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ObjectiveTo identify demographic, premorbid and injury-related factors, or biomarkers associated with long-term (≥3 months) adverse outcomes in children after mild traumatic brain injury (mTBI).DesignScoping review of literature.PatientsChildren and adolescents with mTBI.Risk factorsAny demographic, premorbid and injury-related factors, or biomarkers were included. We excluded genetic and treatment-related factors.Main outcome measuresPostconcussion syndrome (PCS), recovery.ResultsSeventy-three publications were included, reporting 12 long-term adverse outcomes, including PCS in 12 studies and recovery in 29 studies. Additional outcomes studied were symptom scores/severity (n=22), quality of life (n=9) and cognitive function (n=9). Forty-nine risk factors were identified across studies. Risk factors most often assessed were sex (n=28), followed by age (n=23), injury mechanism = (n=22) and prior mTBI (n=18). The influence of these and other risk factors on outcomes of mTBI were inconsistent across the reviewed literature.ConclusionsThe most researched risk factors are sex, age and mechanism of injury, but their effects have been estimated inconsistently and did not show a clear pattern. The most studied outcomes are recovery patterns and symptom severity. However, these may not be the most important outcomes for clinicians and patients. Future primary studies in this area should focus on patient-important outcomes. Population-based prospective studies are needed that address prespecified hypotheses on the relationship of risk factors with given outcomes to enable reliable prediction of long-term adverse outcomes for childhood mTBI.

BackgroundVirtual wards (VWs) deliver multidisciplinary care at home to people with frailty at high risk of a crisis or in-crisis, aiming to mitigate the risk of hospital admission. Different VWs models exist and evidence of effectiveness is inconsistent.AimWe conducted a rapid realist review to identify different types of VWs, and to develop explanations for how and why VWs could deliver effective frailty management.MethodsWe searched published and grey literature to identify evidence on VWs for frailty, based in Great Britain and Ireland. Information on how and why virtual wards might ‘work’ was extracted and synthesised in two rounds with input from clinicians and patient/public contributors, generating 12 hypothesised context-mechanism-outcome configurations.ResultsWe included 17 published and 11 grey literature documents. VWs could be short-term and acute (1-21 days), or longer-term and preventative (3-7 months).Effective VW operation requires common standards agreements, information sharing processes, an appropriate multidisciplinary team that plans patient care remotely, and good co-ordination. VWs may enable delivery of frailty interventions through appropriate selection of patients, comprehensive assessment including medication review, integrated case management, and proactive care. Important components for patients and caregivers are their communication with the VW, their experience of care at home, and feeling included, safe and empowered to manage their condition.ConclusionsInsights gained from this review could inform implementation or evaluation of VWs for frailty. A combination of acute and longer-term VWs may be needed, within a whole system approach. An emphasis on proactive care is recommended.

OBJECTIVE: This study comprehensively reviewed clinical trials that investigated the effect of immediate dentin sealing (IDS) technique on postoperative sensitivity (POS) and clinical performance of indirect restorations.MATERIALS AND METHODS: The systematic review was conducted according to the preferred reporting items for systematic reviews and meta-analyses statement, and was guided by the PICOS strategy. Clinical trials in which adult patients received at least one indirect restoration cemented with IDS approach and one restoration cemented following the delayed dentin sealing (DDS) were considered.RESULTS: Following title screening and full-text reading, four studies met the inclusion criteria and were included for qualitative synthesis, while two studies were selected for quantitative synthesis. According to Risk of bias-2 tool, two studies were classified as "some concerns" for the outcome POS. No statistically significant differences were found between teeth restored with indirect restorations using the IDS and DDS approach for POS (p > 0.05), neither at the baseline (very low certainty of evidence according to GRADE) nor after 2 years of follow-up (low certainty of evidence according to GRADE).CONCLUSION: There is low-certainty evidence that IDS does not reduce POS in teeth restored with indirect restorations.CLINICAL SIGNIFICANCE: There is no clinical evidence to favor IDS over DDS when restoring teeth with indirect restorations.

