Antipsychotic Drugs and Cognitive Function: A Systematic Review and Pairwise Network Meta-Analysis.

Importance: Cognitive deficits are a substantial part of the symptoms of schizophrenia spectrum disorders (SSDs) and contribute heavily to the burden of disease. Antipsychotic drugs are not cognitive enhancers, but due to their different receptor-binding profiles, they could differ in their effects on cognition. No previous network meta-analysis compared antipsychotics to placebo, which is important to determine whether use of these drugs is associated with cognitive performance in SSDs at all. Objective: To determine the association of treatment with various antipsychotics and cognition in patients with SSDs. Data Sources: Cochrane Schizophrenia Trials Register through June 25, 2023. Study Selection: Randomized clinical trials examining the effects on cognition of antipsychotic drugs or placebo in participants with SSD. Data Extraction and Synthesis: A systematic review and random-effects frequentist network meta-analysis was performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses-Network Meta-analysis reporting guideline. Main Outcomes and Measures: The primary outcome was change in overall cognition score calculated for each study. Secondary outcomes included cognitive domains, quality of life, and functioning. Results: This study included 68 studies involving 9525 participants (mean [SD] age, 35.1 [8.9] years; 5878 male [70%] and 2890 [30%] female; some studies did not provide this information). There were few clear differences between antipsychotics, but first-generation dopamine antagonists haloperidol (standardized mean difference [SMD], 0.04; 95% CI, -0.25 to 0.33) and fluphenazine (SMD, 0.15; 95% CI, -0.39 to 0.69) as well as clozapine (SMD, 0.12; 95% CI, -0.23 to 0.48) ranked low. No individual antipsychotic was associated with a clearly better outcome than placebo, but antipsychotics as a group were, with small effect sizes (mean SMDs: adrenergic/low dopamine, 0.21; serotonergic/dopaminergic, 0.26; muscarinic, 0.28; dopaminergic, 0.40). Conclusion and Relevance: Although data are relatively sparse, those reviewed in this study suggest that first-generation dopamine antagonists and clozapine should be avoided when cognitive deficits are a concern. Antipsychotics are not procognitive drugs. The overall small superior outcomes compared to placebo may be explained by less disordered thought patterns associated with fewer positive symptoms rather than cognitive deficits in the proper sense. The findings also suggest that harmonizing measurement of cognitive function in randomized clinical trials would be beneficial.

Trace amine-associated receptor 1 (TAAR1) agonism for psychosis: a living systematic review and meta-analysis of human and non-human data.

Background: Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies. Methods: We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses. Results: Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D 2 receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling. Conclusions: TAAR1 agonists may be less efficacious than dopamine D 2 receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted. Registration: PROSPERO-ID: CRD42023451628.

There is a need for more effective treatments for psychosis, including schizophrenia. Psychosis is a collection of mental health symptoms, such as hearing voices, that can cause distress and impair functioning. These symptoms are thought to be caused by changes in a chemical messenger system in the brain called dopamine. Currently used antipsychotic medications target brain receptors that respond to dopamine. They are not effective in some people and can cause uncomfortable adverse events, such as weight gain and movement disorders, especially with long-term use. A new type of drug is the trace amine-associated receptor 1 (TAAR1) agonists. These drugs act on different brain receptors that can affect the activity of the dopamine system, but do not directly bind to dopamine receptors. We aimed to understand if TAAR1 agonists can reduce symptoms of psychosis, what adverse events they might have, and how they work. We did this by reviewing and collating all available evidence until November 2023. This is a "living" systematic review, so it will be regularly updated in the future. We looked at both human and animal studies investigating TAAR1 agonists. Human studies suggested that two TAAR1 agonists (namely, ulotaront or ralmitaront) might have little to no effect on reducing symptoms of psychosis compared to placebo in people with schizophrenia. They seemed to cause fewer adverse events than current antipsychotics. Data from animal studies suggested that TAAR1 agonists had some positive effects but potentially smaller than other antipsychotics. There were little to no data from both human and animal studies about how TAAR1 agonists actually work. From the current evidence we are uncertain about these results. With the ongoing development of new TAAR1 agonists, more evidence is needed to understand their potential role in the treatment of psychosis.

Techniques to increase lumbar puncture success in newborn babies: the NeoCLEAR RCT.

