Short-Term versus Long-Term Mentalization-Based Therapy for Borderline Personality Disorder: A Randomized Clinical Trial (MBT-RCT).

INTRODUCTION: Borderline personality disorder (BPD) is a severe and prevalent psychiatric disorder. Mentalization-based therapy (MBT) is an evidence-based intervention for BPD, and several countries offer treatment programs for BPD lasting for years, which is resource demanding. No previous trial has compared short-term with long-term MBT. OBJECTIVE: The aim of the study was to assess the efficacy and safety of short-term versus long-term MBT for outpatients with BPD. METHODS: Adult outpatients (≥18 years) with subthreshold or diagnosed BPD were randomly assigned (1:1) to short-term MBT (5 months) or long-term MBT (14 months). The primary outcome was BPD symptoms assessed with the Zanarini Rating Scale for Borderline Personality Disorder. Secondary outcomes were functional impairment, quality of life, global functioning, and severe self-harm. All outcomes were primarily assessed at 16 months after randomization. This trial was prospectively registered at ClinicalTrials.gov, NCT03677037. RESULTS: Between October 4, 2018, and December 3, 2020, we randomly assigned 166 participants to short-term MBT (n = 84) or long-term MBT (n = 82). Regression analyses showed no evidence of a difference when assessing BPD symptoms (MD 0.99; 95% CI: -1.06 to 3.03; p = 0.341), level of functioning (MD 1.44; 95% CI: -1.43 to 4.32; p = 0.321), quality of life (MD -0.91; 95% CI: -4.62 to 2.79; p = 0.626), global functioning (MD -2.25; 95% CI: -6.70 to 2.20; p = 0.318), or severe self-harm (RR 1.37; 95% CI: 0.70-2.84; p = 0.335). More participants in the long-term MBT group had a serious adverse event compared with short-term MBT (RR 1.63; 95% CI: 0.94-3.07; p = 0.088), primarily driven by a difference in psychiatric hospitalizations (RR 2.03; 95% CI: 0.99-5.09; p = 0.056). CONCLUSION: Long-term MBT did not lead to lower levels of BPD symptoms, nor did it influence any of the secondary outcomes compared with short-term MBT.

Higher versus lower blood pressure targets after cardiac arrest: Systematic review with individual patient data meta-analysis.

PURPOSE: Guidelines recommend targeting mean arterial pressure (MAP) > 65 mmHg in patients after cardiac arrest (CA). Recent trials have studied the effects of targeting a higher MAP as compared to a lower MAP after CA. We performed a systematic review and individual patient data meta-analysis to investigate the effects of higher versus lower MAP targets on patient outcome. METHOD: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, LILACS, BIOSIS, CINAHL, Scopus, the Web of Science Core Collection, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry, Google Scholar and the Turning Research into Practice database to identify trials randomizing patients to higher (≥71 mmHg) or lower (≤70 mmHg) MAP targets after CA and resuscitation. We used the Cochrane Risk of Bias tool, version 2 (RoB 2) to assess for risk of bias. The primary outcomes were 180-day all-cause mortality and poor neurologic recovery defined by a modified Rankin score of 4-6 or a cerebral performance category score of 3-5. RESULTS: Four eligible clinical trials were identified, randomizing a total of 1,087 patients. All the included trials were assessed as having a low risk for bias. The risk ratio (RR) with 95% confidence interval for 180-day all-cause mortality for a higher versus a lower MAP target was 1.08 (0.92-1.26) and for poor neurologic recovery 1.01 (0.86-1.19). Trial sequential analysis showed that a 25% or higher treatment effect, i.e., RR < 0.75, can be excluded. No difference in serious adverse events was found between the higher and lower MAP groups. CONCLUSIONS: Targeting a higher MAP compared to a lower MAP is unlikely to reduce mortality or improve neurologic recovery after CA. Only a large treatment effect above 25% (RR < 0.75) could be excluded, and future studies are needed to investigate if relevant but lower treatment effect exists. Targeting a higher MAP was not associated with any increase in adverse effects.

