including randomised clinical trials comparing duloxetine with 'active' placebo, placebo or no intervention for adults with major depressive disorder. Bias domains will be assessed, an eight-step procedure will be used to assess if the thresholds for clinical significance are crossed. We will conduct meta-analyses. Trial sequential analysis will be conducted to control random errors, and the certainty of the evidence will be assessed using GRADE. To identify relevant trials, we will search Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, PsycINFO, Science Citation Index Expanded, Social Sciences Citation Index, Conference Proceedings Citation Index-Science and Conference Proceedings Citation Index-Social Science & Humanities. We will also search Chinese databases and Google Scholar. We will search all databases from their inception to the present. Two review authors will independently extract data and perform risk of bias assessment. Primary outcomes will be the difference in mean depression scores on Hamilton Depression Rating Scale between the intervention and control groups and serious adverse events. Secondary outcomes will be suicide, suicide-attempts, suicidal ideation, quality of life and non-serious adverse events., Discussion: No former systematic review has systematically assessed the beneficial and harmful effects of duloxetine taking into account both the risks of random errors and the risks of systematic errors. Our review will help clinicians weigh the benefits of prescribing duloxetine against its adverse effects and make informed decisions., Systematic Review Registration: PROSPERO 2016 CRD42016053931.

Background: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide. Antidepressants are frequently used to treat major depressive disorder. It has been shown repeatedly that antidepressants seem to reduce depressive symptoms with a statistically significant effect, but the clinical importance of the effect sizes seems questionable. Both beneficial and harmful effects of antidepressants have not previously been sufficiently assessed. The main objective of this review will be to evaluate the beneficial and harmful effects of antidepressants versus placebo, 'active placebo', or no intervention for adults with major depressive disorder., Methods/design: A systematic review with meta-analysis will be reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), bias will be assessed with the Cochrane Risk of Bias tool-version 2 (ROB2), our eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, Trial Sequential Analysis will be conducted to control for random errors, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. To identify relevant trials, we will search both for published and unpublished trials in major medical databases from their inception to the present. Clinical study reports will be obtained from regulatory authorities and pharmaceutical companies. Two review authors will independently screen the results of the literature searches, extract data, and perform risk of bias assessment. We will include any published or unpublished randomised clinical trial comparing one or more antidepressants with placebo, 'active placebo', or no intervention for adults with major depressive disorder. The following active agents will be included: agomelatine, amineptine, amitriptyline, bupropion, butriptyline, cianopramine, citalopram, clomipramine, dapoxetine, demexiptiline, desipramine, desvenlafaxine, dibenzepin, dosulepin, dothiepin, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iprindole, levomilnacipran, lofepramine, maprotiline, melitracen, metapramine, milnacipran, mirtazapine, nefazodone, nortriptyline, noxiptiline, opipramol, paroxetine, protriptyline, quinupramine, reboxetine, sertraline, trazodone, tianeptine, trimipramine, venlafaxine, vilazodone, and vortioxetine. Primary outcomes will be depressive symptoms, serious adverse events, and quality of life. Secondary outcomes will be suicide or suicide attempt, suicidal ideation, and non-serious adverse events., Discussion: As antidepressants are commonly used to treat major depressive disorder in adults, a systematic review evaluating their beneficial and harmful effects is urgently needed. This review will inform best practice in treatment and clinical research of this highly prevalent and burdensome disorder., Systematic Review Registration: PROSPERO CRD42020220279.