Background: Lumbar puncture is an essential tool for diagnosing meningitis. Neonatal lumbar puncture, although frequently performed, has low success rates (50-60%). Standard technique includes lying infants on their side and removing the stylet 'late', that is, after the needle is thought to have entered the cerebrospinal fluid. Modifications to this technique include holding infants in the sitting position and removing the stylet 'early', that is, following transection of the skin. To the best of our knowledge, modified techniques have not previously been tested in adequately powered trials. Objectives: The aim of the Neonatal Champagne Lumbar punctures Every time - An RCT (NeoCLEAR) trial was to compare two modifications to standard lumbar puncture technique, that is, use of the lying position rather than the sitting position and of 'early' rather than 'late' stylet removal, in terms of success rates and short-term clinical, resource and safety outcomes. Methods: This was a multicentre 2 × 2 factorial pragmatic non-blinded randomised controlled trial. Infants requiring lumbar puncture (with a working weight ≥ 1000 g and corrected gestational age from 27+0 to 44+0 weeks), and whose parents provided written consent, were randomised by web-based allocation to lumbar puncture (1) in the sitting or lying position and (2) with early or late stylet removal. The trial was powered to detect a 10% absolute risk difference in the primary outcome, that is, the percentage of infants with a successful lumbar puncture (cerebrospinal fluid containing < 10,000 red cells/mm3). The primary outcome was analysed by modified intention to treat. Results: Of 1082 infants randomised (sitting with early stylet removal, n = 275; sitting with late stylet removal, n = 271; lying with early stylet removal, n = 274; lying with late stylet removal, n = 262), 1076 were followed up until discharge. Most infants were term born (950/1076, 88.3%) and were aged < 3 days (936/1076, 87.0%) with a working weight > 2.5 kg (971/1076, 90.2%). Baseline characteristics were balanced across groups. In terms of the primary outcome, the sitting position was significantly more successful than lying [346/543 (63.7%) vs. 307/533 (57.6%), adjusted risk ratio 1.10 (95% confidence interval 1.01 to 1.21); p = 0.029; number needed to treat = 16 (95% confidence interval 9 to 134)]. There was no significant difference in the primary outcome between early stylet removal and late stylet removal [338/545 (62.0%) vs. 315/531 (59.3%), adjusted risk ratio 1.04 (95% confidence interval 0.94 to 1.15); p = 0.447]. Resource consumption was similar in all groups, and all techniques were well tolerated and safe. Limitations: This trial predominantly recruited term-born infants who were < 3 days old, with working weights > 2.5 kg. The impact of practitioners' seniority and previous experience of different lumbar puncture techniques was not investigated. Limited data on resource use were captured, and parent/practitioner preferences were not assessed. Conclusion: Lumbar puncture success rate was higher with infants in the sitting position but was not affected by timing of stylet removal. Lumbar puncture is a safe, well-tolerated and simple technique without additional cost, and is easily learned and applied. The results support a paradigm shift towards sitting technique as the standard position for neonatal lumbar puncture, especially for term-born infants during the first 3 days of life. Future work: The superiority of the sitting lumbar puncture technique should be tested in larger populations of premature infants, in those aged > 3 days and outside neonatal care settings. The effect of operators' previous practice and the impact on family experience also require further investigation, alongside in-depth analyses of healthcare resource utilisation. Future studies should also investigate other factors affecting lumbar puncture success, including further modifications to standard technique. Trial registration: This trial is registered as ISRCTN14040914 and as Integrated Research Application System registration 223737. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/106) and is published in full in Health Technology Assessment; Vol. 27, No. 33. See the NIHR Funding and Awards website for further award information.

Newborn babies are more susceptible to getting meningitis, and this can be fatal or have lifelong complications. A lumbar puncture is an essential test for diagnosing meningitis. Lumbar puncture involves taking a small amount of spinal fluid from the lower back using a needle. Analysing the fluid confirms or excludes meningitis, allowing the right treatment to be given. Lumbar punctures are commonly performed in newborns, but are technically difficult. In 50­60% of lumbar punctures in newborns, either no fluid is obtained or the sample is mixed with blood, making analysis less reliable. No-one knows which is the best technique, and so practice varies. The baby can be held lying on their side or sat up, and the 'stylet', which is a thin piece of metal that sits inside (and aids insertion of) the needle, can be removed either soon after passing through the skin (i.e. 'early stylet removal') or once the tip is thought to have reached the spinal fluid (i.e. 'late stylet removal'). We wanted to find the best technique for lumbar puncture in newborns. Therefore, we compared sitting with lying position, and 'early' with 'late' stylet removal. We carried out a large trial in newborn care and maternity wards in 21 UK hospitals. With parental consent, we recruited 1082 full-term and premature babies who needed a lumbar puncture. Our results demonstrated that the sitting position was more successful than lying position, but the timing of stylet removal did not affect success. In summary, the sitting position is an inexpensive, safe, well-tolerated and easily learned way to improve lumbar puncture success rates in newborns. Our results strongly support using this technique in newborn babies worldwide.

Estimating and visualising the trade-off between benefits and harms on multiple clinical outcomes in network meta-analysis.

BACKGROUND: The relative treatment effects estimated from network meta-analysis can be employed to rank treatments from the most preferable to the least preferable option. These treatment hierarchies are typically based on ranking metrics calculated from a single outcome. Some approaches have been proposed in the literature to account for multiple outcomes and individual preferences, such as the coverage area inside a spie chart, that, however, does not account for a trade-off between efficacy and safety outcomes. We present the net-benefit standardised area within a spie chart, [Formula: see text] to explore the changes in treatment performance with different trade-offs between benefits and harms, according to a particular set of preferences. METHODS: We combine the standardised areas within spie charts for efficacy and safety/acceptability outcomes with a value λ specifying the trade-off between benefits and harms. We derive absolute probabilities and convert outcomes on a scale between 0 and 1 for inclusion in the spie chart. RESULTS: We illustrate how the treatments in three published network meta-analyses perform as the trade-off λ varies. The decrease of the [Formula: see text] quantity appears more pronounced for some drugs, e.g. haloperidol. Changes in treatment performance seem more frequent when SUCRA is employed as outcome measures in the spie charts. CONCLUSIONS: [Formula: see text] should not be interpreted as a ranking metric but it is a simple approach that could help identify which treatment is preferable when multiple outcomes are of interest and trading-off between benefits and harms is important.

