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Background: Standardised Diagnostic Assessment tools, such as the Development and Well-Being Assessment (DAWBA), may aid detection and diagnosis of emotional disorders but there is limited real-world evidence of their clinical or cost effectiveness., Methods: We conducted a multicentre, two-arm parallel group randomised controlled trial in eight large National Health Service Trusts in England providing multidisciplinary specialist Child and Adolescent Mental Health Services (CAMHS). Participants (5-17 year-olds with emotional difficulties referred to CAMHS) were randomly assigned (1:1), following referral receipt, to either receive the DAWBA and assessment-as-usual (intervention group) or assessment-as-usual (control group). Data were self-reported by participants (parents and/or young person, depending on age) at baseline, 6- and 12-month post-randomisation and collected from clinical records up to 18 months post-randomisation. The primary outcome was a clinician-made diagnosis decision about the presence of an emotional disorder within 12 months of randomisation., Trial Registration: ISRCTN15748675., Results: In total, 1,225 children and young people (58% female sex) were randomised (615 intervention; 610 control). Adherence to the intervention (full/partial completion) was 80% (494/615). At 12 months, 68 (11%) participants in the intervention group received an emotional disorder diagnosis versus 72 (12%) in the control group (adjusted risk ratio (RR) 0.94 [95% CI 0.70, 1.28]). The intervention was not cost effective. There was no evidence of any differences between groups for service-related or participant-reported secondary outcomes, for example, CAMHS acceptance of the index referral (intervention 277 (45%) versus control 262 (43%); RR: 1.06 [95% CI: 0.94, 1.19]) was similar between groups., Conclusions: As delivered in this pragmatic trial, we found no evidence for the effectiveness or cost effectiveness of using a Standardised Diagnostic Assessment tool in aiding the detection of emotional disorders or clinical outcomes in clinically referred children and young people. Despite regular efforts to encourage clinicians to view the DAWBA report and consider its findings as part of assessment and diagnosis, we did not collect data on usage and therefore cannot confirm the extent to which clinicians did this. As a pragmatic trial that aimed to test the effectiveness of incorporating the DAWBA into usual practice and clinical care, our study found that, in the format as delivered in this trial, there was no impact on diagnosis or clinical outcomes., (Journal of Child Psychology and Psychiatry© 2024 The Author(s). Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

To understand whether the mental health of children and young people (CYP) with and without attention-deficit/hyperactivity disorder (ADHD) and/or autism spectrum disorder (ASD) were differentially affected by COVID-19. We analysed data (n = 6507) from the Co-Space study, a UK web-based longitudinal survey. CYP with ADHD (n = 160;2.5%), ASD (n = 465;7%), and ADHD + ASD (n = 155;2.4%) were compared with a reference group (n = 5727;88%) using parent-completed questionnaires [Strengths and Difficulties Questionnaire (SDQ) & Pandemic Anxiety Scale (PAS)]. Baseline to 1-month follow-up differences were compared using linear regression models. CYP with ADHD and/or ASD had higher scores at baseline than other CYP. At follow-up, CYP with ASD showed small but significant improvements in symptoms (SDQ), compared with the reference group. CYP with ASD experienced a worsening of disease anxiety (PAS) and CYP with ADHD a deterioration in functional impairment. These findings indicate a mixed pattern of pandemic-related impact for CYP with ADHD and/or ASD., (© 2023. The Author(s).)

Background: There exist many different methods of allocating participants to treatment groups during a randomised controlled trial. Although there is research that explores trial characteristics that are associated with the choice of method, there is still a lot of variety in practice not explained. This study used qualitative methods to explore more deeply the motivations behind researchers' choice of randomisation, and which features of the method they use to evaluate the performance of these methods., Methods: Data was collected from online focus groups with various stakeholders involved in the randomisation process. Focus groups were recorded and then transcribed verbatim. A thematic analysis was used to analyse the transcripts., Results: Twenty-five participants from twenty clinical trials units across the UK were recruited to take part in one of four focus groups. Four main themes were identified: how randomisation methods are selected; researchers' opinions of the different methods; which features of the method are desirable and ways to measure method features. Most researchers agree that the randomisation method should be selected based on key trial characteristics; however, for many, a unit standard is in place. Opinions of methods were varied with some participants favouring stratified blocks and others favouring minimisation. This was generally due to researchers' perception of the effect these methods had on balance and predictability. Generally, predictability was considered more important than balance as adjustments cannot be made for it; however, most researchers felt that the importance of these two methods was dependent on the design of the study. Balance is usually evaluated by tabulating variables by treatment arm and looking for perceived imbalances, predictability was generally considered much harder to measure, partly due to differing definitions., Conclusion: There is a wide variety in practice on how randomisation methods are selected and researcher's opinions on methods. The difference in practice observed when looking at randomisation method selection can be explained by a difference in unit practice, and also by a difference in researchers prioritisation of balance and predictability. The findings of this study show a need for more guidance on randomisation method selection., (© 2024. The Author(s).)

Objective: Catheter-related sepsis (CRS) is a major complication with significant morbidity and mortality. Evidence is lacking regarding the most appropriate antiseptic for skin disinfection before percutaneous central venous catheter (PCVC) insertion in preterm neonates. To inform the feasibility and design of a definitive randomised controlled trial (RCT) of two antiseptic formulations, we conducted the Antiseptic Randomised Controlled Trial for Insertion of Catheters (ARCTIC) feasibility study to assess catheter colonisation, sepsis, and skin morbidity., Design: Feasibility RCT., Setting: Two UK tertiary-level neonatal intensive care units., Patients: Preterm infants born <34 weeks' gestation scheduled to undergo PCVC insertion., Interventions: Skin disinfection with either 2% chlorhexidine gluconate (CHG)-aqueous or 2% CHG-70% isopropyl alcohol (IPA) before PCVC insertion and at removal., Primary Outcome: Proportion in the 2% CHG-70% IPA arm with a colonised catheter at removal., Main Feasibility Outcomes: Rates of: (1) CRS, catheter-associated sepsis (CAS), and CRS/CAS per 1,000 PCVC days; (2) recruitment and retention; (3) data completeness., Safety Outcomes: Daily skin morbidity scores recorded from catheter insertion until 48 hours post-removal., Results: 116 babies were randomised. Primary outcome incidence was 4.1% (95% confidence interval: 0.9% to 11.5%). Overall catheter colonisation rate was 5.2% (5/97); CRS 2.3/1000 catheter days; CAS 14.8/1000 catheter days. Recruitment, retention and data completeness were good. No major antiseptic-related skin injury was reported., Conclusions: A definitive comparative efficacy trial is feasible, but the very low catheter colonisation rate would make a large-scale RCT challenging due to the very large sample size required. ARCTIC provides preliminary reassurance supporting potential safe use of 2% CHG-70% IPA and 2% CHG-aqueous in preterm neonates., Trial Registration Number: ISRCTN82571474., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