BackgroundCentor and modified Centor (McIsaac) scores are clinical prediction rules used to diagnose group A streptococcus infection in patients with pharyngitis. They aim to identify the patients most likely to benefit from antibiotic treatment and reduce unnecessary antibiotic prescribing.ObjectivesTo systematically review the literature on the diagnostic accuracy of McIsaac and Centor, and produce pooled estimates of accuracy at each score threshold, in patients presenting with acute pharyngitis to secondary care.Data sourcesMEDLINE, Embase and Web of science were searched from inception to June 2021.Eligibility criteriaStudies that included patients who presented with acute pharyngitis to hospital emergency departments and outpatient clinics, reported McIsaac or Centor scores, and used throat cultures and/or rapid antigen detection tests as the reference standard.Review methodsThe review protocol was registered on PROSPERO (CRD42021267413). Study selection was performed by two reviewers independently and risk of bias was assessed using the QUADAS-2 tool. Sensitivities and specificities of McIsaac and Centor scores were pooled at each threshold using bivariate random effects meta-analysis.ResultsThe McIsaac score had higher estimated sensitivity and lower specificity relative to Centor scores at equivalent thresholds, but with wide and overlapping confidence regions. Using either score as a triage to rapid antigen detection tests (RADT) to decide antibiotic treatment would reduce antibiotic prescription to non-GAS pharyngitis patients relative to RADT test for everyone, but also reduce antibiotic prescription to GAS patients.ConclusionOur findings suggest that high thresholds of either score excludes a proportion of true positive patients from potentially beneficial treatment. The use of a low threshold before a RADT test would reduce antibiotic prescription relative to prescribing based on score only but the economics and clinical effectiveness of this combination strategy needs assessment. We recommend continued use of existing antibiotic prescribing guidelines and patient safety netting.

In this experimental study, picosecond laser treatment was performed on a nickel-based superalloy Nimonic 263, aiming to investigate the surface effects induced by irradiation in different atmospheric conditions and, concerning changes in surface composition, regarding the possibility for improvement of its functionality. Besides the varying laser parameters, such as a number of pulses and pulse energy, environmental conditions are also varied. All surface modifications were carried out in standard laboratory conditions and a nitrogen- and argon-rich atmosphere. The resulting topography effects depend on the specific laser treatment and could be categorized as increased roughness, crater formation, and formation of the laser-induced periodic surface structures (LIPSS). Changes in the chemical surface composition are distinguished as the potential formation of the protective oxides/nitrides on the sample surface. Numerous characterization techniques analyse the resulting effects on the topography and surface parameters. The multi-response parametric optimization of the picosecond laser process was performed using an advanced statistical method based on Taguchi’s robust parameter design. Finally, the optimal parameter conditions for Nimonic 263 modification are suggested.

INTRODUCTION: Randomised trials are often funded by commercial companies and methodological studies support a widely held suspicion that commercial funding may influence trial results and conclusions. However, these studies often have a risk of confounding and reporting bias. The risk of confounding is markedly reduced in meta-epidemiological studies that compare fairly similar trials within meta-analyses, and risk of reporting bias is reduced with access to unpublished data. Therefore, we initiated the COMFIT (COMmercial Funding In Trials) study aimed at investigating the impact of commercial funding on estimated intervention effects in randomised clinical trials based on a consortium of researchers who agreed to share meta-epidemiological study datasets with information on meta-analyses and trials included in meta-epidemiological studies. Here, we describe the COMFIT study, its database, and descriptive results.METHODS: We included meta-epidemiological studies with published or unpublished data on trial funding source and results or conclusions. We searched five bibliographic databases and other sources. We invited authors of eligible meta-epidemiological studies to join the COMFIT consortium and to share data. The final construction of the COMFIT database involves checking data quality, identifying trial references, harmonising variable categories, and removing non-informative meta-analyses as well as correlated meta-analyses and trial results.PRELIMINARY RESULTS: We included data from 17 meta-epidemiological studies, covering 728 meta-analyses and 6841 trials. Seven studies (405 meta-analyses, 3272 trials) had not published analyses on the impact of commercial funding, but shared unpublished data on funding source.CONCLUSIONS: We established the COMFIT consortium and database. Once completed, the database will enable comprehensive analyses of the impact of commercial funding on trial results and conclusions with increased statistical power and a markedly reduced risk of confounding and reporting bias. This article is protected by copyright. All rights reserved.

BackgroundAcute respiratory tract infections (RTIs) are the most common reason to seek medical care, with many patients receiving inappropriate antibiotics. Novel testing approaches to identify aetiology at the point-of-care are required to accurately guide antibiotic treatment.ObjectiveTo assess the diagnostic accuracy of biomarker combinations to rapidly differentiate between acute bacterial or viral RTI aetiology.Data sourcesMEDLINE, Embase and Web of Science databases were searched to February 2021.Study eligibility criteriaDiagnostic accuracy studies comparing accuracy of point-of-care and rapid diagnostic tests in primary or secondary care, consisting of biomarker combinations, to identify bacterial or viral aetiology of RTI.MethodsRisk of bias was assessed using the QUADAS-2 tool. Sensitivity and specificity of tests reported by more than one study were meta-analysed using a random effects model.ResultsTwenty observational studies (3514 patients) were identified. Eighteen were judged at high risk of bias. For bacterial aetiologies, sensitivity ranged from 61% to 100% and specificity from 18% to 96%. For viral aetiologies, sensitivity ranged from 59% to 97% and specificity from 74% to 100%. Studies evaluating two commercial tests were meta-analysed. For ImmunoXpert, the summary sensitivity and specificity were 85% (95% CI 75%–91%, k = 4) and 86% (95% CI 73%–93%, k = 4) for bacterial infections, and 90% (95% CI 79%–96%, k = 3) and 92% (95% CI 83%–96%, k = 3) for viral infections, respectively. FebriDx had pooled sensitivity and specificity of 84% (95% CI 75%–90%, k = 4) and 93% (95% CI 90%–95%, k = 4) for bacterial infections, and 87% (95% CI 72%–95%; k = 4) and 82% (95% CI 66%–86%, k = 4) for viral infections, respectively.ConclusionCombinations of biomarkers show potential clinical utility in discriminating the aetiology of RTIs. However, the limitations in the evidence base, due to a high proportion of studies with high risk of bias, preclude firm conclusions. Future research should be in primary care and evaluate patient outcomes and cost-effectiveness with experimental study designs.Clinical trialPROSPERO registration number: CRD42020178973.

