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Introduction Severe SARS-CoV-2 infection is associated with a dysregulated immune response. Inflammatory monocytes and macrophages are crucial, promoting injurious, proinflammatory sequelae. Immunomodulation is, therefore, an attractive therapeutic strategy and we sought to test licensed and novel candidate drugs. Methods and analysis The CATALYST trial is a multiarm, open-label, multicentre, phase II platform trial designed to identify candidate novel treatments to improve outcomes of patients hospitalised with COVID-19 compared with usual care. Treatments with evidence of biomarker improvements will be put forward for larger-scale testing by current national phase III platform trials. Hospitalised patients >16 years with a clinical picture strongly suggestive of SARS-CoV-2 pneumonia (confirmed by chest X-ray or CT scan, with or without a positive reverse transcription PCR assay) and a C reactive protein (CRP) ≥40 mg/L are eligible. The primary outcome measure is CRP, measured serially from admission to day 14, hospital discharge or death. Secondary outcomes include the WHO Clinical Progression Improvement Scale as a principal efficacy assessment. Ethics and dissemination The protocol was approved by the East Midlands-Nottingham 2 Research Ethics Committee (20/EM/0115) and given urgent public health status; initial approval was received on 5 May 2020, current protocol version (V.6.0) approval on 12 October 2020. The MHRA also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. Trial registration numbers EudraCT2020-001684-89,NCT40580903.

SummaryBackgroundDysregulated inflammation is associated with poor outcomes in Coronavirus disease 2019 (COVID-19). We assessed the efficacy of namilumab, a granulocyte-macrophage colony-stimulating factor inhibitor and infliximab, a tumour necrosis factor inhibitor in hospitalised patients with COVID-19 in order to prioritise agents for phase 3 trials.MethodsIn this randomised, multi-arm, parallel group, open label, adaptive phase 2 proof-of-concept trial (CATALYST) we recruited hospitalised patients ≥ 16 years with COVID-19 pneumonia and C-reactive protein (CRP) ≥ 40mg/L in nine UK hospitals. Participants were randomly allocated with equal probability to usual care, or usual care plus a single 150mg intravenous dose of namilumab (150mg) or infliximab (5mg/kg). Randomisation was stratified for ward versus ICU. The primary endpoint was improvement in inflammation in intervention arms compared to control as measured by CRP over time, analysed using Bayesian multi-level models. ISRCTN registry number 40580903.FindingsBetween 15thJune 2020 and 18thFebruary 2021 we randomised 146 participants: 54 to usual care, 57 to namilumab and 35 to infliximab. The probabilities that namilumab and infliximab were superior to usual care in reducing CRP over time were 97% and 15% respectively. Consistent effects were seen in ward and ICU patients and aligned with clinical outcomes, such that the probability of discharge (WHO levels 1-3) at day 28 was 47% and 64% for ICU and ward patients on usual care, versus 66% and 77% for patients treated with namilumab. 134 adverse events occurred in 30/55 (54.5%) namilumab patients compared to 145 in 29/54 (53.7%) usual care patients. 102 events occurred in 20/29 (69.0%) infliximab patients versus 112 events in 17/34 (50.0%) usual care patients.InterpretationNamilumab, but not infliximab, demonstrated proof-of-concept evidence for reduction in inflammation in hospitalised patients with COVID-19 pneumonia which was consistent with secondary clinical outcomes. Namilumab should be prioritised for further investigation in COVID-19.FundingMedical Research Council.

Reproductive medicine is imbued with debates over the results of key trials. This has resulted in heterogeneity in clinical practice and a disconnect between researchers and the patient group they aim to treat. The criticisms of trials originate from the nature of reproductive health conditions and limitations imposed in designing trials to assess effect in a patient group with heterogenous pathologies leading to the same condition. This leads to challenges in balancing the difficulties of recruiting an enriched patient cohort versus the dilutionary effect and need for subgroup analysis from wider recruitment. These challenges manifest as a failure to achieve traditional statistical significance. One potential solution to overcoming these inherent challenges is that of a Bayesian statistical approach. Using examples from the literature we demonstrate the benefits of a Bayesian approach. Taking published data and using a flat prior (no background information used), a Bayesian re-analysis of the PRISM and EAGeR trials is presented. This demonstrated a 94.7% chance of progesterone and a 95.3% probability of aspirin preventing miscarriage, in contrast to the original trial conclusions. These highlight the role a Bayesian approach can play in overcoming the challenges of trials within reproductive health.

Background Optimising techniques to wean patients from invasive mechanical ventilation (IMV) remains a key goal of intensive care practice. The use of non-invasive ventilation (NIV) as a weaning strategy (transitioning patients who are difficult to wean to early NIV) may reduce mortality, ventilator-associated pneumonia and intensive care unit (ICU) length of stay. Objectives Our objectives were to determine the cost effectiveness of protocolised weaning, including early extubation onto NIV, compared with weaning without NIV in a UK National Health Service setting. Methods We conducted an economic evaluation alongside a multicentre randomised controlled trial. Patients were randomised to either protocol-directed weaning from mechanical ventilation or ongoing IMV with daily spontaneous breathing trials. The primary efficacy outcome was time to liberation from ventilation. Bivariate regression of costs and quality-adjusted life-years (QALYs) provided estimates of the incremental cost per QALY and incremental net monetary benefit (INMB) overall and for subgroups [presence/absence of chronic obstructive pulmonary disease (COPD) and operative status]. Long-term cost effectiveness was determined through extrapolation of survival curves using flexible parametric modelling. Results NIV was associated with a mean INMB of £620 ($US885) (cost-effectiveness threshold of £20,000 per QALY) with a corresponding probability of 58% that NIV is cost effective. The probability that NIV is cost effective was higher for those with COPD (84%). NIV was cost effective over 5 years, with an estimated incremental cost-effectiveness ratio of £4618 ($US6594 per QALY gained). Conclusions The probability of NIV being cost effective relative to weaning without NIV ranged between 57 and 59% overall and between 82 and 87% for the COPD subgroup. Electronic supplementary material The online version of this article (10.1007/s41669-020-00210-1) contains supplementary material, which is available to authorized users.

Purpose To examine the time to drug administration in patients with a witnessed cardiac arrest enrolled in the Pre-Hospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest (PARAMEDIC2) randomised controlled trial. Methods The PARAMEDIC2 trial was undertaken across 5 NHS ambulance services in England and Wales with randomisation between December 2014 and October 2017. Patients with an out-of-hospital cardiac arrest who were unresponsive to initial resuscitation attempts were randomly assigned to 1 mg intravenous adrenaline or matching placebo according to treatment packs that were identical apart from treatment number. Participants and study staff were masked to treatment allocation. Results 8016 patients were enrolled, 4902 sustained a witnessed cardiac arrest of whom 2437 received placebo and 2465 received adrenaline. The odds of return of spontaneous circulation decreased in both groups over time but at a greater rate in the placebo arm odds ratio (OR) 0.93 (95% CI 0.92–0.95) compared with the adrenaline arm OR 0.96 (95% CI 0.95–0.97); interaction OR: 1.03, 95% CI 1.01–1.05, p = 0.005. By contrast, although the rate of survival and favourable neurological outcome decreased as time to treatment increased, the rates did not differ between the adrenaline and placebo groups. Conclusion The rate of return of spontaneous circulation, survival and favourable neurological outcomes decrease over time. As time to drug treatment increases, adrenaline increases the chances of return of spontaneous circulation. Longer term outcomes were not affected by the time to adrenaline administration. (ISRCTN73485024). Electronic supplementary material The online version of this article (10.1007/s00134-019-05836-2) contains supplementary material, which is available to authorized users.