The Covid-19 pandemic and mitigation approaches, including lockdowns and school closures, are thought to have negatively impacted children and young people's (CYP) mental health. However, the impact for clinically referred CYP is less clear. We investigated differences in the mental health of CYP referred to specialist Child and Adolescent Mental Health Services (CAMHS) before and since the onset of the pandemic. Using baseline data (self- and parent- completed Mood and Feelings Questionnaire and Strengths and Difficulties Questionnaire) from an ongoing RCT (STADIA; ISRCTN: 15748675) in England involving 5-17-year-olds with emotional difficulties recently referred to CAMHS (non-urgent referrals), with repeated cross-sectional comparisons of CYP (n = 1028) recruited during 5 different time  periods: (1) Before schools were closed (Group 1 (pre-pandemic); n = 308; 27.08.2019-20.03.2020). (2) Early pandemic period until schools fully re-opened, which included the first national lockdown, its easing and the summer holidays (Group 2 (in-pandemic); n = 183; 21.03.2020-31.08.2020). (3) The following school-term-schools fully re-opened and remained open, including during the second national lockdown (Group 3 (in-pandemic); n = 204; 01.09.2020-18.12.2020). (4) Schools closed as part of the third national lockdown (Group 4 (in-pandemic); n = 101; 05.01.2021-07.03.2021). (5) Schools re-opened and remained open, until the school summer holidays (Group 5 (in-pandemic); n = 232; 08.03.2021-16.07.2021). Most CYP scored above cutoff for emotional problems and depression, with three-quarters meeting criteria for a probable disorder ('caseness'). The groups did not differ on parent-rated mental health measures. However, self-rated emotional problems, depression, functional impairment and caseness appeared to be higher amongst participants recruited in the two periods following school re-openings. In particular, functional impairment and caseness were greater in Group 5 compared with Group 2. Although symptom severity or impairment did not change in the initial pandemic period, self-reported difficulties were greater during the periods after schools re-opened. This suggests possible greater stresses in the adjustment to re-starting school following recurrent lockdowns and school closures., (© 2022. The Author(s).)

Background: Patient-reported outcome measures (PROMs) are commonly used in eczema clinical trials. Several trials have used PROMs weekly for symptom monitoring. However, the increased frequency of patient-reported symptom monitoring may prompt participants to enhance the self-management of eczema and increase standard topical treatment use that can lead to improvements in outcomes over time. This is concerning as weekly symptom monitoring may constitute an unplanned intervention, which may mask small treatment effects and make it difficult to identify changes in the eczema resulting from the treatment under investigation., Objectives: To evaluate the effect of weekly patient-reported symptom monitoring on participants' outcomes and to inform the design of future eczema trials., Methods: This was an online parallel-group nonblinded randomized controlled trial. Parents/carers of children with eczema and young people and adults with eczema were recruited online, excluding people scoring < 3 points on the Patient Oriented Eczema Measure (POEM), to avoid floor effects. Electronic PROMs were used for data collection. Participants were allocated using online randomization (1 : 1) to weekly POEM for 7 weeks (intervention) or no POEM during this period (control). The primary outcome was change in eczema severity based on POEM scores, assessed at baseline and week 8. Secondary outcomes included change in standard topical treatment use and data completeness at follow-up. Analyses were conducted according to randomized groups in those with complete data at week 8., Results: A total of 296 participants were randomized from 14 September 2021 to 16 January 2022 (71% female, 77% white, mean age 26.7 years). The follow-up completion rate was 81.7% [n = 242; intervention group, n = 118/147 (80.3%); control group n = 124/149 (83.2%)]. After adjusting for baseline disease severity and age, eczema severity improved in the intervention group (mean difference in POEM score -1.64, 95% confidence interval -2.91 to -0.38; P = 0.01). No between-group differences were noted in the use of standard topical treatments and data completeness at follow-up., Conclusions: Weekly patient-reported symptom monitoring led to a small perceived improvement in eczema severity., Competing Interests: Conflicts of interest K.S.T. is a member of the Harmonising Outcome Measures for Eczema (HOME) Executive Group., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Existing guidelines recommend statisticians remain blinded to treatment allocation prior to the final analysis and that any interim analyses should be conducted by a separate team from the one undertaking the final analysis. However, there remains substantial variation in practice between UK Clinical Trials Units (CTUs) when it comes to blinding statisticians. Therefore, the aim of this study was to develop guidance to advise CTUs on a risk-proportionate approach to blinding statisticians within clinical trials., Methods: This study employed a mixed methods approach involving three stages: (I) a quantitative study using a cohort of 200 studies (from a major UK funder published between 2016 and 2020) to assess the impact of blinding statisticians on the proportion of trials reporting a statistically significant finding for the primary outcome(s); (II) a qualitative study using focus groups to determine the perspectives of key stakeholders on the practice of blinding trial statisticians; and (III) combining the results of stages I and II, along with a stakeholder meeting, to develop guidance for UK CTUs., Results: After screening abstracts, 179 trials were included for review. The results of the primary analysis showed no evidence that involvement of an unblinded trial statistician was associated with the likelihood of statistically significant findings being reported, odds ratio (OR) 1.02 (95% confidence interval (CI) 0.49 to 2.13). Six focus groups were conducted, with 37 participants. The triangulation between stages I and II resulted in developing 40 provisional statements. These were rated independently by the stakeholder group prior to the meeting. Ten statements reached agreement with no agreement on 30 statements. At the meeting, various factors were identified that could influence the decision of blinding the statistician, including timing, study design, types of intervention and practicalities. Guidance including 21 recommendations/considerations was developed alongside a Risk Assessment Tool to provide CTUs with a framework for assessing the risks associated with blinding/not blinding statisticians and for identifying appropriate mitigation strategies., Conclusions: This is the first study to develop a guidance document to enhance the understanding of blinding statisticians and to provide a framework for the decision-making process. The key finding was that the decision to blind statisticians should be based on the benefits and risks associated with a particular trial., (© 2023. The Author(s).)