Semi-automated assessment of the risk of bias due to missing evidence in network meta-analysis: a guidance paper for the ROB-MEN web-application.

Network meta-analysis compares multiple interventions and estimates the relative treatment effects between all interventions, combining both direct and indirect evidence. Recently, a framework was developed to assess the Risk Of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) which is part of the more comprehensive framework to evaluate the Confidence In the evidence for Network Meta-Analysis (CINeMA). To produce an overall risk of bias judgement for each network estimate, ROB-MEN: performs an assessment of the bias due to missing evidence in each possible pairwise comparison; combines the assessment with the contribution from the direct pairwise comparisons; considers the potential for small-study effects. To facilitate and semi-automate this process, ROB-MEN has been implemented in a user-friendly web-application ( https://cinema.ispm.unibe.ch/rob-men ). Here we provide a tutorial detailing the functionality and use of the application consisting of data upload, analysis configuration, output visualisation, and production of the tool's output tables for recording the risk of bias assessment. We also illustrate an example application using the demo dataset available for download on the application's homepage. The ROB-MEN web-application is open-source and freely available ( https://github.com/esm-ispm-unibe-ch/rob-men ).

New living evidence resource of human and non-human studies for early intervention and research prioritisation in anxiety, depression and psychosis.

In anxiety, depression and psychosis, there has been frustratingly slow progress in developing novel therapies that make a substantial difference in practice, as well as in predicting which treatments will work for whom and in what contexts. To intervene early in the process and deliver optimal care to patients, we need to understand the underlying mechanisms of mental health conditions, develop safe and effective interventions that target these mechanisms, and improve our capabilities in timely diagnosis and reliable prediction of symptom trajectories. Better synthesis of existing evidence is one way to reduce waste and improve efficiency in research towards these ends. Living systematic reviews produce rigorous, up-to-date and informative evidence summaries that are particularly important where research is emerging rapidly, current evidence is uncertain and new findings might change policy or practice. Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis (GALENOS) aims to tackle the challenges of mental health science research by cataloguing and evaluating the full spectrum of relevant scientific research including both human and preclinical studies. GALENOS will also allow the mental health community-including patients, carers, clinicians, researchers and funders-to better identify the research questions that most urgently need to be answered. By creating open-access datasets and outputs in a state-of-the-art online resource, GALENOS will help identify promising signals early in the research process. This will accelerate translation from discovery science into effective new interventions for anxiety, depression and psychosis, ready to be translated in clinical practice across the world.

PROTEUS Study: A Prospective Randomized Controlled Trial Evaluating the Use of Artificial Intelligence in Stress Echocardiography.

BACKGROUND: Stress echocardiography (SE) is one of the most commonly used diagnostic imaging tests for coronary artery disease (CAD) but requires clinicians to visually assess scans to identify patients who may benefit from invasive investigation and treatment. EchoGo Pro provides an automated interpretation of SE based on artificial intelligence (AI) image analysis. In reader studies, use of EchoGo Pro when making clinical decisions improves diagnostic accuracy and confidence. Prospective evaluation in real world practice is now important to understand the impact of EchoGo Pro on the patient pathway and outcome. METHODS: PROTEUS is a randomized, multicenter, 2-armed, noninferiority study aiming to recruit 2,500 participants from National Health Service (NHS) hospitals in the UK referred to SE clinics for investigation of suspected CAD. All participants will undergo a stress echocardiogram protocol as per local hospital policy. Participants will be randomized 1:1 to a control group, representing current practice, or an intervention group, in which clinicians will receive an AI image analysis report (EchoGo Pro, Ultromics Ltd, Oxford, UK) to use during image interpretation, indicating the likelihood of severe CAD. The primary outcome will be appropriateness of clinician decision to refer for coronary angiography. Secondary outcomes will assess other health impacts including appropriate use of other clinical management approaches, impact on variability in decision making, patient and clinician qualitative experience and a health economic analysis. DISCUSSION: This will be the first study to assess the impact of introducing an AI medical diagnostic aid into the standard care pathway of patients with suspected CAD being investigated with SE. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT05028179, registered on 31 August 2021; ISRCTN: ISRCTN15113915; IRAS ref: 293515; REC ref: 21/NW/0199.

Metabolic side effects in persons with schizophrenia during mid- to long-term treatment with antipsychotics: a network meta-analysis of randomized controlled trials.