We report a case of hypersensitivity pneumonitis (HP) in a young person secondary to vaping. He presented with a putative diagnosis of asthma and required extracorporeal membrane oxygenationbecause of intractable respiratory failure. He developed a critical illness and steroid myopathy and required prolonged rehabilitation. Our patient fulfils diagnostic criteria for HP secondary to e-cigarettes with a positive exposure history, deterioration after skin prick testing, specific serum IgM antibodies against the implicated liquid raising the possibility that the relevant antigen was present in that liquid and radiological and histopathological features compatible with acute HP. There are two learning points. The first is always to consider a reaction to e-cigarettes in someone presenting with an atypical respiratory illness. The second is that we consider e-cigarettes as ‘much safer than tobacco’ at our peril.

IntroductionIn 2013, a single-centre study reported the safe use of esmolol in patients with septic shock and tachycardia who required vasopressor therapy for more than 24 hours. Although not powered to detect a change in mortality, marked improvements were seen in survival (adjusted HR, 0.39; 95% CI, 0.26 to 0.59; pMethods and analysisSTRESS-L is a randomised, open-label, non-blinded clinical trial which is enrolling a total of 340 patients with septic shock as defined by Sepsis-3 consensus definition and a tachycardia (heart rate ≥95 beats per minute (bpm)) after vasopressor treatment of at least 24 hours. Standard randomisation (1:1 ratio) allocates patients to receive usual care (according to international standards) versus usual care and a continuous landiolol infusion to reduce the heart rate between 80 and 94 bpm. The primary endpoint is the mean Sequential Organ Failure Assessment score over 14 days from entry into the trial and while in intensive care unit. Results will inform current clinical practice guidelines.Ethics and disseminationThis trial has clinical trial authorisation from the UK competent authority, the Medicines and Healthcare products Regulatory Agency, and has been approved by the East of England-Essex Research Ethics Committee (reference: 17/EE/0368).The results of the trial will be reported first to trial collaborators. The main report will be drafted by the trial coordinating team, and the final version will be agreed by the Trial Steering Committee before submission for publication, on behalf of the collaboration.RegistrationThe trial is funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) (Project Number: EME-14/150/85) and registeredISRCTN12600919and EudraCT: 2017-001785-14.

Purpose A systematic review and meta-analysis was conducted to answer the question ‘In adults with respiratory failure requiring invasive ventilation for more than 24 h, does a weaning strategy with early extubation to non-invasive ventilation (NIV) compared to invasive ventilation weaning reduce all-cause hospital mortality?’ Methods We included randomised and quasi-randomised controlled trials that evaluated the use of non-invasive ventilation, compared to invasive ventilation, as a weaning strategy in adults mechanically ventilated for at least 24 h. The EMBASE, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) bibliographic databases were searched from inception to February 2018. Bayesian hierarchical models were used to perform the meta-analysis. The primary outcome was mortality at hospital discharge. Secondary outcomes included mortality (30, 60, 90 and 180 days), quality of life, duration of invasive ventilation, weaning failure, length of stay [intensive care unit (ICU) and hospital] and adverse events. Results Twenty-five relevant studies involving 1609 patients were included in the quantitative analysis. Studies had moderate to high risk of bias due to risk of performance and detection bias. Mortality at hospital discharge was lower in the NIV weaning group compared to the invasive weaning group [pooled odds ratio (OR) 0.58, 95% highest density interval (HDI) 0.29–0.89]. Subgroup analyses showed lower pooled mortality at hospital discharge rates in NIV weaning than those in the control group in chronic obstructive pulmonary disease (COPD) patients (pooled OR 0.43, 95% HDI 0.13–0.81) and the effect is less certain in the mixed ICU population (pooled OR 0.88, 95% HDI 0.25–1.48). NIV weaning reduced the duration of invasive ventilation in patients [standardised mean difference (SMD) − 1.34, 95% HDI − 1.92 to − 0.77] and ICU length of stay (SMD − 0.70, 95% HDI − 0.94 to − 0.46). Reported rates of ventilator associated pneumonia (VAP) were lower in the NIV group. NIV weaning did not reduce overall hospital length of stay or long-term mortality. There were insufficient data to compare other adverse events and health-related quality of life. Conclusions The use of NIV in weaning from mechanical ventilation decreases hospital mortality, the incidence of VAP and ICU length of stay. NIV as a weaning strategy appears to be most beneficial in patients with COPD. Electronic supplementary material The online version of this article (10.1007/s00134-018-5434-z) contains supplementary material, which is available to authorized users.

ObjectiveTo estimate the magnitude of the correlation between neonatal outcomes of twins and demonstrate how this information can be used in the design of randomised controlled trials (RCTs) in women with twin pregnancies.DesignSecondary analysis of data from 12 RCTs.SettingObstetric care in multiple countries, 2004-2012.Population or sample4504 twin pairs born to women who participated in RCTs to assess treatments given during pregnancy.MethodsIntraclass correlation coefficients (ICCs) were estimated using log-binomial and linear models.Main outcome measuresPerinatal death, respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular haemorrhage, necrotising enterocolitis, sepsis, neonatal intensive care unit admission, birthweight, low birthweight and two composite measures of adverse neonatal outcome.ResultsICCs for the composite measures of adverse neonatal outcome were all above 0.5, indicating moderate to strong correlation between adverse outcomes of twins. For individual neonatal outcomes, median ICCs across trials ranged from 0.13 to 0.79 depending on the outcome. An example illustrates how ICCs can be used in sample size calculations for RCTs in women with twin pregnancies.ConclusionsThe correlation between neonatal outcomes of twins varies considerably between outcomes and may be lower than expected. Our ICC estimates can be used for designing and analysing RCTs that recruit women with twin pregnancies and for performing meta-analyses that include such RCTs. Researchers are encouraged to report ICCs for neonatal outcomes in twins in their own RCTs.Tweetable abstractCorrelation between neonatal outcomes of twins depends on the outcome and may be lower than expected.Tweetable abstract Correlation between neonatal outcomes of twins depends on the outcome and may be lower than expected.