Background: Multiple clinical conditions are associated with cerebral hypoxia/ischaemia and thereby an increased risk of hypoxic-ischaemic brain injury. Cerebral near-infrared spectroscopy monitoring (NIRS) is a tool to monitor brain oxygenation and perfusion, and the clinical uptake of NIRS has expanded over recent years. Specifically, NIRS is used in the neonatal, paediatric, and adult perioperative and intensive care settings. However, the available literature suggests that clinical benefits and harms of cerebral NIRS monitoring are uncertain. As rates of clinically significant hypoxic-ischaemic brain injuries are typically low, it is difficult for randomised clinical trials to capture a sufficiently large number of events to evaluate the clinical effect of cerebral NIRS monitoring, when focusing on specific clinical settings. The aim of this systematic review will be to evaluate the benefits and harms of clinical care with access to cerebral NIRS monitoring versus clinical care without cerebral NIRS monitoring in children and adults across all clinical settings., Methods: We will conduct a systematic review with meta-analysis and trial sequential analysis. We will only include randomised clinical trials. The primary outcomes are all-cause mortality, moderate or severe persistent cognitive or neurological deficit, and proportion of participants with one or more serious adverse events. We will search CENTRAL, EMBASE, MEDLINE, and the Science Citation Index Expanded from their inception and onwards. Two reviewers will independently screen all citations, full-text articles, and extract data. The risk of bias will be appraised using the Cochrane risk of bias tool version 2.0. If feasible, we will conduct both random-effects meta-analysis and fixed-effect meta-analysis of outcome data. Additional analysis will be conducted to explore the potential sources of heterogeneity (e.g. risk of bias, clinical setting)., Discussion: As we include trials across multiple clinical settings, there is an increased probability of reaching a sufficient information size. However, heterogeneity between the included trials may impair our ability to interpret results to specific clinical settings. In this situation, we may have to depend on subgroup analyses with inherent increased risks of type I and II errors., Systematic Review Registration: PROSPERO CRD42020202986 . This systematic review protocol has been submitted for registration in the International Prospective Register of Systematic Reviews (PROSPERO) (http://www.crd.york.ac.uk/prospero) on the 12th of October 2020 and published on the 12th of November 2020 (registration ID CRD42020202986 ).

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.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) which has rapidly spread worldwide. Several human randomized clinical trials assessing potential vaccines are currently underway. There is an urgent need for a living systematic review that continuously assesses the beneficial and harmful effects of all available vaccines for COVID-19., Methods/design: We will conduct a living systematic review based on searches of major medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify relevant randomized clinical trials. We will update the literature search once a week to continuously assess if new evidence is available. Two review authors will independently extract data and conduct risk of bias assessments. We will include randomized clinical trials comparing any vaccine aiming to prevent COVID-19 (including but not limited to messenger RNA; DNA; non-replicating viral vector; replicating viral vector; inactivated virus; protein subunit; dendritic cell; other vaccines) with any comparator (placebo; "active placebo;" no intervention; standard care; an "active" intervention; another vaccine for COVID-19) for participants in all age groups. Primary outcomes will be all-cause mortality; a diagnosis of COVID-19; and serious adverse events. Secondary outcomes will be quality of life and non-serious adverse events. The living systematic review will include aggregate data meta-analyses, trial sequential analyses, network meta-analyses, and individual patient data meta-analyses. Within-study bias will be assessed using Cochrane risk of bias tool. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) and Confidence in Network Meta-Analysis (CINeMA) approaches will be used to assess certainty of evidence. Observational studies describing harms identified during the search for trials will also be included and described and analyzed separately., Discussion: COVID-19 has become a pandemic with substantial mortality. A living systematic review assessing the beneficial and harmful effects of different vaccines is urgently needed. This living systematic review will regularly inform best practice in vaccine prevention and clinical research of this highly prevalent disease., Systematic Review Registration: PROSPERO CRD42020196492.

Background: COVID-19 is a rapidly spreading virus infection that has quickly caused extensive burden to individual, families, countries, and the globe. No intervention has yet been proven effective for the treatment of COVID-19. Some randomized clinical trials assessing the effects of different drugs have been published, and more are currently underway. There is an urgent need for a living, dynamic systematic review that continuously evaluates the beneficial and harmful effects of all available interventions for COVID-19., Methods/design: We will conduct a living systematic review based on searches of major medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify relevant randomized clinical trials. We will update the literature search once a week to continuously assess if new evidence is available. Two review authors will independently extract data and perform risk of bias assessment. We will include randomized clinical trials comparing any intervention for the treatment of COVID-19 (e.g., pharmacological interventions, fluid therapy, invasive or noninvasive ventilation, or similar interventions) with any comparator (e.g., an "active" comparator, standard care, placebo, no intervention, or "active placebo") for participants in all age groups with a diagnosis of COVID-19. Primary outcomes will be all-cause mortality and serious adverse events. Secondary outcomes will be admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. The living systematic review will include aggregate data meta-analyses, Trial Sequential Analyses, network meta-analysis, and individual patient data meta-analyses. Risk of bias will be assessed with domains, an eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations (GRADE)., Discussion: COVID-19 has become a pandemic with substantial mortality. A living systematic review evaluating the beneficial and harmful effects of pharmacological and other interventions is urgently needed. This review will continuously inform best practice in treatment and clinical research of this highly prevalent disease., Systematic Review Registration: PROSPERO CRD42020178787.