Metabolic side effects of antipsychotic drugs can have serious health consequences and may increase mortality. Although persons with schizophrenia often take these drugs for a long time, their mid- to long-term metabolic effects have been studied little so far. This study aimed to evaluate the mid- to long-term metabolic side effects of 31 antipsychotics in persons with schizophrenia by applying a random-effects Bayesian network meta-analysis. We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (up to April 27, 2020) and PubMed (up to June 14, 2021). We included published and unpublished, open and blinded randomized controlled trials with a study duration >13 weeks which compared any antipsychotic in any form of administration with another antipsychotic or with placebo in participants diagnosed with schizophrenia. The primary outcome was weight gain measured in kilograms. Secondary outcomes included "number of participants with weight gain", fasting glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. We identified 137 eligible trials (with 35,007 participants) on 31 antipsychotics, with a median follow-up of 45 weeks. Chlorpromazine produced the most weight gain (mean difference to placebo: 5.13 kg, 95% credible interval, CrI: 1.98 to 8.30), followed by clozapine (4.21 kg, 95% CrI: 3.03 to 5.42), olanzapine (3.82 kg, 95% CrI: 3.15 to 4.50), and zotepine (3.87 kg, 95% CrI: 2.14 to 5.58). The findings did not substantially change in sensitivity and network meta-regression analyses, although enriched design, drug company sponsorship, and the use of observed case instead of intention-to-treat data modified the mean difference in weight gain to some extent. Antipsychotics with more weight gain were often also among the drugs with worse outcome in fasting glucose and lipid parameters. The confidence in the evidence ranged from low to moderate. In conclusion, antipsychotic drugs differ in their propensity to induce metabolic side effects in mid- to long-term treatment. Given that schizophrenia is often a chronic disorder, these findings should be given more consideration than short-term data in drug choice.

Pro-dopaminergic pharmacological interventions for anhedonia in depression: protocol for a living systematic review of human and non-human studies.

Background: Anhedonia is a key symptom of depression, and it has been suggested as a potential target for future individualised treatments. However, much is unknown about how interventions enhancing dopaminergic pathways may affect anhedonia symptoms in the context of depression. Methods: We will perform independent searches in multiple electronic databases to identify clinical and animal experimental studies on pro-dopaminergic interventions in individuals with depression or animal models for depression. The primary outcomes will be overall anhedonia symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. At least two independent reviewers will conduct the study selection, data extraction, and risk of bias assessments using pre-defined tools according to each record's study design. We will develop ontologies to facilitate study identification and data extraction. We will synthesise data from clinical and animal studies separately. If appropriate, we will use random-effects meta-analyses, or synthesis without meta-analyses. We will investigate study characteristics as potential sources of heterogeneity. We will evaluate the confidence in the evidence for each outcome and source of evidence, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, we will draw an overall conclusion in a triangulation meeting involving a multidisciplinary team of experts. We plan updates of the review every 6 months, and any future modifications to the protocol will be documented. We will co-produce this review with multiple stakeholders. PROSPERO registration: CRD42023451821.

Trace amine-associated receptor 1 (TAAR1) agonists for psychosis: protocol for a living systematic review and meta-analysis of human and non-human studies.

BACKGROUND: There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis. METHODS: Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis. PROTOCOL REGISTRATION: PROSPERO-ID: CRD42023451628.

Planned delivery for pre-eclampsia between 34 and 37 weeks of gestation: the PHOENIX RCT.