Objectives: (1) To identify risk factors for chronic disability in people with acute whiplash associated disorders (WAD). (2) To estimate the impact of the numbers of risk factors present. Design: Prospective cohort study. Data were collected, on average, 32 days after injury (SD = 10.9) and 12 months later. Baseline measures of pain, disability, neck movement, psychological and behavioural factors were independent variables and chronic disability at 12 months was the dependent variable in a multivariable logistic regression analysis. Setting: National Health Service physiotherapy departments. Participants: Participants (n = 599) with symptoms 3 weeks after injury, self-referred to physiotherapy as part of a randomised controlled trial. 430 (72%) participants provided complete data for this analysis. Main outcome measures: Chronic disability based on Neck Disability Index scores. Results: 136 (30%) participants developed chronic disability. High baseline disability (OR 3.3, 95%CI 1.97 to 5.55), longer predicted recovery time (OR 2.4, 95%CI 1.45 to 3.87), psychological distress (OR 1.9, 95%CI 1.05 to 3.51), passive coping (OR 1.8, 95%CI 1.07 to 2.97) and greater number of symptoms (OR 1.7, 95%CI 1.07 to 2.78) were associated with chronic disability. One risk factor resulted in 3.5 times the risk (95%CI 1.04 to 11.45) of chronic disability but this risk increased to 16 times (95%CI 5.36 to 49.27) in those with four or five risk factors. Conclusion: Baseline disability had the strongest association with chronic disability but psychological and behavioural factors were also important. Treatment strategies should reflect this which may require a change to current physiotherapy approaches for acute WAD. The number of risk factors present should be considered when evaluating potential for poor outcome.

Introduction and objective The role of metformin in gestational diabetes mellitus (GDM) is also increasing. However, almost half of metformin-treated women required additional insulin. Therefore, identifying the characteristics of these women may help define optimal therapeutic strategy. Methods This is a retrospective cohort study done in a District General Hospital, UK. GDM was diagnosed by 75 g OGTT test between 24 and 28 weeks of gestation with fasting levels of ≥6.1 mmol/l and/or 2 h postprandial (PP) level of ≥7.8 mmol/l. Logistic regression and receiver operator curves (ROC) were performed to identify the predictors of metformin failure. Results Out of 228 women with GDM included, 46/228 (20.2%) and 151/228 (66.2%) received insulin and metformin as first-line medication respectively. Among the metformin-treated, 13 stopped treatment and were excluded from analysis. Of the included 138 metformin-treated women, 77 (55.8%) required supplementary insulin (metformin failure). Metformin failure group had higher maternal age and fasting glucose level at OGTT, HbA1c at OGTT and earlier gestational age (GA) at medication initiation. Metformin failure was predicted if fasting OGTT level >4.8 mmol/l (69% sensitivity and 62% specificity). If the fasting levels of IADPSG (International Association of Diabetes and Pregnancy Study Groups) criteria and NICE (National Institute of Health and Care Excellence) were used, the positive predictive value was 78% and 77% respectively. Conclusion As women with higher fasting glucose levels have higher chance of necessitating insulin in later pregnancies, appropriate addition of insulin at metformin initiation for these women could help better glycaemic control throughout pregnancy.

BackgroundMechanical chest compression devices may help to maintain high-quality cardiopulmonary resuscitation (CPR), but little evidence exists for their effectiveness. We evaluated whether or not the introduction of Lund University Cardiopulmonary Assistance System-2 (LUCAS-2; Jolife AB, Lund, Sweden) mechanical CPR into front-line emergency response vehicles would improve survival from out-of-hospital cardiac arrest (OHCA).ObjectiveEvaluation of the LUCAS-2 device as a routine ambulance service treatment for OHCA.DesignPragmatic, cluster randomised trial including adults with non-traumatic OHCA. Ambulance dispatch staff and those collecting the primary outcome were blind to treatment allocation. Blinding of the ambulance staff who delivered the interventions and reported initial response to treatment was not possible. We also conducted a health economic evaluation and a systematic review of all trials of out-of-hospital mechanical chest compression.SettingFour UK ambulance services (West Midlands, North East England, Wales and South Central), comprising 91 urban and semiurban ambulance stations. Clusters were ambulance service vehicles, which were randomly assigned (approximately 1 : 2) to the LUCAS-2 device or manual CPR.ParticipantsPatients were included if they were in cardiac arrest in the out-of-hospital environment. Exclusions were patients with cardiac arrest as a result of trauma, with known or clinically apparent pregnancy, or aged InterventionsPatients received LUCAS-2 mechanical chest compression or manual chest compressions according to the first trial vehicle to arrive on scene.Main outcome measuresSurvival at 30 days following cardiac arrest; survival without significant neurological impairment [Cerebral Performance Category (CPC) score of 1 or 2].ResultsWe enrolled 4471 eligible patients (1652 assigned to the LUCAS-2 device and 2819 assigned to control) between 15 April 2010 and 10 June 2013. A total of 985 (60%) patients in the LUCAS-2 group received mechanical chest compression and 11 (LimitationsThere was substantial non-compliance in the LUCAS-2 arm. For 272 out of 1652 patients (16.5%), mechanical chest compression was not used for reasons that would not occur in clinical practice. We addressed this issue by using complier average causal effect analyses. We attempted to measure CPR quality during the resuscitation attempts of trial participants, but were unable to do so.ConclusionsThere was no evidence of improvement in 30-day survival with LUCAS-2 compared with manual compressions. Our systematic review of recent randomised trials did not suggest that survival or survival without significant disability may be improved by the use of mechanical chest compression.Future workThe use of mechanical chest compression for in-hospital cardiac arrest, and in specific circumstances (e.g. transport), has not yet been evaluated.TriaI registrationCurrent Controlled Trials ISRCTN08233942.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 21, No. 11. See the NIHR Journals Library website for further project information.

Despite its use since the 1960s, the safety or effectiveness of adrenaline as a treatment for cardiac arrest has never been comprehensively evaluated in a clinical trial. Although most studies have found that adrenaline increases the chance of return of spontaneous circulation for short periods, many studies found harmful effects on the brain and raise concern that adrenaline may reduce overall survival and/or good neurological outcome. The PARAMEDIC-2 trial seeks to determine if adrenaline is safe and effective in out-of-hospital cardiac arrest.This is a pragmatic, individually randomised, double blind, controlled trial with a parallel economic evaluation. Participants will be eligible if they are in cardiac arrest in the out-of-hospital environment and advanced life support is initiated. Exclusions are cardiac arrest as a result of anaphylaxis or life threatening asthma, and patient known or appearing to be under 16 or pregnant.8000 participants treated by 5 UK ambulance services will be randomised between December 2014 and August 2017 to adrenaline (intervention) or placebo (control) through opening pre-randomised drug packs. Clinical outcomes are survival to 30 days (primary outcome), hospital discharge, 3, 6 and 12 months, health related quality of life, and neurological and cognitive outcomes (secondary outcomes).Trial registration (ISRCTN73485024).

Background There is an urgent need to develop prehospital research capability in order to improve the care of patients presenting to emergency medical services (EMS). The Prehospital Randomised Assessment of a Mechanical compression Device In Cardiac arrest trial, a pragmatic cluster randomised trial evaluating the LUCAS-2 device, represents the largest randomised controlled trial conducted by UK ambulance services to date. The aim of this study was to identify and analyse factors that may influence paramedic attitudes to, and participation in, clinical trials. Methods Personal and organisational experience from this trial was assessed by feedback from a workshop attended by collaborators from participating EMS and a survey of EMS personnel participating in the trial. A work systems model was used to explain the impact of five interwoven themes—person, organisation, tasks, tools & technology and environment—on trial conduct including gathering of high-quality data. Results The challenge of training a geographically diverse EMS workforce required development of multiple educational solutions. In order to operationalise the trial protocol, internal organisational relationships were perceived as essential. Staff perceptions of the normalisation of participation and ownership of the trial influenced protocol compliance rates. Undertaking research was considered less burdensome when additional tasks were minimised and more difficult when equipment was unavailable. The prehospital environment presents practical challenges for undertaking clinical trials, but our experience suggests these are not insurmountable and should not preclude conducting high-quality research in this setting. Conclusions Application of a human factors model to the implementation of a clinical trial protocol has improved understanding of the work system, which can inform the future conduct of clinical trials and foster a research culture within UK ambulance services. Trial registration number ISRCTN08233942.