Observed intervention effects for mortality in randomised clinical trials: a methodological study protocol.

INTRODUCTION: It is essential to choose a realistic anticipated intervention effect when calculating a sample size for a randomised clinical trial. Unfortunately, anticipated intervention effects are often inflated, when compared with the 'true' intervention effects. This is documented for mortality in critical care trials. A similar pattern might exist across different medical specialties. This study aims to estimate the range of observed intervention effects for all-cause mortality in trials included in Cochrane Reviews, within each Cochrane Review Group. METHODS AND ANALYSIS: We will include randomised clinical trials assessing all-cause mortality as an outcome. Trials will be identified from Cochrane Reviews published in the Cochrane Database of Systematic Reviews. Cochrane Reviews will be clustered according to the registered Cochrane Review Group (eg, Anaesthesia, Emergency and Critical Care) and the statistical analyses will be conducted for each Cochrane Review Group and overall. The median relative risk and IQR for all-cause mortality and the proportion of trials with a relative all-cause mortality risk within seven different ranges will be reported (relative risk below 0.70, 0.70-0.79, 0.80-0.89, 0.90-1.09, 1.10-1.19, 1.20-1.30 and above 1.30). Subgroup analyses will explore the effects of original design, sample size, risk of bias, disease, intervention type, follow-up length, participating centres, funding type, information size and outcome hierarchy. ETHICS AND DISSEMINATION: Since we will use summary data from trials already approved by relevant ethical committees, this study does not require ethical approval. Regardless of our findings, the results will be published in an international peer-reviewed journal.

The difference between shorter- versus longer-term psychotherapy for adult mental health disorders: a systematic review with meta-analysis.

BACKGROUND: The optimal psychotherapy duration for mental health disorders is unclear. Our aim was to assess the beneficial and harmful effects of shorter- versus longer-term psychotherapy for adult mental health disorders. METHOD: We searched relevant databases and websites for published and unpublished randomised clinical trials assessing different durations of the same psychotherapy type before June 27, 2022. Our methodology was based on Cochrane and an eight-step procedure. Primary outcomes were quality of life, serious adverse events, and symptom severity. Secondary outcomes were suicide or suicide-attempts, self-harm, and level of functioning. RESULTS: We included 19 trials randomising 3,447 participants. All trials were at high risk of bias. Three single trials met the required information size needed to confirm or reject realistic intervention effects. One single trial showed no evidence of a difference between 6 versus 12 months dialectical behavioral therapy for borderline personality when assessing quality of life, symptom severity, and level of functioning. One single trial showed evidence of a beneficial effect of adding booster sessions to 8 and 12 weeks of internet-based cognitive behavioral therapy for depression and anxiety when assessing symptom severity and level of functioning. One single trial showed no evidence of a difference between 20 weeks versus 3 years of psychodynamic psychotherapy for mood- or anxiety disorders when assessing symptom severity and level of functioning. It was only possible to conduct two pre-planned meta-analyses. Meta-analysis showed no evidence of a difference between shorter- and longer-term cognitive behavioural therapy for anxiety disorders on anxiety symptoms at end of treatment (SMD: 0.08; 95% CI: -0.47 to 0.63; p = 0.77; I2 = 73%; four trials; very low certainty). Meta-analysis showed no evidence of a difference between shorter and longer-term psychodynamic psychotherapy for mood- and anxiety disorders on level of functioning (SMD 0.16; 95% CI -0.08 to 0.40; p = 0.20; I2 = 21%; two trials; very low certainty). CONCLUSIONS: The evidence for shorter versus longer-term psychotherapy for adult mental health disorders is currently unclear. We only identified 19 randomised clinical trials. More trials at low risk of bias and at low risk of random errors assessing participants at different levels of psychopathological severity are urgently needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128535.