In this study, the design of surface pattering with the co-existence of micrometer and nanometer features was carried out to improve the arrayed surface structures on Ti/Cu/Ti and Ti/Cu/Zr/Ti multilayer thin films by picosecond laser processing. The novel composite structure consisted of two layers of Ti and subsurface distributed Cu and Zr layers (thickness of 10 nm) were deposited by ion sputtering on Si substrate to the total thickness of 300 nm. The changes in the composition, surface morphology, and wetting properties after laser modification was monitored by Scanning Electron Microscopy with Energy Dispersive Spectroscopy (SEM–EDS), optical profilometry, and wettability measurements. It was found that laser irradiation can induce the melting of material with the formation of wrinkled periodic structures at the edges of the laser spots in both systems as a consequence of the hydrodynamic effects. Another interesting result was that the periodic structure in form of LSFL (low spatial frequency LIPSS) ripples was numerous but slightly pronounced in Ti/Cu/Zr/Ti, due to the presence of the Zr component as an ultra-thin subsurface layer, which most likely favored creating LIPSS. Such laser texturing has been used in the biomedical field as a method of developing surface topography, coated with oxides to potentially improve cell response via suitable surface wetting for a biological system.

BackgroundPaediatric abusive head trauma (AHT) occurs in young children due to violent shaking or blunt impact. Educational and behavioural programmes modifying parent/infant interactions may aid primary prevention. This systematic review aims to assess the effectiveness of such interventions to prevent AHT in infants.MethodsWe searched Embase, MEDLINE, PsycINFO, The Cochrane library, CINAHL databases and trial registries to September 2021, for studies assessing the effectiveness of educational and behavioural interventions in preventing AHT. Eligible interventions had to include messaging about avoiding or dangers of infant shaking. Randomised controlled trials (RCTs) reporting results for primary (AHT, infant shaking) or secondary outcomes (including parental responses to infant crying, mental wellbeing), and non-randomised studies (NRSs) reporting primary outcomes were included. Evidence from combinable studies was synthesised using random-effects meta-analyses. Certainty of evidence was assessed using GRADE framework. PROSPERO registration CRD42020195644.FindingsOf 25 identified studies, 16 were included in meta-analyses. Five NRSs reported results for AHT, of which four were meta-analysed (summary odds ratio [OR] 0.95, 95 % confidence intervals [CI] 0.80–1.13). Two studies assessed self-reported shaking (one cluster-RCT, OR 0.11, 95 % CI 0.02–0.53; one cohort study, OR 0.36, 95 % CI 0.20–0.64, not pooled). Meta-analyses of secondary outcomes demonstrated marginal improvements in parental response to inconsolable crying (summary mean difference 1.58, 95 % CI 0.11–3.06, on a 100-point scale) and weak evidence that interventions increased walking away from crying infants (summary incidence rate ratio 1.52, 95 % CI 0.94–2.45). No intervention effects were found in meta-analyses of parental mental wellbeing or other responses to crying.InterpretationLow certainty evidence suggests that educational programmes for AHT prevention are not effective in preventing AHT. There is low to moderate certainty evidence that educational interventions have no effect or only marginally improve some parental responses to infant crying.

Abstract The surface of a titanium-based alloy Ti6Al4V was subjected to modifications by a near-IR femtosecond Ti:Sapphire laser, emitting at 775 nm pulses of 200 fs duration, in single-pulse and multi-pulse regimes, with up to 400 accumulated pulses, and pulse energies ranging from 2.5 to 250 $$\upmu $$ μ J. The whole range of induced effects is presented, from gentle ablation and pattern occurrence to substantial crater formation. Very observable laser-induced parallel periodic surface structures are reported, appearing both within the damage spot area, with low fluences, and at the peripheries of the craters, with higher fluences—but also on crater walls, and inside the crater structures. Damage threshold fluences $$({F}_{\mathrm{th}})$$ ( F th ) and the incubation factor $$(\zeta )$$ ( ζ ) were also determined. Graphic abstract