Summary Background In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS. Methods We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged ≥16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 μg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO 2 /F I O 2 ) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86. Findings We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03–2·08). Interpretation Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of β-2 agonist treatment in ventilated patients with this disorder cannot be recommended. Funding UK Medical Research Council, UK Department of Health, UK Intensive Care Foundation.

Aim This study explores why resuscitation is withheld when emergency medical staff arrive at the scene of a cardiac arrest and identifies modifiable factors associated with this decision. Methods This is a secondary analysis of unselected patients who sustained an out of hospital cardiac arrest attended by ambulance vehicles participating in a randomized controlled trial of a mechanical chest compression device (PARAMEDIC trial). Patients were categorized as ‘non-resuscitation’ patients if there was a do-not-attempt-cardiopulmonary-resuscitation (DNACPR) order, signs unequivocally associated with death or resuscitation was deemed futile (15 min had elapsed since collapse with no bystander-CPR and asystole recorded on EMS arrival). Results Emergency Medical Services attended 11,451 cardiac arrests. Resuscitation was attempted or continued by Emergency Medical Service staff in 4805 (42%) of cases. Resuscitation was withheld in 6646 cases (58%). 711 (6.2%) had a do not attempt resuscitation decision, 4439 (38.8%) had signs unequivocally associated with death and in 1496 cases (13.1%) CPR was considered futile. Those where resuscitation was withheld due to futility were characterised by low bystander CPR rates (7.2%) and by being female. Conclusions Resuscitation was withheld by ambulance staff in over one in ten (13.1%) victims of out of hospital cardiac arrest on the basis of futility. These cases were associated with a very low rate of bystander CPR. Future studies should explore strengthening the ‘Chain of Survival’ to increase the community bystander CPR response and evaluate the effect on the numbers of survivors from out of hospital cardiac arrest.

Importance Interpreting screening mammograms is a difficult repetitive task that can result in missed cancers and false-positive recalls. In the United Kingdom, 2 film readers independently evaluate each mammogram to search for signs of cancer and examine digital mammograms in batches. However, a vigilance decrement (reduced detection rate with time on task) has been observed in similar settings.\ud \ud Objective To determine the effect of changing the order for the second film reader of batches of screening mammograms on rates of breast cancer detection.\ud \ud Design, Setting, and Participants A multicenter, double-blind, cluster randomized clinical trial conducted at 46 specialized breast screening centers from the National Health Service Breast Screening Program in England for 1 year (all between December 20, 2012, and November 3, 2014). Three hundred sixty readers participated (mean, 7.8 readers per center)—186 radiologists, 143 radiography advanced practitioners, and 31 breast clinicians, all fully qualified to report mammograms in the NHS breast screening program.\ud \ud Interventions The 2 readers examined each batch of digital mammograms in the same order in the control group and in the opposite order to one another in the intervention group.\ud \ud Main Outcomes and Measures The primary outcome was cancer detection rate; secondary outcomes were rates of recall and disagreements between readers.\ud \ud Results Among 1 194 147 women (mean age, 59.3; SD, 7.49) who had screening mammograms (596 642 in the intervention group; 597 505 in the control group), the images were interpreted in 37 688 batches (median batch size, 35; interquartile range [IQR]; 16-46), with each reader interpreting a median of 176 batches (IQR, 96-278). After completion of all subsequent diagnostic tests, a total of 10 484 cases (0.88%) of breast cancer were detected. There was no significant difference in cancer detection rate with 5272 cancers (0.88%) detected in the intervention group vs 5212 cancers (0.87%) detected in the control group (difference, 0.01% points; 95% CI, −0.02% to 0.04% points; recall rate, 24 681 [4.14%] vs 24 894 [4.17%]; difference, −0.03% points; 95% CI, −0.10% to 0.04% points; or rate of reader disagreements, 20 471 [3.43%] vs 20 793 [3.48%]; difference, −0.05% points; 95% CI, −0.11% to 0.02% points).\ud \ud Conclusions and Relevance Interpretation of batches of mammograms by qualified screening mammography readers using a different order vs the same order for the second reading resulted in no significant difference in rates of detection of breast cancer.\ud \ud Trial Registration isrctn.org Identifier: ISRCTN46603370

BackgroundMidwives are primary providers of care for childbearing women around the world. However, there is a lack of synthesised information to establish whether there are differences in morbidity and mortality, effectiveness and psychosocial outcomes between midwife-led continuity models and other models of care.ObjectivesTo compare midwife-led continuity models of care with other models of care for childbearing women and their infants.Search methodsWe searched the Cochrane Pregnancy and Childbirth Group's Trials Register (25 January 2016) and reference lists of retrieved studies.Selection criteriaAll published and unpublished trials in which pregnant women are randomly allocated to midwife-led continuity models of care or other models of care during pregnancy and birth.Data collection and analysisTwo review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach.Main resultsWe included 15 trials involving 17,674 women. We assessed the quality of the trial evidence for all primary outcomes (i.e. regional analgesia (epidural/spinal), caesarean birth, instrumental vaginal birth (forceps/vacuum), spontaneous vaginal birth, intact perineum, preterm birth (less than 37 weeks) and all fetal loss before and after 24 weeks plus neonatal death using the GRADE methodology: all primary outcomes were graded as of high quality.For the primary outcomes, women who had midwife-led continuity models of care were less likely to experience regional analgesia (average risk ratio (RR) 0.85, 95% confidence interval (CI) 0.78 to 0.92; participants = 17,674; studies = 14; high quality), instrumental vaginal birth (average RR 0.90, 95% CI 0.83 to 0.97; participants = 17,501; studies = 13; high quality), preterm birth less than 37 weeks (average RR 0.76, 95% CI 0.64 to 0.91; participants = 13,238; studies = eight; high quality) and less all fetal loss before and after 24 weeks plus neonatal death (average RR 0.84, 95% CI 0.71 to 0.99; participants = 17,561; studies = 13; high quality evidence). Women who had midwife-led continuity models of care were more likely to experience spontaneous vaginal birth (average RR 1.05, 95% CI 1.03 to 1.07; participants = 16,687; studies = 12; high quality). There were no differences between groups for caesarean births or intact perineum.For the secondary outcomes, women who had midwife-led continuity models of care were less likely to experience amniotomy (average RR 0.80, 95% CI 0.66 to 0.98; participants = 3253; studies = four), episiotomy (average RR 0.84, 95% CI 0.77 to 0.92; participants = 17,674; studies = 14) and fetal loss less than 24 weeks and neonatal death (average RR 0.81, 95% CI 0.67 to 0.98; participants = 15,645; studies = 11). Women who had midwife-led continuity models of care were more likely to experience no intrapartum analgesia/anaesthesia (average RR 1.21, 95% CI 1.06 to 1.37; participants = 10,499; studies = seven), have a longer mean length of labour (hours) (mean difference (MD) 0.50, 95% CI 0.27 to 0.74; participants = 3328; studies = three) and more likely to be attended at birth by a known midwife (average RR 7.04, 95% CI 4.48 to 11.08; participants = 6917; studies = seven). There were no differences between groups for fetal loss equal to/after 24 weeks and neonatal death, induction of labour, antenatal hospitalisation, antepartum haemorrhage, augmentation/artificial oxytocin during labour, opiate analgesia, perineal laceration requiring suturing, postpartum haemorrhage, breastfeeding initiation, low birthweight infant, five-minute Apgar score less than or equal to seven, neonatal convulsions, admission of infant to special care or neonatal intensive care unit(s) or in mean length of neonatal hospital stay (days).Due to a lack of consistency in measuring women's satisfaction and assessing the cost of various maternity models, these outcomes were reported narratively. The majority of included studies reported a higher rate of maternal satisfaction in midwife-led continuity models of care. Similarly, there was a trend towards a cost-saving effect for midwife-led continuity care compared to other care models.Authors' conclusionsThis review suggests that women who received midwife-led continuity models of care were less likely to experience intervention and more likely to be satisfied with their care with at least comparable adverse outcomes for women or their infants than women who received other models of care.Further research is needed to explore findings of fewer preterm births and fewer fetal deaths less than 24 weeks, and all fetal loss/neonatal death associated with midwife-led continuity models of care.