Drug interventions for prevention of COVID-19 progression to severe disease in outpatients: a systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

OBJECTIVES: To assess the effects of interventions authorised by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) for prevention of COVID-19 progression to severe disease in outpatients. SETTING: Outpatient treatment. PARTICIPANTS: Participants with a diagnosis of COVID-19 and the associated SARS-CoV-2 virus irrespective of age, sex and comorbidities. INTERVENTIONS: Drug interventions authorised by EMA or FDA. PRIMARY OUTCOME MEASURES: Primary outcomes were all-cause mortality and serious adverse events. RESULTS: We included 17 clinical trials randomising 16 257 participants to 8 different interventions authorised by EMA or FDA. 15/17 of the included trials (88.2%) were assessed at high risk of bias. Only molnupiravir and ritonavir-boosted nirmatrelvir seemed to improve both our primary outcomes. Meta-analyses showed that molnupiravir reduced the risk of death (relative risk (RR) 0.11, 95% CI 0.02 to 0.64; p=0.0145, 2 trials; very low certainty of evidence) and serious adverse events (RR 0.63, 95% CI 0.47 to 0.84; p=0.0018, 5 trials; very low certainty of evidence). Fisher's exact test showed that ritonavir-boosted nirmatrelvir reduced the risk of death (p=0.0002, 1 trial; very low certainty of evidence) and serious adverse events (p<0.0001, 1 trial; very low certainty of evidence) in 1 trial including 2246 patients, while another trial including 1140 patients reported 0 deaths in both groups. CONCLUSIONS: The certainty of the evidence was very low, but, from the results of this study, molnupiravir showed the most consistent benefit and ranked highest among the approved interventions for prevention of COVID-19 progression to severe disease in outpatients. The lack of certain evidence should be considered when treating patients with COVID-19 for prevention of disease progression. PROSPERO REGISTRATION NUMBER: CRD42020178787.

Centre for Statistical and Methodological Excellence (CESAME): A Consortium Initiative for Improving Methodology in Randomised Clinical Trials.

When conducting randomised clinical trials, the choice of methodology and statistical analyses will influence the results. If the planned methodology is not of optimal quality and predefined in detail, there is a risk of biased trial results and interpretation. Even though clinical trial methodology is already at a very high standard, there are many trials that deliver biased results due to the implementation of inadequate methodology, poor data quality and erroneous or biased analyses. To increase the internal and external validity of randomised clinical trial results, several international institutions within clinical intervention research have formed The Centre for Statistical and Methodological Excellence (CESAME). Based on international consensus, the CESAME initiative will develop recommendations for the proper methodological planning, conduct and analysis of clinical intervention research. CESAME aims to increase the validity of randomised clinical trial results which will ultimately benefit patients worldwide across medical specialities. The work of CESAME will be performed within 3 closely interconnected pillars: (1) planning randomised clinical trials; (2) conducting randomised clinical trials; and (3) analysing randomised clinical trials.

The risks of adverse events with venlafaxine and mirtazapine versus 'active placebo', placebo, or no intervention for adults with major depressive disorder: a protocol for two separate systematic reviews with meta-analysis and Trial Sequential Analysis.

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.

Melatonin for sleep disorders in children with neurodevelopmental disorders: protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials.