Background: When conducting a randomised controlled trial, there exist many different methods to allocate participants, and a vast array of evidence-based opinions on which methods are the most effective at doing this, leading to differing use of these methods. There is also evidence that study characteristics affect the performance of these methods, but it is unknown whether the study design affects researchers' decision when choosing a method., Methods: We conducted a review of papers published in five journals in 2019 to assess which randomisation methods are most commonly being used, as well as identifying which aspects of study design, if any, are associated with the choice of randomisation method. Randomisation methodology use was compared with a similar review conducted in 2014., Results: The most used randomisation method in this review is block stratification used in 162/330 trials. A combination of simple, randomisation, block randomisation, stratification and minimisation make up 318/330 trials, with only a small number of more novel methods being used, although this number has increased marginally since 2014. More complex methods such as stratification and minimisation seem to be used in larger multicentre studies., Conclusions: Within this review, most methods used can be classified using a combination of simple, block stratification and minimisation, suggesting that there is not much if any increase in the uptake of newer more novel methods. There seems to be a noticeable polarisation of method use, with an increase in the use of simple methods, but an increase in the complexity of more complex methods, with greater numbers of variables included in the analysis, and a greater number of strata., (© 2022. The Author(s).)

Background: Blinding is an established approach in clinical trials which aims to minimise the risk of performance and detection bias. There is little empirical evidence to guide UK clinical trials units (CTUs) about the practice of blinding statisticians. Guidelines recommend that statisticians remain blinded to allocation prior to the final analysis. As these guidelines are not based on empirical evidence, this study undertook a qualitative investigation relating to when and how statisticians should be blinded in clinical trials., Methods: Data were collected through online focus groups with various stakeholders who work in the delivery and oversight of clinical trials. Recordings of the focus groups were transcribed verbatim and thematic analysis was used to analyse the transcripts., Results: Thirty-seven participants from 19 CTUs participated in one of six focus groups. Four main themes were identified, namely statistical models of work, factors affecting the decision to blind statisticians, benefits of blinding/not blinding statisticians and practicalities. Factors influencing the decision to blind the statistician included available resources, study design and types of intervention and outcomes and analysis. Although blinding of the statistician is perceived as a desirable mitigation against bias, there was uncertainty about the extent to which an unblinded statistician might impart bias. Instead, in most cases, the insight that the statistician offers was deemed more important to delivery of a trial than the risk of bias they may introduce if unblinded. Blinding of statisticians was only considered achievable with the appropriate resource and staffing, which were not always available. In many cases, a standard approach to blinding was therefore considered unrealistic and impractical; hence the need for a proportionate risk assessment approach identifying possible mitigations., Conclusions: There was wide variation in practice between UK CTUs regarding the blinding of trial statisticians. A risk assessment approach would enable CTUs to identify risks associated with unblinded statisticians conducting the final analysis and alternative mitigation strategies. The findings of this study will be used to design guidance and a tool to support this risk assessment process., (© 2022. The Author(s).)

Introduction: Emotional disorders (such as anxiety and depression) are associated with considerable distress and impairment in day-to-day function for affected children and young people and for their families. Effective evidence-based interventions are available but require appropriate identification of difficulties to enable timely access to services. Standardised diagnostic assessment (SDA) tools may aid in the detection of emotional disorders, but there is limited evidence on the utility of SDA tools in routine care and equipoise among professionals about their clinical value., Methods and Analysis: A multicentre, two-arm, parallel group randomised controlled trial, with embedded qualitative and health economic components. Participants will be randomised in a 1:1 ratio to either the Development and Well-Being Assessment SDA tool as an adjunct to usual clinical care, or usual care only. A total of 1210 participants (children and young people referred to outpatient, specialist Child and Adolescent Mental Health Services with emotional difficulties and their parent/carers) will be recruited from at least 6 sites in England. The primary outcome is a clinician-made diagnosis about the presence of an emotional disorder within 12 months of randomisation. Secondary outcomes include referral acceptance, diagnosis and treatment of emotional disorders, symptoms of emotional difficulties and comorbid disorders and associated functional impairment., Ethics and Dissemination: The study received favourable opinion from the South Birmingham Research Ethics Committee (Ref. 19/WM/0133). Results of this trial will be reported to the funder and published in full in the Health Technology Assessment (HTA) Journal series and also submitted for publication in a peer reviewed journal., Trial Registration Number: ISRCTN15748675; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: In the UK, approximately 8% of live births are preterm (before 37 weeks gestation), more than 90% of whom are born between 30 and 36 weeks, forming the largest proportion of a neonatal units' workload. Neonatologists are cautious in initiating full milk feeds for preterm infants due to fears of necrotising enterocolitis (NEC). There is now evidence to dispute this fear. Small studies have shown that feeding preterm infants full milk feeds enterally from birth could result in a shorter length of hospital stay, which is important to parents, clinicians and NHS services without increasing the risk of NEC. This trial aims to investigate whether full milk feeds initiated in the first 24 h after birth reduces the length of hospital stay in comparison to introduction of gradual milk feeding with IV fluids or parenteral nutrition., Methods: FEED1 is a multi-centre, open, parallel group, randomised, controlled superiority trial of full milk feeds initiated on the day of birth versus gradual milk feeds for infants born at 30 +0 to 32 +6 (inclusive) weeks gestation. Recruitment will take place in around 40 UK neonatal units. Mothers will be randomised 1:1 to full milk feeds, starting at 60 ml/kg day, or gradual feeds, as per usual local practice. Mother's expressed breast milk will always be the first choice of milk, though will likely be supplemented with formula or donor breast milk in the first few days. Feeding data will be collected until full milk feeds are achieved (≥ 140 ml/kg/day for 3 consecutive days). The primary outcome is length of infant hospital stay. Additional data will be collected 6 weeks post-discharge. Follow-up at 2 years (corrected gestational age) is planned. The sample size is 2088 infants to detect a between group difference in length of stay of 2 days. Accounting for multiple births, this requires 1700 women to be recruited. Primary analysis will compare the length of hospital stay between groups, adjusting for minimisation variables and accounting for multiple births., Discussion: This trial will provide high-quality evidence on feeding practices for preterm infants. Full milk feeds from day of birth could result in infants being discharged sooner., Trial Registration: ISRCTN ISRCTN89654042 . Prospectively registered on 23 September 2019: ISRCTN is a primary registry of the WHO ICTRP network, and all items from the WHO Trial Registration dataset are included., (© 2022. The Author(s).)