Background: The prevalence of overweight is increasing worldwide in children. Multi-component interventions incorporating diet, physical activity, and behavioural change have been shown to reduce body mass index (BMI). Whilst many children have their own smartphone, the clinical effects of using smartphone applications (apps) for overweight are unknown. This systematic review aims to ascertain the effects of mHealth apps in children with overweight., Methods: We will include randomised clinical trials irrespective of publication type, year, status, or language. Children between 0 and 18 years with overweight will be included. We will compare apps targeting overweight versus sham app, no app, or usual intervention. No distinction about operative system will be considered (i.e. Android, iOS, and Window Mobile will be included). The following databases will be searched: The Cochrane Library, Excerpta Medica database (Embase), PsycINFO, PubMed, IEEE Explore, Web of Science, CINAHL, and LILACS. Primary outcomes will be body weight, quality of life, and serious adverse event. Secondary outcomes will be self-efficacy, anxiety, depression, and adverse event not considered serious. Trial inclusion, data extraction, and bias risk assessment will be conducted independently by at least two authors. We will assess risk of bias through eight domains 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 (GRADE)., Discussion: We will provide evidence of the beneficial and harmful effects of smartphone apps for children with overweight and highlight any gaps in the evidence in order to shape future potential interventions. By only including randomised clinical trials, we know that we bias our review towards benefits., Systematic Review Registration: PROSPERO CRD42019120210.

Background: Hypertension, type 2 diabetes mellitus and cardiovascular disease are among the leading causes of mortality globally. Exercise is one of the commonly recommended interventions/preventions for hypertension, type 2 diabetes mellitus and cardiovascular disease. However, the previous reviews have shown conflicting evidence on the effects of exercise. Our objective is to assess the beneficial and harmful effects of adding exercise to usual care for people with hypertension, type 2 diabetes mellitus and/or cardiovascular disease., Methods: This protocol for a systematic review was undertaken using the recommendations of The Cochrane Collaboration, the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) and the eight-step assessment procedure suggested by Jakobsen et al. We plan to include all relevant randomised clinical trials and cluster-randomised trials assessing the effects of adding exercise to usual care for people with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP) and BIOSIS. We will systematically assess the risks of random errors using Trial Sequential Analysis as well as risks of bias of all included trials. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE)., Discussion: The present systematic review will have the potential to aid patients, clinicians and decision-makers recommending exercise and thereby, benefit patients with hypertension, type 2 diabetes mellitus and/or cardiovascular disease., Systematic Review Registration: PROSPERO CRD42019142313.

Background: Sepsis is a major cause of morbidity and mortality among neonates and infants. Antibiotics are a central part of the first line treatment for sepsis in neonatal intensive care units worldwide. However, the evidence on the clinical effects of the commonly used antibiotic regimens for sepsis in neonates remains scarce. This systematic review aims to assess the efficacy and harms of antibiotic regimens for neonatal sepsis., Methods: Electronic searches will be conducted in MEDLINE, Embase, The Cochrane Library, CINAHL, ZETOC and clinical trial registries (clinicaltrials.gov and ISRCTN). We will include randomised controlled trials of different antibiotic regimens for sepsis of neonates and infants. Eligible interventions will be any antibiotic regimen. Two reviewers will independently screen, select, and extract data. The methodological quality of individual studies will be appraised following Cochrane methodology. Primary outcomes will be 'all-cause mortality' and 'serious adverse events'. Secondary outcomes will be 'need for respiratory support', 'need for circulatory support', 'neurodevelopmental impairment', ototoxicity, nephrotoxicity and necrotizing enterocolitis. We plan to perform a meta-analysis with trial sequential analysis., Discussion: This is the study protocol for a systematic review on the effects of different antibiotic regimens for neonatal sepsis. The results of this systematic review intent to adequately inform stakeholders or health care professionals in the field of neonatal sepsis, and to aid appropriate development of treatment guidelines., Systematic Review Registration: PROSPERO reference number: CRD42019134300.

Background: Heart failure is a highly prevalent disease with a global prevalence of 37 million, and the prevalence is increasing. Patients with heart failure are at an increased risk of death and morbidity. Traditionally, patients with heart failure have been treated with a beta-blocker in addition to an inhibitor of the renin-angiotensin-aldosterone system. However, new drugs are currently being added to the recommended guideline therapy. The latest drug to be added combines inhibition of the renin-angiotensin-aldosterone system pathway with inhibiting the neprilysin enzyme and is therefore classified as an ARNI. Our objective is to identify the beneficial and harmful effects of ARNIs in the treatment of patient with heart failure., Methods: This protocol for a systematic review was undertaken using the recommendations of the Cochrane, the Preferred Report Items of Systematic reviews with Meta-Analysis Protocols, and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the use of ARNIs in the treatment of patients with heart failure. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP), and BIOSIS to identify relevant trials. We will also search for grey literature and unpublished trials. Extracted data will be analysed using Review Manager 5, STATA 5, and Trial Sequential Analysis. Our primary outcomes will be all-cause mortality and serious adverse events. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the GRADE assessment., Discussion: The present systematic review will have the potential to aid clinicians in decision-making and thereby, benefit patients with heart failure., Systematic Review Registration: PROSPERO CRD42019129336.