INTRODUCTION: Neurodevelopmental disorders are a group of disorders thought to be associated with the functioning of the brain and the nervous system. Children with neurodevelopmental disorders often have sleep-related comorbidities that may negatively affect quality of life for both the children and their families. Melatonin is one of the most used interventions in children with neurodevelopmental disorders and sleep disorders. Previous reviews have investigated the effects of melatonin for sleep disorders in children with neurodevelopmental disorders, but these had important limitations, such as inadequate analysis of adverse effects, small sample sizes and short follow-up. METHODS AND ANALYSIS: This is a protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials. The protocol is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. We will search for published and unpublished trials in the Cochrane Central Register of Controlled Trials, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, PsycINFO, ClinicalTrials.gov and the International Clinical Trials Registry Platform. We will search the databases from their inception without language restrictions. We will also request clinical study reports from regulatory authorities and pharmaceutical companies. Review authors working in pairs will screen reports, extract data and conduct risk of bias assessments using the Cochrane Risk of Bias tool. We will include randomised clinical trials comparing melatonin versus placebo or no intervention for sleep disorders in children with neurodevelopmental disorders. Primary outcomes will be total sleep time and adverse effects. Secondary outcomes will be quality of life of the child and caregivers and sleep onset latency. Data will be analysed using random-effects and fixed-effect meta-analyses. Certainty of evidence will be assessed with Grading of Recommendations, Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: Ethical approval was not required for this protocol. The systematic review will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022337530.

Deep brain stimulation for neurological disorders: a protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials.

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.

Protocol for an individual patient data meta-analysis on blood pressure targets after cardiac arrest.

BACKGROUND: Hypotension is common after cardiac arrest (CA), and current guidelines recommend using vasopressors to target mean arterial blood pressure (MAP) higher than 65 mmHg. Pilot trials have compared higher and lower MAP targets. We will review the evidence on whether higher MAP improves outcome after cardiac arrest. METHODS: This systematic review and meta-analysis will be conducted based on a systematic search of relevant major medical databases from their inception onwards, including MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL), as well as clinical trial registries. We will identify randomised controlled trials published in the English language that compare targeting a MAP higher than 65-70 mmHg in CA patients using vasopressors, inotropes and intravenous fluids. The data extraction will be performed separately by two authors (a third author will be involved in case of disagreement), followed by a bias assessment with the Cochrane Risk of Bias tool using an eight-step procedure for assessing if thresholds for clinical significance are crossed. The outcomes will be all-cause mortality, functional long-term outcomes and serious adverse events. We will contact the authors of the identified trials to request individual anonymised patient data to enable individual patient data meta-analysis, aggregate data meta-analyses, trial sequential analyses and multivariable regression, controlling for baseline characteristics. The certainty of the evidence will be assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. We will register this systematic review with Prospero and aim to redo it when larger trials are published in the near future. CONCLUSIONS: This protocol defines the performance of a systematic review on whether a higher MAP after cardiac arrest improves patient outcome. Repeating this systematic review including more data likely will allow for more certainty regarding the effect of the intervention and possible sub-groups differences.

Tricyclic antidepressants versus 'active placebo', placebo or no intervention for adults with major depressive disorder: a protocol for a systematic review with meta-analysis and Trial Sequential Analysis.

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 .

Beneficial and harmful effects of antidepressants versus placebo, 'active placebo', or no intervention for adults with major depressive disorder: a protocol for a systematic review of published and unpublished data with meta-analyses and trial sequential analyses.

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.

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

BACKGROUND: COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. METHODS AND FINDINGS: We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses. CONCLUSIONS: No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020178787.

Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. METHODS AND FINDINGS: This is the first edition of a living systematic review of randomized clinical trials comparing the effects of all treatment interventions for participants in all age groups with COVID-19. We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review is based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Cochrane guidelines, and our 8-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and nonserious adverse events. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until August 7, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 33 randomized clinical trials enrolling a total of 13,312 participants. All trials were at overall high risk of bias. We identified one trial randomizing 6,425 participants to dexamethasone versus standard care. This trial showed evidence of a beneficial effect of dexamethasone on all-cause mortality (rate ratio 0.83; 95% confidence interval [CI] 0.75-0.93; p < 0.001; low certainty) and on mechanical ventilation (risk ratio [RR] 0.77; 95% CI 0.62-0.95; p = 0.021; low certainty). It was possible to perform meta-analysis of 10 comparisons. Meta-analysis showed no evidence of a difference between remdesivir versus placebo on all-cause mortality (RR 0.74; 95% CI 0.40-1.37; p = 0.34, I2 = 58%; 2 trials; very low certainty) or nonserious adverse events (RR 0.94; 95% CI 0.80-1.11; p = 0.48, I2 = 29%; 2 trials; low certainty). Meta-analysis showed evidence of a beneficial effect of remdesivir versus placebo on serious adverse events (RR 0.77; 95% CI 0.63-0.94; p = 0.009, I2 = 0%; 2 trials; very low certainty) mainly driven by respiratory failure in one trial. Meta-analyses and trial sequential analyses showed that we could exclude the possibility that hydroxychloroquine versus standard care reduced the risk of all-cause mortality (RR 1.07; 95% CI 0.97-1.19; p = 0.17; I2 = 0%; 7 trials; low certainty) and serious adverse events (RR 1.07; 95% CI 0.96-1.18; p = 0.21; I2 = 0%; 7 trials; low certainty) by 20% or more, and meta-analysis showed evidence of a harmful effect on nonserious adverse events (RR 2.40; 95% CI 2.01-2.87; p < 0.00001; I2 = 90%; 6 trials; very low certainty). Meta-analysis showed no evidence of a difference between lopinavir-ritonavir versus standard care on serious adverse events (RR 0.64; 95% CI 0.39-1.04; p = 0.07, I2 = 0%; 2 trials; very low certainty) or nonserious adverse events (RR 1.14; 95% CI 0.85-1.53; p = 0.38, I2 = 75%; 2 trials; very low certainty). Meta-analysis showed no evidence of a difference between convalescent plasma versus standard care on all-cause mortality (RR 0.60; 95% CI 0.33-1.10; p = 0.10, I2 = 0%; 2 trials; very low certainty). Five single trials showed statistically significant results but were underpowered to confirm or reject realistic intervention effects. None of the remaining trials showed evidence of a difference on our predefined outcomes. Because of the lack of relevant data, it was not possible to perform other meta-analyses, network meta-analysis, or individual patient data meta-analyses. The main limitation of this living review is the paucity of data currently available. Furthermore, the included trials were all at risks of systematic errors and random errors. CONCLUSIONS: Our results show that dexamethasone and remdesivir might be beneficial for COVID-19 patients, but the certainty of the evidence was low to very low, so more trials are needed. We can exclude the possibility of hydroxychloroquine versus standard care reducing the risk of death and serious adverse events by 20% or more. Otherwise, no evidence-based treatment for COVID-19 currently exists. This review will continuously inform best practice in treatment and clinical research of COVID-19.

Eye gaze and facial displays of emotion during emotional film clips in remitted patients with bipolar disorder.

BACKGROUND: Aberrant emotional reactivity is a putative endophenotype for bipolar disorder (BD), but the findings of behavioral studies are often negative due to suboptimal sensitivity of the employed paradigms. This study aimed to investigate whether visual gaze patterns and facial displays of emotion during emotional film clips can reveal subtle behavioral abnormalities in remitted BD patients. METHODS: Thirty-eight BD patients in full or partial remission and 40 healthy controls viewed 7 emotional film clips. These included happy, sad, and neutral scenarios and scenarios involving winning, risk-taking, and thrill-seeking behavior of relevance to the BD phenotype. Eye gaze and facial expressions were recorded during the film clips, and participants rated their emotional reactions after each clip. RESULTS: BD patients showed a negative bias in both facial displays of emotion and self-rated emotional responses. Specifically, patients exhibited more fearful facial expressions during all film clips. This was accompanied by less positive self-rated emotions during the winning and happy film clips, and more negative emotions during the risk-taking/thrill-related film clips. CONCLUSIONS: These findings suggest that BD is associated with trait-related abnormalities in subtle behavioral displays of emotion processing. Future studies comparing patients with BD and unipolar depression are warranted to clarify whether these differences are specific to BD. If so, assessments of visual gaze and facial displays of emotion during emotional film clips may have the potential to be implemented in clinical assessments to aid diagnostic accuracy.