Childhood obesity is a global public health concern. While evidence from a recent comprehensive Cochrane review indicates school-based interventions can prevent obesity, we still do not know how or for whom these work best. We aimed to identify the contextual and mechanistic factors associated with obesity prevention interventions implementable in primary schools. A realist synthesis following the Realist And Meta-narrative Evidence Syntheses–Evolving Standards (RAMESES) guidance was with eligible studies from the 2019 Cochrane review on interventions in primary schools. The initial programme theory was developed through expert consensus and stakeholder input and refined with data from included studies to produce a final programme theory including all of the context-mechanism-outcome configurations. We included 24 studies (71 documents) in our synthesis. We found that baseline standardised body mass index (BMIz) affects intervention mechanisms variably as a contextual factor. Girls, older children and those with higher parental education consistently benefitted more from school-based interventions. The key mechanisms associated with beneficial effect were sufficient intervention dose, environmental modification and the intervention components working together as a whole. Education alone was not associated with favourable outcomes. Future interventions should go beyond education and incorporate a sufficient dose to trigger change in BMIz. Contextual factors deserve consideration when commissioning interventions to avoid widening health inequalities.

Time-integrated optical emission analysis of laser-induced plasma on Teflon is presented. Plasma was induced under atmospheric pressure air using transversely excited atmospheric CO2 laser pulses. Teflon is a C-based polymer that is, among other things, interesting as a substrate for laser-induced breakdown spectroscopy analysis of liquid samples. This study aimed to determine the optimal experimental conditions for obtaining neutral and ionized C spectral lines and C2 and CN molecular band emission suitable for spectrochemical purposes. Evaluation of plasma parameters was done using several spectroscopic techniques. Stark profiles of appropriate C ionic lines were used to determine electron number density. The ratio of the integral intensity of ionic-to-atomic C spectral lines was used to determine the ionization temperature. A spectral emission of C2 Swan and CN violet bands system was used to determine the temperature of the colder, peripheral parts of plasma. We critically analyzed the use of molecular emission bands as a tool for plasma diagnostics and suggested methods for possible improvements.

Background Systematic reviews of prenatal alcohol exposure effects generally only include conventional observational studies. However, estimates from such studies are prone to confounding and other biases. Objectives To systematically review the evidence on the effects of prenatal alcohol exposure from randomized controlled trials (RCTs) and observational designs using alternative analytical approaches to improve causal inference. Search strategy Medline, Embase, Web of Science, PsychINFO from inception to 21 June 2018. Manual searches of reference lists of retrieved papers. Selection criteria RCTs of interventions to stop/reduce drinking in pregnancy and observational studies using alternative analytical methods (quasi-experimental studies e.g. Mendelian randomization and natural experiments, negative control comparisons) to determine the causal effects of prenatal alcohol exposure on pregnancy and longer-term offspring outcomes in human studies. Data collection and analysis One reviewer extracted data and another checked extracted data. Risk of bias was assessed using customized risk of bias tools. A narrative synthesis of findings was carried out and a meta-analysis for one outcome. Main results Twenty-three studies were included, representing five types of study design, including 1 RCT, 9 Mendelian randomization and 7 natural experiment studies, and reporting on over 30 outcomes. One study design–outcome combination included enough independent results to meta-analyse. Based on evidence from several studies, we found a likely causal detrimental role of prenatal alcohol exposure on cognitive outcomes, and weaker evidence for a role in low birthweight. Conclusion None of the included studies was judged to be at low risk of bias in all domains, results should therefore be interpreted with caution. Systematic review registration This study is registered with PROSPERO, registration number CRD42015015941

Summary Limited uptake of minimally invasive surgery (MIS) of the aorta hinders assessment of its efficacy compared to median sternotomy (MS). The objective of this systematic review is to compare operative and perioperative outcomes for MIS versus MS. Online databases Medline, EMBASE, Cochrane Library and Web of Science were searched from inception until July 2018. Both randomized and observational studies of patients undergoing aortic root, ascending aorta or aortic arch surgery by MIS versus MS were eligible for inclusion. Primary outcomes were 30-day mortality, reoperation for bleeding, perioperative renal impairment and neurological events. Intraoperative and postoperative timing measures were also evaluated. Thirteen observational studies were included comparing 1101 MIS and 1405 MS patients. The overall quality of evidence was very low for all outcomes. Mortality and the incidence of stroke were similar between the 2 cohorts. Meta-analysis demonstrated increased length of cardiopulmonary bypass (CPB) time for patients undergoing MS [standardized mean difference 0.36, 95% confidence interval (CI) 0.15–0.58; P = 0.001]. Patients receiving MS spent more time in hospital (standardized mean difference 0.30, 95% CI 0.17–0.43; P