Background: Loss to follow-up resulting in missing outcomes compromises the validity of trial results by reducing statistical power, negatively affecting generalisability and undermining assumptions made at analysis, leading to potentially biased and misleading results. Evidence that incentives are effective at improving response rates exists, but there is little evidence regarding the best approach, especially in the field of perinatal medicine. The NIHR-funded SIFT trial follow-up of infants at 2 years of age provided an ideal opportunity to address this remaining uncertainty., Methods: Participants: parents of infants from participating neonatal units in the UK and Ireland followed up for SIFT (multicentre RCT investigating two speeds of feeding in babies with gestational age at birth < 32 weeks and/or birthweight < 1500 g)., Interventions: parents were randomly allocated to receive incentives (£15 gift voucher) before or after questionnaire return. The objective was to establish whether offering an unconditional incentive in advance or promising an incentive on completion of a questionnaire (conditional) improved the response rate in parents of premature babies. The primary outcome was questionnaire response rate. Permuted block randomisation was performed (variable size blocks), stratified by SIFT allocation (slower/faster feeds) and single/multiple birth. Multiple births were given the same incentives allocation. Parents were unaware that they were in an incentives SWAT; SIFT office staff were not blinded to allocation., Results: Parents of 923 infants were randomised: 459 infants allocated to receive incentive before, 464 infants allocated to receive incentive after; analysis was by intention to treat. Allocation to the incentive before completion led to a significantly higher response rate, 83.0% (381/459) compared to the after-completion group, 76.1% (353/464); adjusted absolute difference of 6.8% (95% confidence interval 1.6% to 12.0%). Giving an incentive in advance is the more costly approach, but the mean difference of ~£3 per infant is small given the higher return., Conclusions: An unconditional incentive in advance led to a significantly higher response rate compared to the promise of an incentive on completion. Against a backdrop of falling response rates to questionnaires, incentives can be an effective way to increase returns., Trial Registration: SIFT ( ISRCTN76463425 ). Registered on March 5, 2013.; SWAT registration (SWAT 69 available from http://www.qub.ac.uk/sites/TheNorthernIrelandNetworkforTrialsMethodologyResearch/FileStore/Filetoupload,864297,en.pdf ). Registered on June 27, 2016., (© 2021. The Author(s).)

Objective: To evaluate the cost-effectiveness of two rates of enteral feed advancement (18 vs 30 mL/kg/day) in very preterm and very low birth weight infants., Design: Within-trial economic evaluation alongside a multicentre, two-arm parallel group, randomised controlled trial (Speed of Increasing milk Feeds Trial)., Setting: 55 UK neonatal units from May 2013 to June 2015., Patients: Infants born <32 weeks' gestation or <1500 g, receiving less than 30 mL/kg/day of milk at trial enrolment. Infants with a known severe congenital anomaly, no realistic chance of survival, or unlikely to be traceable for follow-up, were ineligible., Interventions: When clinicians were ready to start advancing feed volumes, infants were randomised to receive daily increments in feed volume of 30 mL/kg (intervention) or 18 mL/kg (control)., Main Outcome Measure: Cost per additional survivor without moderate to severe neurodevelopmental disability at 24 months of age corrected for prematurity., Results: Average costs per infant were slightly higher for faster feeds compared with slower feeds (mean difference £267, 95% CI -6928 to 8117). Fewer infants achieved the principal outcome of survival without moderate to severe neurodevelopmental disability at 24 months in the faster feeds arm (802/1224 vs 848/1246). The stochastic cost-effectiveness analysis showed a likelihood of worse outcomes for faster feeds compared with slower feeds., Conclusions: The stochastic cost-effectiveness analysis shows faster feeds are broadly equivalent on cost grounds. However, in terms of outcomes at 24 months age (corrected for prematurity), faster feeds are harmful. Faster feeds should not be recommended on either cost or effectiveness grounds to achieve the primary outcome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Adjudication of the primary outcome in randomised trials is thought to control misclassification. We investigated the amount of misclassification needed before adjudication changed the primary trial results. Patients (or materials) and methods: We included data from five randomised stroke trials. Differential misclassification was introduced for each primary outcome until the estimated treatment effect was altered. This was simulated 1000 times. We calculated the between-simulation mean proportion of participants that needed to be differentially misclassified to alter the treatment effect. In addition, we simulated hypothetical trials with a binary outcome and varying sample size (1000-10,000), overall event rate (10%-50%) and treatment effect (0.67-0.90). We introduced non-differential misclassification until the treatment effect was non-significant at 5% level., Results: For the five trials, the range of unweighted kappa values were reduced from 0.89-0.97 to 0.65-0.85 before the treatment effect was altered. This corresponded to 2.1%-6% of participants misclassified differentially for trials with a binary outcome. For the hypothetical trials, those with a larger sample size, stronger treatment effect and overall event rate closer to 50% needed a higher proportion of events non-differentially misclassified before the treatment effect became non-significant., Discussion: We found that only a small amount of differential misclassification was required before adjudication altered the primary trial results, whereas a considerable proportion of participants needed to be misclassified non-differentially before adjudication changed trial conclusions. Given that differential misclassification should not occur in trials with sufficient blinding, these results suggest that central adjudication is of most use in studies with unblinded outcome assessment., Conclusion: For trials without adequate blinding, central adjudication is vital to control for differential misclassification. However, for large blinded trials, adjudication is of less importance and may not be necessary., (© European Stroke Organisation 2020.)