BACKGROUND Operations on structures in the chest (usually the lungs) involve cutting between the ribs (thoracotomy). Severe post-thoracotomy pain can result from pleural (lung lining) and muscular damage, costovertebral joint (ribcage) disruption and intercostal nerve (nerves that run along the ribs) damage during surgery. Poor pain relief after surgery can impede recovery and increase the risks of developing complications such as lung collapse, chest infections and blood clots due to ineffective breathing and clearing of secretions. Effective management of acute pain following thoracotomy may prevent these complications and reduce the likelihood of developing chronic pain. A multi-modal approach to analgesia is widely employed by thoracic anaesthetists using a combination of regional anaesthetic blockade and systemic analgesia, with both non-opioid and opioid medications and local anaesthesia blockade.There is some evidence that blocking the nerves as they emerge from the spinal column (paravertebral block, PVB) may be associated with a lower risk of major complications in thoracic surgery but the majority of thoracic anaesthetists still prefer to use a thoracic epidural blockade (TEB) as analgesia for their patients undergoing thoracotomy. In order to bring about a change in practice, anaesthetists need a review that evaluates the risk of all major complications associated with thoracic epidural and paravertebral block in thoracotomy. OBJECTIVES To compare the two regional techniques of TEB and PVB in adults undergoing elective thoracotomy with respect to:1. analgesic efficacy;2. the incidence of major complications (including mortality);3. the incidence of minor complications;4. length of hospital stay;5. cost effectiveness. SEARCH METHODS We searched for studies in the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 9); MEDLINE via Ovid (1966 to 16 October 2013); EMBASE via Ovid (1980 to 16 October 2013); CINAHL via EBSCO host (1982 to 16 October 2013); and reference lists of retrieved studies. We handsearched the Journal of Cardiothoracic Surgery and Journal of Cardiothoracic and Vascular Anesthesia (16 October 2013). We reran the search on 31st January 2015. We found one additional study which is awaiting classification and will be addressed when we update the review. SELECTION CRITERIA We included all randomized controlled trials (RCTs) comparing PVB with TEB in thoracotomy, including upper gastrointestinal surgery. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Two review authors (JY and SG) independently assessed the studies for inclusion and then extracted data as eligible for inclusion in qualitative and quantitative synthesis (meta-analysis). MAIN RESULTS We included 14 studies with a total of 698 participants undergoing thoracotomy. There are two studies awaiting classification. The studies demonstrated high heterogeneity in insertion and use of both regional techniques, reflecting real-world differences in the anaesthesia techniques. Overall, the included studies have a moderate to high potential for bias, lacking details of randomization, group allocation concealment or arrangements to blind participants or outcome assessors. There was low to very low-quality evidence that showed no significant difference in 30-day mortality (2 studies, 125 participants. risk ratio (RR) 1.28, 95% confidence interval (CI) 0.39 to 4.23, P value = 0.68) and major complications (cardiovascular: 2 studies, 114 participants. Hypotension RR 0.30, 95% CI 0.01 to 6.62, P value = 0.45; arrhythmias RR 0.36, 95% CI 0.04 to 3.29, P value = 0.36, myocardial infarction RR 3.19, 95% CI 0.13, 76.42, P value = 0.47); respiratory: 5 studies, 280 participants. RR 0.62, 95% CI 0.26 to 1.52, P value = 0.30). There was moderate-quality evidence that showed comparable analgesic efficacy across all time points both at rest and after coughing or physiotherapy (14 studies, 698 participants). There was moderate-quality evidence that showed PVB had a better minor complication profile than TEB including hypotension (8 studies, 445 participants. RR 0.16, 95% CI 0.07 to 0.38, P value < 0.0001), nausea and vomiting (6 studies, 345 participants. RR 0.48, 95% CI 0.30 to 0.75, P value = 0.001), pruritis (5 studies, 249 participants. RR 0.29, 95% CI 0.14 to 0.59, P value = 0.0005) and urinary retention (5 studies, 258 participants. RR 0.22, 95% CI 0.11 to 0.46, P value < 0.0001). There was insufficient data in chronic pain (six or 12 months). There was no difference found in and length of hospital stay (3 studies, 124 participants). We found no studies that reported costs. AUTHORS' CONCLUSIONS Paravertebral blockade reduced the risks of developing minor complications compared to thoracic epidural blockade. Paravertebral blockade was as effective as thoracic epidural blockade in controlling acute pain. There was a lack of evidence in other outcomes. There was no difference in 30-day mortality, major complications, or length of hospital stay. There was insufficient data on chronic pain and costs. Results from this review should be interpreted with caution due to the heterogeneity of the included studies and the lack of reliable evidence. Future studies in this area need well-conducted, adequately-powered RCTs that focus not only on acute pain but also on major complications, chronic pain, length of stay and costs.

This systematic literature review aims to assess the prognostic value of psychological factors in the development of late whiplash syndrome (LWS). We included prospective cohort studies that provided a baseline measure of at least one psychological variable and used outcome measures relating to LWS (i.e. pain or disability persisting 6 months post injury). A search of electronic databases (Pubmed, Medline, Cinahl, Embase and Psychinfo) up to August 2006 was done using a predetermined search strategy. Methodological quality was assessed independently by two assessors. Data extraction were carried out using a standardised data extraction form. Twenty-five articles representing data from 17 cohorts were included. Fourteen articles were rated as low quality with 11 rated as adequate quality. Meta-analysis was not undertaken due to the heterogeneity of prognostic factors, outcome measures and methods used. Results were tabulated and predefined criterion applied to rate the overall strength of evidence for associations between psychological factors and LWS. Data on 21 possible psychological risk factors were included. The majority of findings were inconclusive. Limited evidence was found to support an association between lower self-efficacy and greater post-traumatic stress with the development of LWS. No association was found between the development of LWS and personality traits, general psychological distress, wellbeing, social support, life control and psychosocial work factors. The lack of conclusive findings and poor methodological quality of the studies reviewed highlights the need for better quality research. Self-efficacy and post-traumatic distress may be associated with the development of LWS but this needs further investigation.