BACKGROUND: In women with late preterm pre-eclampsia (i.e. at 34+0 to 36+6 weeks' gestation), the optimal delivery time is unclear because limitation of maternal-fetal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether or not planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of perinatal or infant outcomes, compared with expectant management, in women with late preterm pre-eclampsia. METHODS: We undertook an individually randomised, triple non-masked controlled trial in 46 maternity units across England and Wales, with an embedded health economic evaluation, comparing planned delivery and expectant management (usual care) in women with late preterm pre-eclampsia. The co-primary maternal outcome was a maternal morbidity composite or recorded systolic blood pressure of ≥ 160 mmHg (superiority hypothesis). The co-primary short-term perinatal outcome was a composite of perinatal deaths or neonatal unit admission (non-inferiority hypothesis). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The primary 2-year infant neurodevelopmental outcome was measured using the PARCA-R (Parent Report of Children's Abilities-Revised) composite score. The planned sample size of the trial was 900 women; the trial is now completed. We undertook two linked substudies. RESULTS: Between 29 September 2014 and 10 December 2018, 901 women were recruited; 450 women [448 women (two withdrew consent) and 471 infants] were allocated to planned delivery and 451 women (451 women and 475 infants) were allocated to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group [289 (65%) women] than in the expectant management group [338 (75%) women] (adjusted relative risk 0.86, 95% confidence interval 0.79 to 0.94; p = 0.0005). The incidence of the co-primary perinatal outcome was significantly higher in the planned delivery group [196 (42%) infants] than in the expectant management group [159 (34%) infants] (adjusted relative risk 1.26, 95% confidence interval 1.08 to 1.47; p = 0.0034), but indicators of neonatal morbidity were similar in both groups. At 2-year follow-up, the mean PARCA-R scores were 89.5 points (standard deviation 18.2 points) for the planned delivery group (290 infants) and 91.9 points (standard deviation 18.4 points) for the expectant management group (256 infants), both within the normal developmental range (adjusted mean difference -2.4 points, 95% confidence interval -5.4 to 0.5 points; non-inferiority p = 0.147). Planned delivery was significantly cost-saving (-£2711, 95% confidence interval -£4840 to -£637) compared with expectant management. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. CONCLUSION: In women with late preterm pre-eclampsia, planned delivery reduces short-term maternal morbidity compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater short-term neonatal morbidity (such as need for respiratory support). At 2-year follow-up, around 60% of parents reported follow-up scores. Average infant development was within the normal range for both groups; the small between-group mean difference in PARCA-R scores is unlikely to be clinically important. Planned delivery was significantly cost-saving to the health service. These findings should be discussed with women with late preterm pre-eclampsia to allow shared decision-making on timing of delivery. LIMITATIONS: Limitations of the trial include the challenges of finding a perinatal outcome that adequately represented the potential risks of both groups and a maternal outcome that reflects the multiorgan manifestations of pre-eclampsia. The incidences of maternal and perinatal primary outcomes were higher than anticipated on the basis of previous studies, but this did not limit interpretation of the analysis. The trial was limited by a higher loss to follow-up rate than expected, meaning that the extent and direction of bias in outcomes (between responders and non-responders) is uncertain. A longer follow-up period (e.g. up to 5 years) would have enabled us to provide further evidence on long-term infant outcomes, but this runs the risk of greater attrition and increased expense. FUTURE WORK: We identified a number of further questions that could be prioritised through a formal scoping process, including uncertainties around disease-modifying interventions, prognostic factors, longer-term follow-up, the perspectives of women and their families, meta-analysis with other studies, effect of a similar intervention in other health-care settings, and clinical effectiveness and cost-effectiveness of other related policies around neonatal unit admission in late preterm birth. TRIAL REGISTRATION: The trial was prospectively registered as ISRCTN01879376. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in Health Technology Assessment. See the NIHR Journals Library website for further project information.

ROB-MEN: a tool to assess risk of bias due to missing evidence in network meta-analysis.

BACKGROUND: Selective outcome reporting and publication bias threaten the validity of systematic reviews and meta-analyses and can affect clinical decision-making. A rigorous method to evaluate the impact of this bias on the results of network meta-analyses of interventions is lacking. We present a tool to assess the Risk Of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN). METHODS: ROB-MEN first evaluates the risk of bias due to missing evidence for each of the possible pairwise comparison that can be made between the interventions in the network. This step considers possible bias due to the presence of studies with unavailable results (within-study assessment of bias) and the potential for unpublished studies (across-study assessment of bias). The second step combines the judgements about the risk of bias due to missing evidence in pairwise comparisons with (i) the contribution of direct comparisons to the network meta-analysis estimates, (ii) possible small-study effects evaluated by network meta-regression, and (iii) any bias from unobserved comparisons. Then, a level of "low risk", "some concerns", or "high risk" for the bias due to missing evidence is assigned to each estimate, which is our tool's final output. RESULTS: We describe the methodology of ROB-MEN step-by-step using an illustrative example from a published NMA of non-diagnostic modalities for the detection of coronary artery disease in patients with low risk acute coronary syndrome. We also report a full application of the tool on a larger and more complex published network of 18 drugs from head-to-head studies for the acute treatment of adults with major depressive disorder. CONCLUSIONS: ROB-MEN is the first tool for evaluating the risk of bias due to missing evidence in network meta-analysis and applies to networks of all sizes and geometry. The use of ROB-MEN is facilitated by an R Shiny web application that produces the Pairwise Comparisons and ROB-MEN Table and is incorporated in the reporting bias domain of the CINeMA framework and software.

Network meta-analysis results against a fictional treatment of average performance: Treatment effects and ranking metric.

BACKGROUND: Network meta-analysis (NMA) produces complex outputs as many comparisons between interventions are of interest. The estimated relative treatment effects are usually displayed in a forest plot or in a league table and several ranking metrics are calculated and presented. METHODS: In this article, we estimate relative treatment effects of each competing treatment against a fictional treatment of average performance using the "deviation from the means" coding that has been used to parametrize categorical covariates in regression models. We then use this alternative parametrization of the NMA model to present a ranking metric (PreTA: Preferable Than Average) interpreted as the probability that a treatment is better than a fictional treatment of average performance. RESULTS: We illustrate the alternative parametrization of the NMA model using two networks of interventions, a network of 18 antidepressants for acute depression and a network of four interventions for heavy menstrual bleeding. We also use these two networks to highlight differences among PreTA and existing ranking metrics. We further examine the agreement between PreTA and existing ranking metrics in 232 networks of interventions and conclude that their agreement depends on the precision with which relative effects are estimated. CONCLUSIONS: A forest plot with NMA relative treatment effects using "deviation from means" coding could complement presentation of NMA results in large networks and in absence of an obvious reference treatment. PreTA is a viable alternative to existing probabilistic ranking metrics that naturally incorporates uncertainty.