Background: Despite increasing survival, cardiovascular disease remains the primary cause of death worldwide with an estimated 7.4 million annual deaths. The main symptom of ischaemic heart disease is chest pain (angina pectoris) most often caused by blockage of a coronary artery. The aim of coronary artery bypass surgery is revascularisation achieved by surgically grafting harvested arteries or veins distal to the coronary lesion restoring blood flow to the heart muscle. Older evidence suggested a clear survival benefit of coronary artery bypass graft surgery, but more recent trials yield less clear evidence. We want to assess the benefits and harms of coronary artery bypass surgery combined with different medical therapies versus medical therapy alone in patients with ischaemic heart disease., Methods: This protocol for a systematic review follows the recommendations of Cochrane and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all randomised clinical trials assessing coronary artery bypass surgery combined with different medical therapies versus medical therapy alone in patients with ischaemic heart disease. We plan to search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, Science Citation Index Expanded on Web of Science, and BIOSIS to identify relevant trials. Any eligible trial will be assessed as high risk or low risk of bias, and our conclusions will primarily be based on trials at low risk of bias. The analyses of the extracted data will be performed using Review Manager 5, STATA 16 and trial sequential analysis. For both our primary and secondary outcomes, we will create a 'Summary of Findings' table and use GRADE to assess the certainty of the evidence., Discussion: Coronary artery bypass surgery is invasive and can cause death, which is why its use must be thoroughly studied to determine if it yields a large enough long-term benefit for the thousands of patients receiving it every year., Systematic Review Registration: PROSPERO ID 131924.

Background: Psychiatric disorders are highly prevalent and associated with great symptomatic, functional, and health economic burdens. Psychotherapy is among the recommended and used interventions for most psychiatric disorders and is becoming widely accessible in mental health systems. The effects of specific forms of psychotherapy (e.g., psychodynamic therapies, cognitive and behavioral therapies, humanistic therapies, and systemic therapies) have been assessed previously in systematic reviews, but the appropriate psychotherapy duration for psychiatric disorders has not been reviewed. The aim of this systematic review will be to synthesize the evidence of the effects of short-term compared with long-term psychotherapy for all adult psychiatric disorders., Methods/design: A comprehensive search for relevant published literature will be undertaken in Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), PsycINFO, Science Citation Index Expanded (SCI-EXPANDED), Social Sciences Citation Index (SSCI), Conference Proceedings Citation Index-Science (CPCI-S), and Conference Proceedings Citation Index-Social Science & Humanities (CPCI-SSH) to identify relevant trials. We will search all databases from their inception to the present. We will include randomized clinical trials comparing a short-term and a long-term version of the same psychotherapy type for adult psychiatric disorders including attention deficit hyperactivity disorder, psychotic disorders, depressive disorders, bipolar disorders, anxiety disorders, obsessive-compulsive disorder, trauma- and stressor-related disorders, eating disorders, and personality disorders (as defined by standardized diagnostic criteria). We will rely on the trialists defining their compared interventions as short term and long term (or similar terminology). Primary outcomes will be quality of life, serious adverse events, and symptom severity. Secondary outcomes will be suicide or suicide attempts, self-harm, and level of functioning. Two review authors will independently extract data and perform risk of bias assessment using the Cochrane risk of bias tool. A meta-analysis will be performed as recommended by the Cochrane Handbook for Systematic Review of Interventions, bias will be assessed with domains, and Trial Sequential Analysis will be conducted to control random errors. Certainty of the evidence will be assessed by GRADE., Discussion: As psychotherapy is among the treatments of choice for most adult psychiatric disorders, a systematic review evaluating the benefits and harms of short-term compared with long-term psychotherapy is urgently needed. It is the hope that this review will be able to inform best practice in treatment and clinical research of these highly prevalent and burdensome disorders., Systematic Review Registration: PROSPERO CRD42019128535.