BackgroundThere is growing interest in the potential utility of real-time polymerase chain reaction (PCR) in diagnosing bloodstream infection by detecting pathogen deoxyribonucleic acid (DNA) in blood samples within a few hours. SeptiFast (Roche Diagnostics GmBH, Mannheim, Germany) is a multipathogen probe-based system targeting ribosomal DNA sequences of bacteria and fungi. It detects and identifies the commonest pathogens causing bloodstream infection. As background to this study, we report a systematic review of Phase III diagnostic accuracy studies of SeptiFast, which reveals uncertainty about its likely clinical utility based on widespread evidence of deficiencies in study design and reporting with a high risk of bias.ObjectiveDetermine the accuracy of SeptiFast real-time PCR for the detection of health-care-associated bloodstream infection, against standard microbiological culture.DesignProspective multicentre Phase III clinical diagnostic accuracy study using the standards for the reporting of diagnostic accuracy studies criteria.SettingCritical care departments within NHS hospitals in the north-west of England.ParticipantsAdult patients requiring blood culture (BC) when developing new signs of systemic inflammation.Main outcome measuresSeptiFast real-time PCR results at species/genus level compared with microbiological culture in association with independent adjudication of infection. Metrics of diagnostic accuracy were derived including sensitivity, specificity, likelihood ratios and predictive values, with their 95% confidence intervals (CIs). Latent class analysis was used to explore the diagnostic performance of culture as a reference standard.ResultsOf 1006 new patient episodes of systemic inflammation in 853 patients, 922 (92%) met the inclusion criteria and provided sufficient information for analysis. Index test assay failure occurred on 69 (7%) occasions. Adult patients had been exposed to a median of 8 days (interquartile range 4–16 days) of hospital care, had high levels of organ support activities and recent antibiotic exposure. SeptiFast real-time PCR, when compared with culture-proven bloodstream infection at species/genus level, had better specificity (85.8%, 95% CI 83.3% to 88.1%) than sensitivity (50%, 95% CI 39.1% to 60.8%). When compared with pooled diagnostic metrics derived from our systematic review, our clinical study revealed lower test accuracy of SeptiFast real-time PCR, mainly as a result of low diagnostic sensitivity. There was a low prevalence of BC-proven pathogens in these patients (9.2%, 95% CI 7.4% to 11.2%) such that the post-test probabilities of both a positive (26.3%, 95% CI 19.8% to 33.7%) and a negative SeptiFast test (5.6%, 95% CI 4.1% to 7.4%) indicate the potential limitations of this technology in the diagnosis of bloodstream infection. However, latent class analysis indicates that BC has a low sensitivity, questioning its relevance as a reference test in this setting. Using this analysis approach, the sensitivity of the SeptiFast test was low but also appeared significantly better than BC. Blood samples identified as positive by either culture or SeptiFast real-time PCR were associated with a high probability (> 95%) of infection, indicating higher diagnostic rule-in utility than was apparent using conventional analyses of diagnostic accuracy.ConclusionSeptiFast real-time PCR on blood samples may have rapid rule-in utility for the diagnosis of health-care-associated bloodstream infection but the lack of sensitivity is a significant limiting factor. Innovations aimed at improved diagnostic sensitivity of real-time PCR in this setting are urgently required. Future work recommendations include technology developments to improve the efficiency of pathogen DNA extraction and the capacity to detect a much broader range of pathogens and drug resistance genes and the application of new statistical approaches able to more reliably assess test performance in situation where the reference standard (e.g. blood culture in the setting of high antimicrobial use) is prone to error.Study registrationThe systematic review is registered as PROSPERO CRD42011001289.FundingThe National Institute for Health Research Health Technology Assessment programme. Professor Daniel McAuley and Professor Gavin D Perkins contributed to the systematic review through their funded roles as codirectors of the Intensive Care Foundation (UK).

Objective The purpose of this study was to conduct pilot studies for large randomized controlled trials to compare low-molecular-weight heparin with placebo for antenatal thromboprophylaxis (trial 1), and for thromboprophylaxis after cesarean delivery (trial 2). Study design Multicenter randomized controlled trials (trial 1, 23 units; trial 2, 8 units) were conducted. Pregnant women at increased risk for thromboembolic disease were eligible for trial 1; women who underwent cesarean delivery were eligible for trial 2. The interventions were once daily injections of low-molecular-weight heparin or placebo. Primary outcomes were as follows: trial 1, confirmed symptomatic thromboembolic events and symptomatic osteoporotic fractures; trial 2, confirmed symptomatic thromboembolic events and wound complications. Results Sixteen women were recruited for trial 1; 1 woman in the placebo group had a symptomatic thromboembolic event. One hundred forty-one women were recruited for trial 2; 1 woman in the low molecular weight heparin group had a symptomatic thromboembolic event. Conclusion Poor recruitment indicates that large-scale trials using these designs would be difficult. Collection of data on the number of women that are eligible and the reasons for nonrecruitment in future trials of these interventions would allow a better understanding of the reasons for poor recruitment.

Purpose: There is an urgent need to develop diagnostic tests to improve the detection of pathogens causing life-threatening infection (sepsis). SeptiFast is a CE-marked multi-pathogen real-time PCR system capable of detecting DNA sequences of bacteria and fungi present in blood samples within a few hours. We report here a systematic review and meta-analysis of diagnostic accuracy studies of SeptiFast in the setting of suspected sepsis.Methods: A comprehensive search strategy was developed to identify studies that compared SeptiFast with blood culture in suspected sepsis. Methodological quality was assessed using QUADAS. Heterogeneity of studies was investigated using a coupled forest plot of sensitivity and specificity and a scatter plot in receiver operator characteristic space. Bivariate model method was used to estimate summary sensitivity and specificity.Results: From 41 phase III diagnostic accuracy studies, summary sensitivity and specificity for SeptiFast compared with blood culture were 0.68 (95 % CI 0.63–0.73) and 0.86 (95 % CI 0.84–0.89) respectively. Study quality was judged to be variable with important deficiencies overall in design and reporting that could impact on derived diagnostic accuracy metrics.Conclusions: SeptiFast appears to have higher specificity than sensitivity, but deficiencies in study quality are likely to render this body of work unreliable. Based on the evidence presented here, it remains difficult to make firm recommendations about the likely clinical utility of SeptiFast in the setting of suspected sepsis.