Objectiveto identify contextual and mechanistic factors associated with outcomes of school-based obesity prevention interventions which may be implementable in UK primary schools.Designrealist synthesis following REMESES guidance. We developed an initial programme theory through expert consensus and stakeholder input and refined it with data from included studies to produce a final programme theory including all context-mechanism-outcome configurations.Settingprimary schoolsParticipantschildren aged 4-12Interventionsincluded in the 2019 Cochrane review on prevention of childhood obesityOutcomesBMIzResultsWe included 24 studies comprised of 71 documents in our synthesis. We found that contextual factors such as baseline BMIz affects intervention mechanisms variably, while girls, older children and those with higher parental education consistently benefitted more from school-based interventions. Key mechanisms associated with beneficial effect were sufficient intervention dose, environmental modification, and the intervention components working together as a whole. Education alone did not produce favourable outcomes.ConclusionsInterventions should go beyond education and incorporate a sufficient dose to trigger change in BMIz. Contextual factors deserve consideration when commissioning interventions to avoid widening health inequalities.

IMPORTANCE: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. OBJECTIVE: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. DESIGN, SETTING, AND PARTICIPANTS: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I(2) statistic. The primary analysis was an inverse variance–weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance–weighted fixed-effect analysis using risk ratios. EXPOSURES: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). MAIN OUTCOMES AND MEASURES: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. RESULTS: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as “low” for 6 of the 7 mortality results and as “some concerns” in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P

There is increasing interest in the influence of place on health, and the need to distinguish between environmental and individual level factors. For environmental-level factors, current evidence tends to show associations through cross-sectional and uncontrolled longitudinal analyses rather than through more robust study designs that can provide stronger causal evidence. We restricted this systematic review to randomised (or cluster) randomised controlled trials and controlled before-and-after studies of changes to the built environment. Date of search was December 2016. We identified 14 studies. No evidence was found of an effect on mental health from ‘urban regeneration’ and ‘improving green infrastructure’ studies. Beneficial effects on quality-of-life outcomes from ‘improving green infrastructure’ were found in two studies. One ‘improving green infrastructure’ study reported an improvement in social isolation. Risk-of-bias assessment indicated robust data from only four studies. Overall, evidence for the impact of built environment interventions on mental health and quality-of-life is weak. Future research requires more robust study designs and interdisciplinary research involving public health, planning and urban design experts.

Background The evidence for treatment decision‐making in emergency general surgery has not been summarized previously. The aim of this overview was to review the quantity and quality of systematic review evidence for the most common emergency surgical conditions. Methods Systematic reviews of the most common conditions requiring unplanned admission and treatment managed by general surgeons were eligible for inclusion. The Centre for Reviews and Dissemination databases were searched to April 2014. The number and type (randomized or non‐randomized) of included studies and patients were extracted and summarized. The total number of unique studies was recorded for each condition. The nature of the interventions (surgical, non‐surgical invasive or non‐invasive) was documented. The quality of reviews was assessed using the AMSTAR checklist. Results The 106 included reviews focused mainly on bowel conditions (42), appendicitis (40) and gallstone disease (17). Fifty‐one (48·1 per cent) included RCTs alone, 79 (74·5 per cent) included at least one RCT and 25 (23·6 per cent) summarized non‐randomized evidence alone. Reviews included 727 unique studies, of which 30·3 per cent were RCTs. Sixty‐five reviews compared different types of surgical intervention and 27 summarized trials of surgical versus non‐surgical interventions. Fifty‐seven reviews (53·8 per cent) were rated as low risk of bias. Conclusion This overview of reviews highlights the need for more and better research in this field., Evidence still limited

Background: Randomised trials included in meta-analyses are often affected by bias caused by methodological flaws or limitations, but the degree of bias is unknown. Two proposed methods adjust trial results for bias using: (1) empirical evidence from published meta-epidemiological studies; or (2) expert opinion.Methods: We investigated agreement between data-based and opinion-based approaches to assessing bias in each of four domains: sequence generation, allocation concealment, blinding and incomplete outcome data. From each sampled meta-analysis, a pair of trials with the highest and lowest empirical model-based bias estimates was selected. Independent assessors were asked which trial within each pair was judged more biased on the basis of detailed trial design summaries.Results: Assessors judged trials to be equally biased in 68% of pairs evaluated. When assessors judged one trial as more biased, the proportion of judgements agreeing with the model-based ranking was highest for allocation concealment (79%) and blinding (79%) and lower for sequence generation (59%) and incomplete outcome data (56%).Conclusions: Most trial pairs found to be discrepant empirically were judged to be equally biased by assessors. We found moderate agreement between opinion and data-based evidence in pairs where assessors ranked one trial as more biased.