Background: Coronary artery disease and heart failure are both highly prevalent diseases with a global prevalence of 93 million and 40 million. These patients are at increased risk of morbidity and mortality. The management of these patients involves medical therapy, and both diseases can be treated using the heart rate-lowering drug ivabradine. However, the evidence regarding the use of ivabradine in the treatment of coronary artery disease and/or heart failure is unclear. Our objective is to assess the beneficial and harmful effects of ivabradine in the treatment of coronary artery disease and/or heart failure., Methods: This protocol for a systematic review was undertaken using the recommendations of The Cochrane Collaboration, the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P), and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the use of ivabradine in the treatment of coronary artery disease and/or heart failure. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP), and BIOSIS in order to identify relevant trials. We will begin the searches in February 2019. All included trials will be assessed and classified at low risk of bias or at high risk of bias. Our primary conclusions will be based on the results from the primary outcomes at low risk of bias. Extracted data will be analysed using Review Manager 5.3 and Trial Sequential Analysis 0.9.5.10. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE)., Discussion: The systematic review will have the potential to aid clinicians in decision-making regarding ivabradine and to benefit patients with coronary artery disease and/or heart failure., Systematic Review Registration: PROSPERO CRD42018112082.

Background: Acute critical bleeding is one of the most feared complications during treatment with oral anticoagulating agents. As more patients undergo treatment with anticoagulating agents, critically bleeding episodes in patients with vitamin K antagonists, thrombin inhibitor, or factor Xa inhibitor-inducted coagulopathy will be encountered frequently by physicians. Hence, an effective treatment capable of reversing the iatrogenic coagulopathy in the acute setting is needed. In randomised clinical trials and observational studies, prothrombin complex concentrate has been reported to be superior to other acute interventions, and many guidelines recommend prothrombin complex concentrate in treatment of critically bleeding patients. The aim of this systematic review is to synthesise the evidence of the effects of prothrombin complex concentrate compared with placebo, no intervention, or other treatment options in critically bleeding patients treated with oral anticoagulants., Methods/design: A comprehensive search for relevant published literature will be undertaken in Cochrane Central Register of Controlled Trials, MEDLINE, Embase, WHO International Clinical Trials Registry Platform, Science Citation Index, regulatory databases, and trial registers. We will include randomised clinical trials comparing prothrombin complex concentrate versus placebo, no intervention, or other interventions in critically bleeding patients with oral anticoagulant-induced coagulopathy. Data extraction and risk of bias assessment will be handled by two independent review authors. Meta-analysis will be performed as recommended by Cochrane Handbook for Systematic Reviews of Interventions, bias will be assessed with domains, and trial sequential analysis will be conducted to control random errors. Certainty will be assessed by GRADE., Discussion: As critical bleeding in patients treated with oral anticoagulants is an increasing problem, an up-to-date systematic review evaluating the benefits and harms of prothrombin complex concentrate is urgently needed. It is the hope that this review will be able to guide best practice in treatment and clinical research of these critically bleeding patients., Systematic Review Registration: PROSPERO CRD42018084371.

Background: Stress ulcer prophylaxis is considered standard of care in many critically ill patients in the intensive care unit (ICU). However, the quality of evidence supporting this has recently been questioned, and clinical equipoise exists. Whether there is overall benefit or harm of stress ulcer prophylaxis in adult hospitalised acutely ill patients is unknown. Accordingly, we aim to assess patient-important benefits and harms of stress ulcer prophylaxis versus placebo or no treatment in adult hospitalised acutely ill patients with high risk of gastrointestinal bleeding irrespective of hospital setting., Methods/design: We will conduct a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis and assess use of proton pump inhibitors (PPIs) or histamine-2-receptor antagonists (H2RAs) in any dose, formulation and duration. We will accept placebo or no prophylaxis as control interventions. The participants will be adult hospitalised acutely ill patients with high risk of gastrointestinal bleeding. We will systematically search the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS and Epistemonikos for relevant literature. We will follow the recommendations by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The risk of systematic errors (bias) and random errors will be assessed, and the overall quality of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach., Discussion: There is a need for a high-quality systematic review to summarise the benefits and harms of stress ulcer prophylaxis in hospitalised patients to inform practice and future research. Although stress ulcer prophylaxis is used worldwide, no firm evidence for benefit or harm as compared to placebo or no treatments has been established. Critical illness is a continuum not limited to the ICU setting, which is why it is important to assess the benefits and harms of stress ulcer prophylaxis in a wider perspective than exclusively in ICU patients., Systematic Review Registration: PROSPERO CRD42017055676.