BACKGROUND: Venous thromboembolism (VTE), although rare, is a major cause of maternal mortality and morbidity. Some women are at increased risk of VTE during pregnancy and the early postnatal period (e.g. caesarean section, family history of VTE, or thrombophilia), and so prophylaxis may be considered. As some methods of prophylaxis carry risks of adverse effects, and risk of VTE is often low, benefits of thromboprophylaxis may be outweighed by harms. OBJECTIVES: To assess the effects of thromboprophylaxis during pregnancy and the early postnatal period on the risk of venous thromboembolic disease and adverse effects in women at increased risk of VTE. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (18 October 2019). In addition, we searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for unpublished, planned and ongoing trial reports (18 October 2019). SELECTION CRITERIA: Randomised trials comparing one method of thromboprophylaxis with placebo or no treatment, or two (or more) methods of thromboprophylaxis. DATA COLLECTION AND ANALYSIS: At least two review authors assessed trial eligibility, extracted data, assessed risk of bias, and judged certainty of evidence for selected critical outcomes (using GRADE). We conducted fixed‐effect meta‐analysis and reported data (all dichotomous) as summary risk ratios (RRs) with 95% confidence intervals (CIs). MAIN RESULTS: Twenty‐nine trials (involving 3839 women), overall at moderate to high risk of bias were included. Trials were conducted across the antenatal, peripartum and postnatal periods, with most in high‐income countries. Interventions included types and regimens of heparin (low molecular weight heparin (LMWH) and unfractionated heparin (UFH)), hydroxyethyl starch (HES), and compression stockings or devices. Data were limited due to a small number of trials in comparisons and/or few or no events reported. All critical outcomes (assessed for comparisons of heparin versus no treatment/placebo, and LMWH versus UFH) were considered to have very low‐certainty evidence, downgraded mainly for study limitations and imprecise effect estimates. Maternal death was not reported in most studies. Antenatal (± postnatal) prophylaxis For the primary outcomes symptomatic thromboembolic events pulmonary embolism (PE) and/or deep vein thrombosis (DVT), and the critical outcome of adverse effects sufficient to stop treatment, the evidence was very uncertain. Symptomatic thromboembolic events: ‐ heparin versus no treatment/placebo (RR 0.39; 95% CI 0.08 to 1.98; 4 trials, 476 women; very low‐certainty evidence); ‐ LMWH versus UFH (RR 0.47; 95% CI 0.09 to 2.49; 4 trials, 404 women; very low‐certainty evidence); Symptomatic PE: ‐ heparin versus no treatment/placebo (RR 0.33; 95% CI 0.02 to 7.14; 3 trials, 187 women; very low‐certainty evidence); ‐ LMWH versus UFH (no events; 3 trials, 287 women); Symptomatic DVT: ‐ heparin versus no treatment/placebo (RR 0.33; 95% CI 0.04 to 3.10; 4 trials, 227 women; very low‐certainty evidence); ‐ LMWH versus UFH (no events; 3 trials, 287 women); Adverse effects sufficient to stop treatment: ‐ heparin versus no treatment/placebo (RR 0.49; 95% CI 0.05 to 5.31; 1 trial, 139 women; very low‐certainty evidence); ‐ LMWH versus UFH (RR 0.07; 95% CI 0.01 to 0.54; 2 trials, 226 women; very low‐certainty evidence). Peripartum/postnatal prophylaxis Vaginal or caesarean birth When UFH and no treatment were compared, the effects on symptomatic thromboembolic events (RR 0.16; 95% CI 0.02 to 1.36; 1 trial, 210 women; very low‐certainty evidence), symptomatic PE (RR 0.16; 95% CI 0.01 to 3.34; 1 trial, 210 women; very low‐certainty evidence), and symptomatic DVT (RR 0.27; 95% CI 0.03 to 2.55; 1 trial, 210 women; very low‐certainty evidence) were very uncertain. Maternal death and adverse effects sufficient to stop treatment were not reported. Caesarean birth Symptomatic thromboembolic events: ‐ heparin versus no treatment/placebo (RR 1.30; 95% CI 0.39 to 4.27; 4 trials, 840 women; very low‐certainty evidence); ‐ LMWH versus UFH (RR 0.33; 95% CI 0.01 to 7.99; 3 trials, 217 women; very low‐certainty evidence); Symptomatic PE: ‐ heparin versus no treatment/placebo (RR 1.10; 95% CI 0.25 to 4.87; 4 trials, 840 women; very low‐certainty evidence); ‐ LMWH versus UFH (no events; 3 trials, 217 women); Symptomatic DVT: ‐ heparin versus no treatment/placebo (RR 1.30; 95% CI 0.24 to 6.94; 5 trials, 1140 women; very low‐certainty evidence); LMWH versus UFH (RR 0.33; 95% CI 0.01 to 7.99; 3 trials, 217 women; very low‐certainty evidence); Maternal death: ‐ heparin versus placebo (no events, 1 trial, 300 women); Adverse effects sufficient to stop treatment: ‐ heparin versus placebo (no events; 1 trial, 140 women). Postnatal prophylaxis No events were reported for LMWH versus no treatment/placebo for: symptomatic thromboembolic events, symptomatic PE and symptomatic DVT (all 2 trials, 58 women), or maternal death (1 trial, 24 women). Adverse effects sufficient to stop treatment were not reported. We were unable to conduct subgroup analyses due to lack of data. Sensitivity analysis including the nine studies at low risk of bias did not impact overall findings. AUTHORS' CONCLUSIONS: The evidence is very uncertain about benefits and harms of VTE thromboprophylaxis in women during pregnancy and the early postnatal period at increased risk of VTE. Further high‐quality very large‐scale randomised trials are needed to determine effects of currently used treatments in women with different VTE risk factors. As sufficiently large definitive trials are unlikely to be funded, secondary data analyses based on high‐quality registry data are important.

Recent publications have produced some new estimates of the incidence of pregnancy-related venous thromboembolic disease, and have found increasing evidence of an association between inherited thrombophilias and pregnancy complications and fetal loss. The balance of benefit and risk of thromboprophylaxis remains to be evaluated, and studies are needed to provide a sound basis for clinical practice.