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ObjectiveTo examine the design characteristics, risk of bias, and reporting adequacy of pivotal randomised controlled trials of cancer drugs approved by the European Medicines Agency (EMA).DesignCross sectional analysis.SettingEuropean regulatory documents, clinical trial registry records, protocols, journal publications, and supplementary appendices.Eligibility criteriaPivotal randomised controlled trials of new cancer drugs approved by the EMA between 2014 and 2016.Main outcome measuresStudy design characteristics (randomisation, comparators, and endpoints); risk of bias using the revised Cochrane tool (bias arising from the randomisation process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result); and reporting adequacy (completeness and consistency of information in trial protocols, publications, supplementary appendices, clinical trial registry records, and regulatory documents).ResultsBetween 2014 and 2016, the EMA approved 32 new cancer drugs on the basis of 54 pivotal studies. Of these, 41 (76%) were randomised controlled trials and 13 (24%) were either non-randomised studies or single arm studies. 39/41 randomised controlled trials had available publications and were included in our study. Only 10 randomised controlled trials (26%) measured overall survival as either a primary or coprimary endpoint, with the remaining trials evaluating surrogate measures such as progression free survival and response rates. Overall, 19 randomised controlled trials (49%) were judged to be at high risk of bias for their primary outcome. Concerns about missing outcome data (n=10) and measurement of the outcome (n=7) were the most common domains leading to high risk of bias judgments. Fewer randomised controlled trials that evaluated overall survival as the primary endpoint were at high risk of bias than those that evaluated surrogate efficacy endpoints (2/10 (20%)v16/29 (55%), respectively). When information available in regulatory documents and the scientific literature was considered separately, overall risk of bias judgments differed for eight randomised controlled trials (21%), which reflects reporting inadequacies in both sources of information. Regulators identified additional deficits beyond the domains captured in risk of bias assessments for 10 drugs (31%). These deficits included magnitude of clinical benefit, inappropriate comparators, and non-preferred study endpoints, which were not disclosed as limitations in scientific publications.ConclusionsMost pivotal studies forming the basis of EMA approval of new cancer drugs between 2014 and 2016 were randomised controlled trials. However, almost half of these were judged to be at high risk of bias based on their design, conduct, or analysis, some of which might be unavoidable because of the complexity of cancer trials. Regulatory documents and the scientific literature had gaps in their reporting. Journal publications did not acknowledge the key limitations of the available evidence identified in regulatory documents.

Assessment of risk of bias is regarded as an essential component of a systematic review on the effects of an intervention. The most commonly used tool for randomised trials is the Cochrane risk-of-bias tool. We updated the tool to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.

Summary Flaws in the conduct of randomized trials can lead to biased estimation of the intervention effect. Methods for adjustment of within-trial biases in meta-analysis include the use of empirical evidence from an external collection of meta-analyses, and the use of expert opinion informed by the assessment of detailed trial information. Our aim is to present methods to combine these two approaches to gain the advantages of both. We make use of the risk of bias information that is routinely available in Cochrane reviews, by obtaining empirical distributions for the bias associated with particular bias profiles (combinations of risk of bias judgements). We propose three methods: a formal combination of empirical evidence and opinion in a Bayesian analysis; asking experts to give an opinion on bias informed by both summary trial information and a bias distribution from the empirical evidence, either numerically or by selecting areas of the empirical distribution. The methods are demonstrated through application to two example binary outcome meta-analyses. Bias distributions based on opinion informed by trial information alone were most dispersed on average, and those based on opinions obtained by selecting areas of the empirical distribution were narrowest. Although the three methods for combining empirical evidence with opinion vary in ease and speed of implementation, they yielded similar results in the two examples.

Randomized clinical trials underpin evidence-based clinical practice, but flaws in their conduct may lead to biased estimates of intervention effects and hence invalid treatment recommendations. The main approach to the empirical study of bias is to collate a number of meta-analyses and, within each, compare the results of trials with and without a methodological characteristic such as blinding of participants and health professionals. Estimated within-meta-analysis differences are combined across meta-analyses, leading to an estimate of mean bias. Such “meta-epidemiological” studies are published in increasing numbers and have the potential to inform trial design, assessment of risk of bias, and reporting guidelines. However, their interpretation is complicated by issues of confounding, imprecision, and applicability. We developed a guide for interpreting meta-epidemiological studies, illustrated using MetaBLIND, a large study on the impact of blinding. Applying generally accepted principles of research methodology to meta-epidemiology, we framed 10 questions covering the main issues to consider when interpreting results of such studies, including risk of systematic error, risk of random error, issues related to heterogeneity, and theoretical plausibility. We suggest that readers of a meta-epidemiological study reflect comprehensively on the research question posed in the study, whether an experimental intervention was unequivocally identified for all included trials, the risk of misclassification of the trial characteristic, and the risk of confounding, i.e the adequacy of any adjustment for the likely confounders. We hope that our guide to interpretation of results of meta-epidemiological studies is helpful for readers of such studies.