Agreement between ranking metrics in network meta-analysis: an empirical study.

OBJECTIVE: To empirically explore the level of agreement of the treatment hierarchies from different ranking metrics in network meta-analysis (NMA) and to investigate how network characteristics influence the agreement. DESIGN: Empirical evaluation from re-analysis of NMA. DATA: 232 networks of four or more interventions from randomised controlled trials, published between 1999 and 2015. METHODS: We calculated treatment hierarchies from several ranking metrics: relative treatment effects, probability of producing the best value [Formula: see text] and the surface under the cumulative ranking curve (SUCRA). We estimated the level of agreement between the treatment hierarchies using different measures: Kendall's τ and Spearman's ρ correlation; and the Yilmaz [Formula: see text] and Average Overlap, to give more weight to the top of the rankings. Finally, we assessed how the amount of the information present in a network affects the agreement between treatment hierarchies, using the average variance, the relative range of variance and the total sample size over the number of interventions of a network. RESULTS: Overall, the pairwise agreement was high for all treatment hierarchies obtained by the different ranking metrics. The highest agreement was observed between SUCRA and the relative treatment effect for both correlation and top-weighted measures whose medians were all equal to 1. The agreement between rankings decreased for networks with less precise estimates and the hierarchies obtained from [Formula: see text] appeared to be the most sensitive to large differences in the variance estimates. However, such large differences were rare. CONCLUSIONS: Different ranking metrics address different treatment hierarchy problems, however they produced similar rankings in the published networks. Researchers reporting NMA results can use the ranking metric they prefer, unless there are imprecise estimates or large imbalances in the variance estimates. In this case treatment hierarchies based on both probabilistic and non-probabilistic ranking metrics should be presented.

Study protocol: NeoCLEAR: Neonatal Champagne Lumbar punctures Every time - An RCT: a multicentre, randomised controlled 2 × 2 factorial trial to investigate techniques to increase lumbar puncture success.

BACKGROUND: The neonatal period carries the highest risk of bacterial meningitis (~ 1 in 5000 births), bearing high mortality (~ 10%) and morbidity (20-50%) rates. Lumbar puncture (LP) remains essential to the diagnosis of meningitis. Though LP is a common procedure in neonates, success rates are lower (50-60%) than in other patient populations. None of the currently-practised neonatal LP techniques are supported by evidence from adequately-powered, randomised controlled trials (RCTs). NeoCLEAR aims to compare two modifications to the traditional technique which are free, accessible, and commonly practised: sitting (as opposed to lying) position, and 'early' (as opposed to 'late') stylet removal. METHODS/DESIGN: Written parental informed consent permitting, infants in neonatal/maternity wards, of 27+ 0 to 44+ 0 weeks corrected gestational age and weighing ≥1000 g, who require an LP, will be randomly allocated to sitting or lying position, and to early or late stylet removal. The co-primary objectives are to compare success rates (the proportion of infants with cerebrospinal fluid red cell count < 10,000/mm3 on first LP procedure) in 1020 infants between the two positions, and between the two methods of stylet removal. Secondary outcomes relate to LP procedures, complications, diagnoses of meningitis, duration of antibiotics and hospital stay. A modified intention-to-treat analysis will be conducted. DISCUSSION: Two modifications to the traditional LP technique (sitting vs lying position; and early vs late stylet removal) will be simultaneously investigated in an efficient and appropriately-powered 2 × 2 factorial RCT design. Analysis will identify the optimal techniques (in terms of obtaining easily-interpretable cerebrospinal fluid), as well as the impact on infants, parents and healthcare systems whilst providing robust safety data. Using a pragmatic RCT design, all practitioners will be trained in all LP techniques, but there will inevitably be variation between unit practice guidelines and other aspects of individual care. An improved LP technique would result in: • Fewer uninterpretable samples, repeated attempts and procedures • Reduced distress for infants and families • Decreased antibiotic use and risk of antibiotic resistance • Reduced healthcare costs due to fewer procedures, reduced length of stay, shorter antibiotic courses, and minimised antibiotic-associated complications TRIAL REGISTRATION: ISRCTN14040914. Date assigned: 26/06/2018.

Intravenous co-amoxiclav to prevent infection after operative vaginal delivery: the ANODE RCT.