Background: A nested case-control study is an efficient design that can be embedded within an existing cohort study or randomised trial. It has a number of advantages compared to the conventional case-control design, and has the potential to answer important research questions using untapped prospectively collected data., Methods: We demonstrate the utility of the matched nested case-control design by applying it to a secondary analysis of the Abnormal Doppler Enteral Prescription Trial. We investigated the role of milk feed type and changes in milk feed type in the development of necrotising enterocolitis in a group of 398 high risk growth-restricted preterm infants., Results: Using matching, we were able to generate a comparable sample of controls selected from the same population as the cases. In contrast to the standard case-control design, exposure status was ascertained prior to the outcome event occurring and the comparison between the cases and matched controls could be made at the point at which the event occurred. This enabled us to reliably investigate the temporal relationship between feed type and necrotising enterocolitis., Conclusions: A matched nested case-control study can be used to identify credible associations in a secondary analysis of clinical trial data where the exposure of interest was not randomised, and has several advantages over a standard case-control design. This method offers the potential to make reliable inferences in scenarios where it would be unethical or impractical to perform a randomised clinical trial.

Objective: The objective of this study was to examine methodological and reporting characteristics of systematic reviews and meta-analyses which compare diagnostic test accuracy (DTA) of multiple index tests, identify good practice, and develop guidance for better reporting., Study Design and Setting: Methodological survey of 127 comparative or multiple tests reviews published in 74 different general medical and specialist journals. We summarized methods and reporting characteristics that are likely to differ between reviews of a single test and comparative reviews. We then developed guidance to enhance reporting of test comparisons in DTA reviews., Results: Of 127 reviews, 16 (13%) reviews restricted study selection and test comparisons to comparative accuracy studies while the remaining 111 (87%) reviews included any study type. Fifty-three reviews (42%) statistically compared test accuracy with only 18 (34%) of these using recommended methods. Reporting of several items-in particular the role of the index tests, test comparison strategy, and limitations of indirect comparisons (i.e., comparisons involving any study type)-was deficient in many reviews. Five reviews with exemplary methods and reporting were identified., Conclusion: Reporting quality of reviews which evaluate and compare multiple tests is poor. The guidance developed, complemented with the exemplars, can assist review authors in producing better quality comparative reviews., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background: Observational data suggest that slowly advancing enteral feeds in preterm infants may reduce necrotising enterocolitis but increase late-onset sepsis. The Speed of Increasing milk Feeds Trial (SIFT) compared two rates of feed advancement., Objective: To determine if faster (30 ml/kg/day) or slower (18 ml/kg/day) daily feed increments improve survival without moderate or severe disability and other morbidities in very preterm or very low-birthweight infants., Design: This was a multicentre, two-arm, parallel-group, randomised controlled trial. Randomisation was via a web-hosted minimisation algorithm. It was not possible to safely and completely blind caregivers and parents., Setting: The setting was 55 UK neonatal units, from May 2013 to June 2015., Participants: The participants were infants born at < 32 weeks' gestation or a weight of < 1500 g, who were receiving < 30 ml/kg/day of milk at trial enrolment., Interventions: When clinicians were ready to start advancing feed volumes, the infant was randomised to receive daily feed increments of either 30 ml/kg/day or 18 ml/kg/day. In total, 1400 infants were allocated to fast feeds and 1404 infants were allocated to slow feeds., Main Outcome Measures: The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months of age, corrected for gestational age. The secondary outcomes were mortality; moderate or severe neurodevelopmental disability at 24 months corrected for gestational age; death before discharge home; microbiologically confirmed or clinically suspected late-onset sepsis; necrotising enterocolitis (Bell's stage 2 or 3); time taken to reach full milk feeds (tolerating 150 ml/kg/day for 3 consecutive days); growth from birth to discharge; duration of parenteral feeding; time in intensive care; duration of hospital stay; diagnosis of cerebral palsy by a doctor or other health professional; and individual components of the definition of moderate or severe neurodevelopmental disability., Results: The results showed that survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 out of 1224 (65.5%) infants allocated to faster increments and 848 out of 1246 (68.1%) infants allocated to slower increments (adjusted risk ratio 0.96, 95% confidence interval 0.92 to 1.01). There was no significant difference between groups in the risk of the individual components of the primary outcome or in the important hospital outcomes: late-onset sepsis (adjusted risk ratio 0.96, 95% confidence interval 0.86 to 1.07) or necrotising enterocolitis (adjusted risk ratio 0.88, 95% confidence interval 0.68 to 1.16). Cost-consequence analysis showed that the faster feed increment rate was less costly but also less effective than the slower rate in terms of achieving the primary outcome, so was therefore found to not be cost-effective. Four unexpected serious adverse events were reported, two in each group. None was assessed as being causally related to the intervention., Limitations: The study could not be blinded, so care may have been affected by knowledge of allocation. Although well powered for comparisons of all infants, subgroup comparisons were underpowered., Conclusions: No clear advantage was identified for the important outcomes in very preterm or very low-birthweight infants when milk feeds were advanced in daily volume increments of 30 ml/kg/day or 18 ml/kg/day. In terms of future work, the interaction of different milk types with increments merits further examination, as may different increments in infants at the extremes of gestation or birthweight., Trial Registration: Current Controlled Trials ISRCTN76463425., 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. 24, No. 18. See the NIHR Journals Library website for further project information., Competing Interests: Jane Abbott, Janet Berrington, Elaine Boyle, Ursula Bowler, Jon Dorling, Nicholas Embleton, Kenny McCormick, William McGuire, Edmund Jaszczuk, Samantha Johnson, Madeleine Hurd, Oliver Hewer, Andrew King, Alison Leaf, Louise Linsell, Christopher Partlett, David Murray, Ben Stenson, Judith Rankin and Tracy Roberts report funding from the National Institute for Health Research (NIHR) for the trial. Jon Dorling, Janet Berrington, Elaine Boyle, Nicholas Embleton, Edmund Jaszczuk, Samantha Johnson, Andrew King, Louise Linsell, William McGuire, Christopher Partlett and Tracy Roberts report receipt of funding from NIHR, outside the submitted work. Jon Dorling reports grants from Nutrinia (Nazareth, Israel) outside the submitted work; specifically, he was funded for part of his salary to work as an expert advisor on a trial of enteral insulin. Furthermore, he was a member of the NIHR Health Technology Assessment (HTA) General Board (2017–18) and the NIHR HTA Maternity, Newborn and Child Health Panel (2013–18). Elaine Boyle reports grants from the Medical Research Council and East Midlands Specialised Commissioning Group outside the submitted work. Janet Berrington reports grants and personal fees from Danone Early Life Nutrition (Paris, France) and grants from Prolacta Biosciences US (Duarte, CA, USA) outside the submitted work. Nicholas Embleton reports grants from Prolacta Biosciences US and Danone Early Life Nutrition and personal fees from Nestlé Nutrition Institute (Vevey, Switzerland), Baxter (Deerfield, IL, USA) and Fresenius Kabi (Bad Homburg vor der Höhe, Germany) outside the submitted work. Samantha Johnson reports grants from Action Medical Research (Horsham, UK), EU Horizon 2020 (Brussels, Belguim), the Medical Research Council (London, UK), Sparks (London, UK) and the Nuffield Foundation (London, UK) outside the submitted work. William McGuire is a member of the NIHR HTA Commissioning Board (2013 to present) and the HTA and Efficacy and Mechanism Evaluation Editorial Board (2012 to present). Edmund Juszczak was a member of the NIHR HTA General Board from 2016 to 2017 and the HTA funding committee (commissioning) from 2013 to 2016.