To develop ROBIS, a new tool for assessing the risk of bias in systematic reviews (rather than in primary studies).We used four-stage approach to develop ROBIS: define the scope, review the evidence base, hold a face-to-face meeting, and refine the tool through piloting.ROBIS is currently aimed at four broad categories of reviews mainly within health care settings: interventions, diagnosis, prognosis, and etiology. The target audience of ROBIS is primarily guideline developers, authors of overviews of systematic reviews ("reviews of reviews"), and review authors who might want to assess or avoid risk of bias in their reviews. The tool is completed in three phases: 1) assess relevance (optional), 2) identify concerns with the review process, and 3) judge risk of bias. Phase 2 covers four domains through which bias may be introduced into a systematic review: 1) study eligibility criteria; 2) identification and selection of studies; 3) data collection and study appraisal; and 4) synthesis and findings. Phase 3 assesses the overall risk of bias in the interpretation of review findings and whether this considered limitations identified in any of the phase 2 domains. Signaling questions are included to help judge concerns with the review process (phase 2) and the overall risk of bias in the review (phase 3); these questions flag aspects of review design related to the potential for bias and aim to help assessors judge risk of bias in the review process, results, and conclusions.ROBIS is the first rigorously developed tool designed specifically to assess the risk of bias in systematic reviews.

Unplanned general surgery represents a major workload and requires comprehensive evaluation with appropriate outcomes. This study aimed to summarize current reporting of patient-reported outcomes (PROs) in randomized clinical trials (RCTs) in unplanned general surgery. A systematic review identified RCTs reporting PROs in the commonest six areas of unplanned general surgery. Details of the PRO measures were examined using the CONSORT extension for PRO reporting in RCTs. Extracted information about each PRO domain included the reporting of baseline PROs, rationale for PRO selection and whether PRO findings were used in conjunction with clinical outcomes to inform treatment recommendations. The internal validity of included studies was assessed using the Cochrane risk of bias tool. 12,519 abstracts were screened and 20 RCTs containing data from 2037 patients included. Included studies used 14 separate PRO measures covering 35 different health domains. A visual analogue assessment of pain was most frequently reported (n = 13). Reporting of baseline PRO data was uncommon (11/35 PRO domains). The rationale for PRO data collection and a PRO-specific hypothesis were provided for 9 (25.7 %) and 5 (14.3 %) domains, respectively. Seventeen RCTs (85.0 %) used the PRO data alongside clinical outcomes to inform treatment recommendations. Of the 116 risk of bias assessments, 77 (66.0 %) were judged as high or unclear. There is a lack of well designed, and conducted RCTs in unplanned general surgery that include PROs. Future work to define relevant PROs and methods for optimal assessment are needed to inform health care decision-making.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Objectives To evaluate the association between the quality of relationship between a person with dementia and their family carer and outcomes for the person with dementia. Design Systematic review. Eligibility criteria Cohort studies of people with clinically diagnosed dementia and their main carers. Exposures of interest were any elements of relationship quality, for example, attachment style, expressed emotion and coping style. Our primary outcome was institutionalisation, and secondary outcomes were hospitalisation, death, quality of life and behavioural and psychiatric symptoms of dementia ('challenging behaviour'). Data sources MEDLINE, Embase, Web of Science, PsycInfo, the Cochrane Library and Opengrey were searched from inception to May 2017. Study appraisal and synthesis methods The Newcastle-Ottawa Scale was used to assess risk of bias. A narrative synthesis of results was performed due to differences between studies. Results Twenty studies were included. None of the studies controlled for all prespecified confounding factors (age, gender, socioeconomic status and severity of dementia). Reporting of results was inadequate with many studies simply reporting whether associations were statistically significant' without providing effect size estimates or CIs. There was a suggestion of an association between relationship factors and global challenging behaviour. All studies evaluating global challenging behaviour provided statistical evidence of an association (most P values below 0.02). There was no consistent evidence for an association for any other outcome assessed. Conclusions There is currently no strong or consistent evidence on the effects of relationship factors on institutionalisation, hospitalisation, death or quality of life for people with dementia. There was a suggestion of an association between relationship factors and challenging behaviour, although the evidence for this was weak. To improve our ability to support those with dementia and their families, further robust studies are needed. PROSPERO registration number CRD42015020518.

Objective To compare the efficacy, safety, and cost effectiveness of direct acting oral anticoagulants (DOACs) for patients with atrial fibrillation. Design Systematic review, network meta-analysis, and cost effectiveness analysis. Data sources Medline, PreMedline, Embase, and The Cochrane Library. Eligibility criteria for selecting studies Published randomised trials evaluating the use of a DOAC, vitamin K antagonist, or antiplatelet drug for prevention of stroke in patients with atrial fibrillation. Results 23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with warfarin dosed to achieve a target INR of 2.0-3.0. Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin. Conclusions The network meta-analysis informs the choice of DOACs for prevention of stroke in patients with atrial fibrillation. Several DOACs are of net benefit compared with warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis. Systematic review registration PROSPERO CRD 42013005324.