BACKGROUND: Sepsis is a leading cause of direct and indirect maternal death in both the UK and globally. All forms of operative delivery are associated with an increased risk of sepsis, and the National Institute for Health and Care Excellence's guidance recommends the use of prophylactic antibiotics at all caesarean deliveries, based on substantial randomised controlled trial evidence of clinical effectiveness. A Cochrane review, updated in 2017 (Liabsuetrakul T, Choobun T, Peeyananjarassri K, Islam QM. Antibiotic prophylaxis for operative vaginal delivery. Cochrane Database Syst Rev 2017;8:CD004455), identified only one small previous trial of prophylactic antibiotics following operative vaginal birth (forceps or ventouse/vacuum extraction) and, given the small study size and extreme result, suggested that further robust evidence is needed. OBJECTIVES: To investigate whether or not a single dose of prophylactic antibiotic following operative vaginal birth is clinically effective for preventing confirmed or presumed maternal infection, and to investigate the associated impact on health-care costs. DESIGN: A multicentre, randomised, blinded, placebo-controlled trial. SETTING: Twenty-seven maternity units in the UK. PARTICIPANTS: Women who had an operative vaginal birth at ≥ 36 weeks' gestation, who were not known to be allergic to penicillin or constituents of co-amoxiclav and who had no indication for ongoing antibiotics. INTERVENTIONS: A single dose of intravenous co-amoxiclav (1 g of amoxicillin/200 mg of clavulanic acid) or placebo (sterile saline) allocated through sealed, sequentially numbered, indistinguishable packs. MAIN OUTCOME MEASURES: Primary outcome - confirmed or suspected infection within 6 weeks of giving birth. Secondary outcomes - severe sepsis, perineal wound infection, perineal pain, use of pain relief, hospital bed stay, hospital/general practitioner visits, need for additional perineal care, dyspareunia, ability to sit comfortably to feed the baby, maternal general health, breastfeeding, wound breakdown, occurrence of anaphylaxis and health-care costs. RESULTS: Between March 2016 and June 2018, 3427 women were randomised: 1719 to the antibiotic arm and 1708 to the placebo arm. Seven women withdrew, leaving 1715 women in the antibiotic arm and 1705 in the placebo arm for analysis. Primary outcome data were available for 3225 out of 3420 women (94.3%). Women randomised to the antibiotic arm were significantly less likely to have confirmed or suspected infection within 6 weeks of giving birth (180/1619, 11%) than women randomised to the placebo arm (306/1606, 19%) (relative risk 0.58, 95% confidence interval 0.49 to 0.69). Three serious adverse events were reported: one in the placebo arm and two in the antibiotic arm (one was thought to be causally related to the intervention). LIMITATIONS: The follow-up rate achieved for most secondary outcomes was 76%. CONCLUSIONS: This trial has shown clear evidence of benefit of a single intravenous dose of prophylactic co-amoxiclav after operative vaginal birth. These results may lead to reconsideration of official policy/guidance. Further analysis of the mechanism of action of this single dose of antibiotic is needed to investigate whether earlier, pre-delivery or repeated administration could be more effective. Until these analyses are completed, there is no indication for administration of more than a single dose of prophylactic antibiotic, or for pre-delivery administration. TRIAL REGISTRATION: Current Controlled Trials ISRCTN11166984. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 54. See the National Institute for Health Research Journals Library website for further project information.

Maternal infection is a common problem after women have had a baby with the assistance of forceps or ventouse (vacuum/suction cup). We estimate that up to 1 in 10 women will have an infection around their birth canal, and almost 1 in 20 may have a more severe infection, such as an infection in the bloodstream (sepsis). A single dose of antibiotics at the time of giving birth has been shown to be effective in preventing maternal infection after caesarean birth. The aim of this trial was to investigate whether or not a single dose of preventative antibiotics was similarly effective at preventing maternal infection after giving birth with the assistance of forceps or ventouse. Women who were giving birth at > 36 weeks of pregnancy with the assistance of forceps or ventouse were randomly allocated (i.e. by chance, like tossing a coin) to receive an injection of antibiotics into a vein (intravenous) or an injection of salt solution without any antibiotics after their baby was born. Around 11 in 100 new mothers who received antibiotics had an infection within 6 weeks of delivery, compared with 19 out of 100 who did not receive antibiotics. Women receiving antibiotics also reported better healing and less discomfort from the wounds around the birth canal [either from tears or from the cut (episiotomy) used to help delivery] at 6 weeks after giving birth, and had fewer outpatient or general practitioner visits because of concerns about the wounds around the birth canal. This trial, therefore, showed that a single dose of antibiotics was very effective at preventing maternal infection after giving birth with the assistance of forceps or ventouse, as well as leading to better healing and less pain, and suggests that a single dose of antibiotics could become part of normal care.

Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial.

BACKGROUND: In women with late preterm pre-eclampsia, the optimal time to initiate delivery is unclear because limitation of maternal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of neonatal or infant outcomes, compared with expectant management (usual care) in women with late preterm pre-eclampsia. METHODS: In this parallel-group, non-masked, multicentre, randomised controlled trial done in 46 maternity units across England and Wales, we compared planned delivery versus expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia from 34 to less than 37 weeks' gestation and a singleton or dichorionic diamniotic twin pregnancy. The co-primary maternal outcome was a composite of maternal morbidity or recorded systolic blood pressure of at least 160 mm Hg with a superiority hypothesis. The co-primary perinatal outcome was a composite of perinatal deaths or neonatal unit admission up to infant hospital discharge with a non-inferiority hypothesis (non-inferiority margin of 10% difference in incidence). Analyses were by intention to treat, together with a per-protocol analysis for the perinatal outcome. The trial was prospectively registered with the ISRCTN registry, ISRCTN01879376. The trial is closed to recruitment but follow-up is ongoing. FINDINGS: Between Sept 29, 2014, and Dec 10, 2018, 901 women were recruited. 450 women (448 women and 471 infants analysed) were allocated to planned delivery and 451 women (451 women and 475 infants analysed) to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group (289 [65%] women) compared with the expectant management group (338 [75%] women; adjusted relative risk 0·86, 95% CI 0·79-0·94; p=0·0005). The incidence of the co-primary perinatal outcome by intention to treat was significantly higher in the planned delivery group (196 [42%] infants) compared with the expectant management group (159 [34%] infants; 1·26, 1·08-1·47; p=0·0034). The results from the per-protocol analysis were similar. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. INTERPRETATION: There is strong evidence to suggest that planned delivery reduces maternal morbidity and severe hypertension compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater neonatal morbidity. This trade-off should be discussed with women with late preterm pre-eclampsia to allow shared decision making on timing of delivery. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Prophylactic antibiotics in the prevention of infection after operative vaginal delivery (ANODE): a multicentre randomised controlled trial.