Background: Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited., Methods: We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy., Results: Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16)., Conclusions: There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.)., (Copyright © 2019 Massachusetts Medical Society.)

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., Competing Interests: Oliver Rivero-Arias, Ursula Bowler, Edmund Juszczak, Marian Knight, Louise Linsell and Julia Sanders report receipt of funding from the National Institute for Health Research (NIHR) outside the submitted work. Edmund Juszczak reports Clinical Trials Unit infrastructure support funding received from NIHR and active membership of the Health Technology Assessment (HTA) Commissioning Board and the HTA General Board while the study was being undertaken.

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., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Interferon gamma release assays (IGRAs) are blood tests recommended for the diagnosis of tuberculosis (TB) infection. There is currently uncertainty about the role and clinical utility of IGRAs in the diagnostic workup of suspected active TB in routine NHS clinical practice., Objectives: To compare the diagnostic accuracy and cost-effectiveness of T-SPOT. TB ® (Oxford Immunotec, Abingdon, UK) and QuantiFERON ® TB GOLD In-Tube (Cellestis, Carnegie, VIC, Australia) for diagnosis of suspected active TB and to estimate the diagnostic accuracy of second-generation IGRAs., Design: Prospective within-patient comparative diagnostic accuracy study., Setting: Secondary care., Participants: Adults (aged ≥ 16 years) presenting as inpatients or outpatients at 12 NHS hospital trusts in London, Slough, Oxford, Leicester and Birmingham with suspected active TB., Interventions: The index tests [T-SPOT. TB and QuantiFERON GOLD In-Tube (QFT-GIT)] and new enzyme-linked immunospot assays utilising novel Mycobacterium tuberculosis antigens (Rv3615c, Rv2654, Rv3879c and Rv3873) were verified against a composite reference standard applied by a panel of clinical experts blinded to IGRA results., Main Outcome Measures: Sensitivity, specificity, predictive values and likelihood ratios were calculated to determine diagnostic accuracy. A decision tree model was developed to calculate the incremental costs and incremental health utilities [quality-adjusted life-years (QALYs)] of changing from current practice to using an IGRA as an initial rule-out test., Results: A total of 363 patients had active TB (culture-confirmed and highly probable TB cases), 439 had no active TB and 43 had an indeterminate final diagnosis. Comparing T-SPOT. TB and QFT-GIT, the sensitivities [95% confidence interval (CI)] were 82.3% (95% CI 77.7% to 85.9%) and 67.3% (95% CI 62.1% to 72.2%), respectively, whereas specificities were 82.6% (95% CI 78.6% to 86.1%) and 80.4% (95% CI 76.1% to 84.1%), respectively. T-SPOT. TB was more sensitive than QFT-GIT (relative sensitivity 1.22, 95% CI 1.14 to 1.31; p  < 0.001), but the specificities were similar (relative specificity 1.02, 95% CI 0.97 to 1.08; p  = 0.3). For both IGRAs the sensitivity was lower and the specificity was higher for human immunodeficiency virus (HIV)-positive than for HIV-negative patients. The most promising novel antigen was Rv3615c. The added value of Rv3615c to T-SPOT. TB was a 9% (95% CI 5% to 12%) relative increase in sensitivity at the expense of specificity, which had a relative decrease of 7% (95% CI 4% to 10%). The use of current IGRA tests for ruling out active TB is unlikely to be considered cost-effective if a QALY was valued at £20,000 or £30,000. For T-SPOT. TB , the probability of being cost-effective for a willingness to pay of £20,000/QALY was 26% and 21%, when patients with indeterminate test results were excluded or included, respectively. In comparison, the QFT-GIT probabilities were 8% and 6%. Although the use of IGRAs is cost saving, the health detriment is large owing to delay in diagnosing active TB, leading to prolonged illness. There was substantial between-patient variation in the tests used in the diagnostic pathway., Limitations: The recruitment target for the HIV co-infected population was not achieved., Conclusions: Although T-SPOT. TB was more sensitive than QFT-GIT for the diagnosis of active TB, the tests are insufficiently sensitive for ruling out active TB in routine clinical practice in the UK. Novel assays offer some promise., Future Work: The novel assays require evaluation in distinct clinical settings and in immunosuppressed patient groups., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and the NIHR Health Protection Research Unit in Respiratory Infections, Imperial College London, London, UK., Competing Interests: Ajit Lalvani is the named inventor for several patents underpinning T-cell-based diagnosis including interferon gamma, enzyme-linked immunospot assay, ESAT-6, CFP-10, Rv3615c, Rv3873 and Rv3879c. He has royalty entitlements from the University of Oxford spin-out company (Oxford Immunotec plc), in which he has held a minority share of equity and he is a member of the Efficacy and Mechanism Evaluation Board. Jonathan J Deeks is a member of the Health Technology Assessment (HTA) Commissioning Board and the HTA Efficient Study Designs Board. Onn Min Kon is chairperson of the UK Joint Tuberculosis Committee. Peter White has received research funding from Otsuka SA for a retrospective study of multidrug-resistant tuberculosis treatment in several eastern European countries outside the submitted work. He received grants from the Medical Research Council during the conduct of the study.