Background: Atrial fibrillation is the most common arrhythmia of the heart with a prevalence of approximately 2% in the western world. Atrial flutter, another arrhythmia, occurs less often with an incidence of approximately 200,000 new patients per year in the USA. Patients with atrial fibrillation and atrial flutter have an increased risk of death and morbidities. In the management of atrial fibrillation and atrial flutter, it is often necessary to use medical interventions to lower the heart rate. Lowering the heart rate may theoretically prevent the development of heart failure and tachycardia-mediated cardiomyopathy. The evidence on the benefits and harms of digoxin compared with placebo or with other medical interventions is unclear. This protocol for a systematic review aims at identifying the beneficial and harmful effects of digoxin compared with placebo, no intervention, or with other medical interventions for atrial fibrillation and atrial flutter., Methods: This protocol for a systematic review was conducted following the recommendations of Cochrane and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials comparing digoxin with placebo, no intervention, or with other medical interventions. We plan to search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, Science Citation Index Expanded on Web of Science, and BIOSIS to identify relevant trials. Any eligible trial will be assessed and classified as either at high risk of bias or low risk of bias, and our primary conclusions will be based on trials with low risk of bias. We will perform our meta-analyses of the extracted data using Review Manager 5.3 and Trial Sequential Analysis ver. 0.9.5.5 beta. For both our primary and secondary outcomes, we will create a 'Summary of Findings' table based on GRADE assessments of the quality of the evidence., Discussion: The results of this systematic review have the potential to benefit millions of patients worldwide as well as healthcare economy., Systematic Review Registration: PROSPERO CRD42016052935.

Background: Atrial fibrillation is the most common arrhythmia of the heart with a prevalence of approximately 2% in the western world. Atrial flutter, another arrhythmia, occurs less often with an incidence of approximately 200,000 new patients per year in the USA. Patients with atrial fibrillation and atrial flutter have an increased risk of death and morbidities. The management of atrial fibrillation and atrial flutter is often based on interventions aiming at either a rhythm control strategy or a rate control strategy. The evidence on the comparable effects of these strategies is unclear. This protocol for a systematic review aims at identifying the best overall treatment strategy for atrial fibrillation and atrial flutter., Methods: This protocol for a systematic review was performed following the recommendations of the Cochrane Collaboration and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the effects of any rhythm control strategy versus any rate control strategy. We plan to search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, Science Citation Index Expanded on Web of Science, and BIOSIS to identify relevant trials. Any eligible trial will be assessed and classified as either high risk of bias or low risk of bias, and our conclusions will be based on trials with low risk of bias. The analyses of the extracted data will be performed using Review Manager 5 and Trial Sequential Analysis. For both our primary and secondary outcomes, we will create a 'Summary of Findings' table and use GRADE assessment to assess the quality of the evidence., Discussion: The results of this systematic review have the potential to benefit thousands of patients worldwide as well as healthcare systems and healthcare economy., Systematic Review Registration: PROSPERO CRD42016051433.

Background: The prevalence of delirium in intensive care unit (ICU) patients is high. Delirium has been associated with morbidity and mortality including more ventilator days, longer ICU stay, increased long-term mortality and cognitive impairment. Thus, the burden of delirium for patients, relatives and societies is considerable. Today, reviews of randomised clinical trials are produced in large scales sometimes making it difficult to get an overview of the available evidence. A preliminary search identified several reviews investigating the effects of pharmacological interventions for the management and prevention of delirium in ICU patients. The conclusions of the reviews showed conflicting results. Despite this unclear evidence, antipsychotics, in particular, haloperidol is often the recommended pharmacological intervention for delirium in ICU patients. The objective of this overview of reviews is to critically assess the evidence of reviews of randomised clinical trials on the effect of pharmacological management and prevention of delirium in ICU patients., Methods/design: We will search for reviews in the following databases: Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS, Cumulative Index to Nursing and Allied Health Literature, Latin American and Caribbean Health Sciences Literature, and Allied and Complementary Medicine Database. Two authors will independently select references for inclusion using Covidence, extract data and assess the methodological quality of the included systematic reviews using the ROBIS tool. Any disagreement will be resolved by consensus. We will present the data as a narrative synthesis and summarise the main results of the included reviews. In addition, we will present an overview of the bias risk assessment of the systematic reviews., Discussion: Results of this overview may establish a way forward to find and update or to design a high quality systematic review assessing the effects of the most promising pharmacological intervention for delirium in ICU patients., Systematic Review Registration: PROSPERO - CRD42016046628 .