BACKGROUND: Risk factors for maternal infection are clearly recognised, including caesarean section and operative vaginal birth. Antibiotic prophylaxis at caesarean section is widely recommended because there is clear systematic review evidence that it reduces incidence of maternal infection. Current WHO guidelines do not recommend routine antibiotic prophylaxis for women undergoing operative vaginal birth because of insufficient evidence of effectiveness. We aimed to investigate whether antibiotic prophylaxis prevented maternal infection after operative vaginal birth. METHODS: In a blinded, randomised controlled trial done at 27 UK obstetric units, women (aged ≥16 years) were allocated to receive a single dose of intravenous amoxicillin and clavulanic acid or placebo (saline) following operative vaginal birth at 36 weeks gestation or later. The primary outcome was confirmed or suspected maternal infection within 6 weeks of delivery defined by a new prescription of antibiotics for specific indications, confirmed systemic infection on culture, or endometritis. We did an intention-to-treat analysis. This trial is registered with ISRCTN, number 11166984, and is closed to accrual. FINDINGS: Between March 13, 2016, and June 13, 2018, 3427 women were randomly assigned to treatment: 1719 to amoxicillin and clavulanic acid, and 1708 to placebo. Seven women withdrew, leaving 1715 in the amoxicillin and clavulanic acid group and 1705 in the placebo groups. Primary outcome data were missing for 195 (6%) women. Significantly fewer women allocated to amoxicillin and clavulanic acid had a confirmed or suspected infection (180 [11%] of 1619) than women allocated to placebo (306 [19%] of 1606; risk ratio 0·58, 95% CI 0·49-0·69; p<0·0001). One woman in the placebo group reported a skin rash and two women in the amoxicillin and clavulanic acid reported other allergic reactions, one of which was reported as a serious adverse event. Two other serious adverse events were reported, neither was considered causally related to the treatment. INTERPRETATION: This trial shows benefit of a single dose of prophylactic antibiotic after operative vaginal birth and guidance from WHO and other national organisations should be changed to reflect this. FUNDING: NIHR Health Technology Assessment programme.

Planned delivery or expectant management for late preterm pre-eclampsia: study protocol for a randomised controlled trial (PHOENIX trial).

BACKGROUND: Pre-eclampsia is a pregnancy disorder, characterised by hypertension and multisystem complications in the mother. The adverse outcomes of pre-eclampsia include severe hypertension, stroke, renal and hepatic injury, haemorrhage, fetal growth restriction and even death. The optimal time to instigate delivery to prevent morbidity when pre-eclampsia occurs between 34 and 37 weeks' gestation, without increasing problems related to infant immaturity or complications, remains unclear. METHODS/DESIGN: The PHOENIX trial is a non-masked, randomised controlled trial, comparing planned early delivery (with initiation of delivery within 48 h of randomisation) with usual care (expectant management) in women with pre-eclampsia between 34+ 0 and 36+ 6 weeks' gestation. The primary objectives of the trial are to determine if planned delivery reduces adverse maternal outcomes, without increasing the short-term harm to infants (composite of perinatal deaths or neonatal unit admissions up to infant hospital discharge) or impacting long-term infant neurodevelopmental status at 2 years corrected age (Parent Report of Cognitive Abilities-Revised). DISCUSSION: Current practice in the UK at the time of trial commencement for management of pre-eclampsia varies by gestation. Previous trials have shown that in women with pre-eclampsia after 37 weeks of gestion, delivery is initiated, as maternal complications are reduced without increasing fetal risks. Prior to 34 weeks of gestation, usual management aims to prolong pregnancy for fetal benefit, unless severe complications occur, necessitating preterm delivery. This trial aims to address the uncertainty for women where the balance of benefits and risks of delivery compared to expectant management are uncertain. Previous trials in this area have been undertaken, but have not provided a definitive answer, and the research question remains active. The results of this trial are expected to influence clinical practice internationally, through direct adoption and by incorporation into guidelines in countries with similar settings. TRIAL REGISTRATION: ISRCTN01879376 . Registered on 25 November 2013.