Background: The clinical utility of interferon-γ release assays (IGRAs) for diagnosis of active tuberculosis is unclear, although they are commonly used in countries with a low incidence of tuberculosis. We aimed to resolve this clinical uncertainty by determining the accuracy and utility of commercially available and second-generation IGRAs in the diagnostic assessment of suspected tuberculosis in a low-incidence setting., Methods: We did a prospective cohort study of adults with suspected tuberculosis in routine secondary care in England. Patients were tested for Mycobacterium tuberculosis infection at baseline with commercially available (T-SPOT.TB and QuantiFERON-TB Gold In-Tube [QFT-GIT]) and second-generation (incorporating novel M tuberculosis antigens) IGRAs and followed up for 6-12 months to establish definitive diagnoses. Sensitivity, specificity, positive and negative likelihood ratios, and predictive values of the tests were determined., Findings: Of the 1060 adults enrolled in the study, 845 were included in the analyses and 363 were diagnosed with tuberculosis. Sensitivity of T-SPOT.TB for all tuberculosis diagnosis, including culture-confirmed and highly probable cases, was 81·4% (95% CI 76·6-85·3), which was higher than QFT-GIT (67·3% [62·0-72·1]). Second-generation IGRAs had a sensitivity of 94·0% (90·0-96·4) for culture-confirmed tuberculosis and 89·2% (85·2-92·2) when including highly probable tuberculosis, giving a negative likelihood ratio for all tuberculosis cases of 0·13 (95% CI 0·10-0·19). Specificity ranged from 86·2% (95% CI 82·3-89·4) for T-SPOT.TB to 80·0% (75·6-83·8) for second-generation IGRAs., Interpretation: Commercially available IGRAs do not have sufficient accuracy for diagnostic evaluation of suspected tuberculosis. Second-generation tests, however, might have sufficiently high sensitivity, low negative likelihood ratio, and correspondingly high negative predictive value in low-incidence settings to facilitate prompt rule-out of tuberculosis., Funding: National Institute for Health Research., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications., Objective: To determine whether or not enteral supplementation with bovine lactoferrin (The Tatua Cooperative Dairy Company Ltd, Morrinsville, New Zealand) reduces the risk of late-onset infection (acquired > 72 hours after birth) and other morbidity and mortality in very preterm infants., Design: Randomised, placebo-controlled, parallel-group trial. Randomisation was via a web-based portal and used an algorithm that minimised for recruitment site, weeks of gestation, sex and single versus multiple births., Setting: UK neonatal units between May 2014 and September 2017., Participants: Infants born at < 32 weeks' gestation and aged < 72 hours at trial enrolment., Interventions: Eligible infants were allocated individually (1 : 1 ratio) to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) or sucrose (British Sugar, Peterborough, UK) placebo (same dose) once daily from trial entry until a postmenstrual age of 34 weeks. Parents, caregivers and outcome assessors were unaware of group assignment., Outcomes: Primary outcome - microbiologically confirmed or clinically suspected late-onset infection. Secondary outcomes - microbiologically confirmed infection; all-cause mortality; severe necrotising enterocolitis (NEC); retinopathy of prematurity (ROP); bronchopulmonary dysplasia (BPD); a composite of infection, NEC, ROP, BPD and mortality; days of receipt of antimicrobials until 34 weeks' postmenstrual age; length of stay in hospital; and length of stay in intensive care, high-dependency and special-care settings., Results: Of 2203 enrolled infants, primary outcome data were available for 2182 infants (99%). In the intervention group, 316 out of 1093 (28.9%) infants acquired a late-onset infection versus 334 out of 1089 (30.7%) infants in the control group [adjusted risk ratio (RR) 0.95, 95% confidence interval (CI) 0.86 to 1.04]. There were no significant differences in any secondary outcomes: microbiologically confirmed infection (RR 1.05, 99% CI 0.87 to 1.26), mortality (RR 1.05, 99% CI 0.66 to 1.68), NEC (RR 1.13, 99% CI 0.68 to 1.89), ROP (RR 0.89, 99% CI 0.62 to 1.28), BPD (RR 1.01, 99% CI 0.90 to 1.13), or a composite of infection, NEC, ROP, BPD and mortality (RR 1.01, 99% CI 0.94 to 1.08). There were no differences in the number of days of receipt of antimicrobials, length of stay in hospital, or length of stay in intensive care, high-dependency or special-care settings. There were 16 reports of serious adverse events for infants in the lactoferrin group and 10 for infants in the sucrose group., Conclusions: Enteral supplementation with bovine lactoferrin does not reduce the incidence of infection, mortality or other morbidity in very preterm infants., Future Work: Increase the precision of the estimates of effect on rarer secondary outcomes by combining the data in a meta-analysis with data from other trials. A mechanistic study is being conducted in a subgroup of trial participants to explore whether or not lactoferrin supplementation affects the intestinal microbiome and metabolite profile of very preterm infants., Trial Registration: Current Controlled Trials ISRCTN88261002., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 74. See the NIHR Journals Library website for further project information. This trial was also sponsored by the University of Oxford, Oxford, UK. The funder provided advice and support and monitored study progress but did not have a role in study design or data collection, analysis and interpretation., Competing Interests: Since November 2013, Edmund Juszczak has been a member of the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) General Funding Committee and HTA Commissioning Funding Committee. William McGuire is a member of the NIHR HTA Commissioning Board and the NIHR HTA and Efficacy and Mechanism Evaluation Editorial Board. Jon Dorling is a member of the NIHR HTA General Board (from 2017) and the Maternal, Neonatal and Child Health Panel (from 2013). Nicholas Embleton reports grants from Prolacta Biosciences Inc. (Duarte, CA, USA), grants from Danone Nutricia Early Life Nutrition (Paris, France), personal fees from Nestlé Nutrition Institute (Vevey, Switzerland) and personal fees from Baxter Healthcare Ltd (Newbury, UK) outside the submitted work.