Objectives: To determine the effects of low-to-moderate levels of maternal alcohol consumption in pregnancy on pregnancy and longer-term offspring outcomes.Search Strategy: Medline, Embase, Web of Science, and Psychinfo from inception to 11-07-2016. Selection Criteria: Prospective observational studies, negative control and quasi-experimental studies of pregnant women estimating effects of light drinking in pregnancy (≤32g/week) versus abstaining. Pregnancy outcomes such as birth weight, and features of fetal alcohol syndrome were examined. Data Collection and Analysis: One reviewer extracted data and another checked extracted data. Random effects meta-analyses were performed where applicable, and a narrative summary of findings was carried out otherwise. Main Results: 24 cohort and two quasi-experimental studies were included. With the exception of birth size and gestational age, there was insufficient data to meta-analyse or make robust conclusions. Odds of small-for-gestational-age (SGA) and preterm birth were higher for babies whose mothers consumed up to 32g/week versus none, but estimates for preterm birth were also compatible with no association: summary odd ratios (OR) 1·08, 95% confidence intervals (CI) (1·02 to 1·14), I2 0%, (7 studies, all estimates were adjusted) OR 1·10, 95%CI (0·95 to1·28), I2 60%, (9 studies, includes one unadjusted estimates) respectively. The earliest time points of exposure were used in the analysis.Conclusion: Evidence of the effects of drinking

Objectives Overcrowding in the emergency department (ED) is common in the UK as in other countries worldwide. Computer simulation is one approach used for understanding the causes of ED overcrowding and assessing the likely impact of changes to the delivery of emergency care. However, little is known about the usefulness of computer simulation for analysis of ED patient flow. We undertook a systematic review to investigate the different computer simulation methods and their contribution for analysis of patient flow within EDs in the UK.Methods We searched eight bibliographic databases (MEDLINE, EMBASE, COCHRANE, WEB OF SCIENCE, CINAHL, INSPEC, MATHSCINET and ACM DIGITAL LIBRARY) from date of inception until 31 March 2016. Studies were included if they used a computer simulation method to capture patient progression within the ED of an established UK National Health Service hospital. Studies were summarised in terms of simulation method, key assumptions, input and output data, conclusions drawn and implementation of results.Results Twenty-one studies met the inclusion criteria. Of these, 19 used discrete event simulation and 2 used system dynamics models. The purpose of many of these studies (n=16; 76%) centred on service redesign. Seven studies (33%) provided no details about the ED being investigated. Most studies (n=18; 86%) used specific hospital models of ED patient flow. Overall, the reporting of underlying modelling assumptions was poor. Nineteen studies (90%) considered patient waiting or throughput times as the key outcome measure. Twelve studies (57%) reported some involvement of stakeholders in the simulation study. However, only three studies (14%) reported on the implementation of changes supported by the simulation.Conclusions We found that computer simulation can provide a means to pretest changes to ED care delivery before implementation in a safe and efficient manner. However, the evidence base is small and poorly developed. There are some methodological, data, stakeholder, implementation and reporting issues, which must be addressed by future studies.

Objectives To summarise evidence on temporary discontinuation of medications to prevent acute kidney injury (AKI). Design Systematic review and meta-analysis of randomised and non-randomised studies. Participants Adults taking diuretics, ACE inhibitors (ACEI), angiotensin receptor blockers (ARB), direct renin inhibitors, non-steroidal anti-inflammatories, metformin or sulfonylureas, experiencing intercurrent illnesses, radiological or surgical procedures. Interventions Temporary discontinuation of any of the medications of interest. Primary and secondary outcome measures Risk of AKI. Secondary outcome measures were estimated glomerular filtration rate and creatinine post-AKI, urea, systolic and diastolic blood pressure, death, clinical outcomes and biomarkers. Results 6 studies were included (1663 participants), 3 randomised controlled trials (RCTs) and 3 prospective cohort studies. The mean age ranged from 65 to 73 years, and the proportion of women ranged from 31% to 52%. All studies were in hospital settings; 5 evaluated discontinuation of medication prior to coronary angiography and 1 prior to cardiac surgery. 5 studies evaluated discontinuation of ACEI and ARBs and 1 small cohort study looked at discontinuation of non-steroidal anti-inflammatory drugs. No studies evaluated discontinuation of medication in the community following an acute intercurrent illness. There was an increased risk of AKI of around 15% in those in whom medication was continued compared with those in whom it was discontinued (relative risk (RR) 1.17, 95% CI 0.99 to 1.38; 5 studies). When only results from RCTs were pooled, the increase in risk was almost 50% (RR 1.48, 95% CI 0.84 to 2.60; 3 RCTs), but the CI was wider. There was no difference between groups for any secondary outcomes. Conclusions There is low-quality evidence that withdrawal of ACEI/ARBs prior to coronary angiography and cardiac surgery may reduce the incidence of AKI. There is no evidence of the impact of drug cessation interventions on AKI incidence during intercurrent illness in primary or secondary care. Trial registration number PROSPERO CRD42015023210.