Background: Sepsis is one of the most important causes of maternal death and severe morbidity worldwide. Studies conducted both in the UK and US have documented an additional risk associated with operative vaginal delivery. However, a Cochrane review, updated in 2017, identified only one small trial of prophylactic antibiotics following operative vaginal delivery, which included a total of 393 women. Given the small size of that trial, it recommended that further robust evidence is needed. Operative vaginal delivery rates vary worldwide, but typically 5-10% of women have operative vaginal births. A conservative estimated incidence of maternal infection following operative vaginal delivery is 4%, based on the one previous trial. There is, therefore, considerable scope for direct patient benefit from an effective preventive strategy., Methods/design: This protocol describes a multicentre, randomised, blinded, placebo-controlled trial aiming to recruit 3424 participants from over 20 hospital sites in the UK. Women who have undergone an operative vaginal delivery at 36 +0 weeks or greater gestation with no indication for ongoing antibiotics in the postpartum period and no contra-indications to prophylactic co-amoxiclav, will be randomised to receive a single intravenous dose of co-amoxiclav or placebo. The primary outcome will be confirmed or suspected maternal infection within 6 weeks of delivery, as defined by one of (a) a new prescription of antibiotics for presumed perineal wound-related infection, endometritis or uterine infection, urinary tract infection with systemic features or other systemic infection, (b) systemic infection confirmed with a culture or (c) endometritis as defined by the US Centers for Disease Control and Prevention. Outcome information will be collected by a single telephone interview and questionnaire, with clinical data collected from medical records or the hospital laboratory if necessary, at 6 weeks post-delivery., Discussion: This randomised trial will investigate whether a prophylactic dose of antibiotic following operative vaginal delivery can reduce the incidence of infection and sepsis. If shown to be effective, this could lead to a change in recommended practice and the prevention of infection. Conversely, if there is no significant difference between the two arms, then this could contribute to a reduction in antibiotic use and improved antimicrobial stewardship., Trial Registration: ISRCTN11166984 . Registered on 23 September 2015.

Background: In a random effects meta-analysis model, true treatment effects for each study are routinely assumed to follow a normal distribution. However, normality is a restrictive assumption and the misspecification of the random effects distribution may result in a misleading estimate of overall mean for the treatment effect, an inappropriate quantification of heterogeneity across studies and a wrongly symmetric prediction interval., Methods: We focus on problems caused by an inappropriate normality assumption of the random effects distribution, and propose a novel random effects meta-analysis model where a Box-Cox transformation is applied to the observed treatment effect estimates. The proposed model aims to normalise an overall distribution of observed treatment effect estimates, which is sum of the within-study sampling distributions and the random effects distribution. When sampling distributions are approximately normal, non-normality in the overall distribution will be mainly due to the random effects distribution, especially when the between-study variation is large relative to the within-study variation. The Box-Cox transformation addresses this flexibly according to the observed departure from normality. We use a Bayesian approach for estimating parameters in the proposed model, and suggest summarising the meta-analysis results by an overall median, an interquartile range and a prediction interval. The model can be applied for any kind of variables once the treatment effect estimate is defined from the variable., Results: A simulation study suggested that when the overall distribution of treatment effect estimates are skewed, the overall mean and conventional I 2 from the normal random effects model could be inappropriate summaries, and the proposed model helped reduce this issue. We illustrated the proposed model using two examples, which revealed some important differences on summary results, heterogeneity measures and prediction intervals from the normal random effects model., Conclusions: The random effects meta-analysis with the Box-Cox transformation may be an important tool for examining robustness of traditional meta-analysis results against skewness on the observed treatment effect estimates. Further critical evaluation of the method is needed.

A random effects meta-analysis combines the results of several independent studies to summarise the evidence about a particular measure of interest, such as a treatment effect. The approach allows for unexplained between-study heterogeneity in the true treatment effect by incorporating random study effects about the overall mean. The variance of the mean effect estimate is conventionally calculated by assuming that the between study variance is known; however, it has been demonstrated that this approach may be inappropriate, especially when there are few studies. Alternative methods that aim to account for this uncertainty, such as Hartung-Knapp, Sidik-Jonkman and Kenward-Roger, have been proposed and shown to improve upon the conventional approach in some situations. In this paper, we use a simulation study to examine the performance of several of these methods in terms of the coverage of the 95% confidence and prediction intervals derived from a random effects meta-analysis estimated using restricted maximum likelihood. We show that, in terms of the confidence intervals, the Hartung-Knapp correction performs well across a wide-range of scenarios and outperforms other methods when heterogeneity was large and/or study sizes were similar. However, the coverage of the Hartung-Knapp method is slightly too low when the heterogeneity is low (I 2  < 30%) and the study sizes are quite varied. In terms of prediction intervals, the conventional approach is only valid when heterogeneity is large (I 2  > 30%) and study sizes are similar. In other situations, especially when heterogeneity is small and the study sizes are quite varied, the coverage is far too low and could not be consistently improved by either increasing the number of studies, altering the degrees of freedom or using variance inflation methods. Therefore, researchers should be cautious in deriving 95% prediction intervals following a frequentist random-effects meta-analysis until a more reliable solution is identified. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd., (© 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.)