Background Twin-twin transfusion syndrome, a condition affecting monochorionic twin pregnancies, is associated with a high risk of perinatal mortality and morbidity. A number of treatments have been introduced to treat the condition but it is unclear which intervention improves maternal and fetal outcome. Objectives The objective of this review was to evaluate the impact of treatment modalities in twin-twin transfusion syndrome. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013). Selection criteria Randomised and quasi-randomised studies of amnioreduction versus laser coagulation, septostomy versus laser coagulation or septostomy versus amnioreduction. Data collection and analysis Two review authors independently assessed eligibility and extracted data. We contacted study authors for additional information. Main results Three studies (253 women and 506 babies) were included. All three trials were judged to be of moderate quality. One study compared amnioreduction with septostomy (71 women), whilst the other two studies compared amnioreduction with endoscopic laser coagulation (182 women). Not all trials provided outcome data that could be included in all meta-analyses. Amnioreduction compared with laser coagulation Although there was no difference in overall death between amnioreduction and laser coagulation (average risk ratio (RR) 0.87; 95% confidence interval (CI) 0.55 to 1.38 adjusted for clustering, two trials) or death of at least one infant per pregnancy (RR 0.91; 95% CI 0.75 to 1.09, two trials), or death of both infants per pregnancy (average RR 0.76; 95% 0.27 to 2.10, two trials), more babies were alive without neurological abnormality at the age of six years in the laser group than in the amnioreduction groups (RR 1.57; 95% CI 1.05 to 2.34 adjusted for clustering, one trial). There were no significant differences in the babies alive at six years with major neurological abnormality treated by laser coagulation or amnioreduction (RR 0.97; 95% CI 0.34 to 2.77 adjusted for clustering, one trial). Outcomes for death in this 2013 update are different from the previous 2008 update, where improvements in perinatal death and death of both infants per pregnancy were shown in the laser intervention arm. The NIHCD trial included in this update exerts an opposite direction of effects to the Eurofetus study, which was previously the only included laser study, hence the difference in outcome. Amnioreduction compared with septostomy There are no differences in overall death (RR 0.83; 95% CI 0.47 to 1.47, adjusted for clustering, one trial), death of at least one infant per pregnancy (RR 0.80; 95% CI 0.48 to 1.35, one trial), or death of both infants per pregnancy (RR 0.90; 95% CI 0.37 to 2.22, one trial) or gestational age at birth (RR 1.20; 95% CI -0.81 to 3.21, one trial) between amnioreduction and septostomy. Authors' conclusions Endoscopic laser coagulation of anastomotic vessels should continue to be considered in the treatment of all stages of twin-twin transfusion syndrome to improve neurodevelopmental outcomes. Further research targeted towards assessing the effect of treatment on milder (Quintero stage 1 and 2) and more severe (Quintero stage 4) forms of twin-twin transfusion syndrome is required. Studies should aim to assess long-term outcomes of survivors.

BACKGROUND: X-ray mammography remains the predominant test for screening for breast cancer, with the aim of reducing breast cancer mortality. In the English NHS Breast Screening Programme each woman's mammograms are examined separately by two expert readers. The two readers read each batch in the same order and each indicates if there should be recall for further tests. This is a highly skilled, pressurised, repetitive and frequently intellectually unchallenging activity where readers examine one or more batches of 30-50 women's mammograms in each session. A vigilance decrement or performance decrease over time has been observed in similar repetitive visual tasks such as radar operation. METHODS/DESIGN: The CO-OPS study is a pragmatic, multi-centre, two-arm, double blind cluster randomised controlled trial of a computer software intervention designed to reduce the effects of a vigilance decrement in breast cancer screening. The unit of randomisation is the batch. Intervention batches will be examined in the opposite order by the two readers (one forwards, one backwards). Control batches will be read in the same order as one another, as is current standard practice. The hypothesis is that cancer detection rates will be higher in the intervention group because each readers' peak performance will occur when examining different women's mammograms. The trial will take place in 44 English breast screening centres for 1 year and 4 months. The primary outcome is cancer detection rate, which will be extracted from computer records after 1 year of the trial. The secondary outcomes include rate of disagreement between readers (a more statistically powerful surrogate for cancer detection rate), recall rate, positive predictive value, and interval cancer rate (cancers found between screening rounds which will be measured three years after the end of the trial). DISCUSSION: This is the first trial of an intervention to ameliorate a vigilance decrement in breast cancer screening. TRIAL REGISTRATION: ISRCTN46603370 (submitted: 24 October 2012, date of registration: 26 March 2013).

Background Subcutaneous and sub rectus sheath wound drains are sometimes used in women who have undergone caesarean section. The indications for using drains vary by clinician. Objectives To compare the effects of using a wound drain with not using a wound drain at caesarean section, and of different types of drain, on maternal health and healthcare resource use. Search methods In November 2013, for this second update, we searched the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid Medline; Ovid Medline - In-Process & Other Non-Indexed Citations; Ovid Embase; and EBSCO CINAHL. No date, language or publication status limits were applied Selection criteria Studies were included if they allocated women to groups at random and they compared any type of wound drain with no wound drainage, or with any other type of drain, in women undergoing caesarean section. Data collection and analysis Trials were evaluated for appropriateness for inclusion and methodological quality without consideration of their results. This was done by two reviewers according to pre-stated eligibility criteria. Main results Ten trials that recruited 5248 women were included in the review. Meta-analysis found no evidence of a difference in the risk of wound infection, other wound complications, febrile morbidity or pain in women who had wound drains compared with those who did not. There was some evidence from one trial that a subcutaneous drain may increase wound infection compared to a sub-sheath drain (RR 5.42, 95% CI 1.28 to 22.98). No differences in outcomes were found between subcutaneous drainage and subcutaneous suturing in the three trials that made this comparison. Authors' conclusions Existing evidence suggests that the routine use of wound drains at caesarean section does not confer any substantial benefit to the women involved. However, neither moderate benefit nor harm are excluded.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a major cause of mortality in intensive care patients and lacks effective treatments. A previous randomised controlled Phase II trial suggested that an intravenous (i.v.) infusion of salbutamol may be beneficial, as it reduced extravascular lung water and plateau airway pressure. The Beta-Agonist Lung injury TrIal-2 (BALTI-2) was initiated to evaluate the effects of this intervention on mortality in patients with ARDS. OBJECTIVES: To evaluate whether or not, in patients with ARDS, an i.v. infusion of salbutamol given at 15 μg/kg ideal body weight (IBW)/hour for up to 7 days, compared with a placebo (0.9% sodium chloride) infusion, reduces 28-day all-cause mortality and other clinical outcomes. To evaluate salbutamol's clinical effectiveness and its cost-effectiveness in subgroups of patients. DESIGN: A multicentre, randomised, placebo-controlled trial. SETTING: Forty-six intensive care units (ICUs) in the UK. PARTICIPANTS: Patients were eligible if they (1) were intubated and mechanically ventilated patients in participating ICUs; (2) were within 72 hours of onset of ARDS; (3) fulfilled American-European Consensus Conference definition for ARDS {acute-onset, severe hypoxaemic respiratory failure [partial pressure of oxygen in arterial blood/fraction of inspired oxygen ≤ 26.7 kPa (200 mmHg)] and bilateral infiltrates on the chest radiograph in the absence of clinical evidence of left atrial hypertension}; and (4) were aged ≥ 16 years. INTERVENTIONS: Intravenous infusion of salbutamol (15 μg/kg IBW/hour) or placebo (0.9% saline) for up to 7 days. MAIN OUTCOME MEASURES: All-cause mortality 28 days after randomisation, mortality at (first) discharge from ICU, mortality at (first) discharge from hospital, number of ventilator-free days, number of organ failure-free days, mortality at 12 months post randomisation, side effects (tachycardia/new arrhythmia/lactic acidosis) sufficient to stop treatment with trial drug, health-related quality of life (European Quality of Life-5 Dimensions and Short Form questionnaire-12 items at 6 and 12 months after randomisation), length of stay in critical care unit and length of stay in hospital. RESULTS: Forty-six ICUs recruited patients to the trial. A total of 326 patients were randomised; 162 were allocated to salbutamol and 164 to placebo. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality: 55 (34%) of 161 patients died in the salbutamol group compared with 38 (23%) of 163 in the placebo group (risk ratio 1.47, 95% confidence interval 1.03 to 2.08). CONCLUSIONS: Treatment with i.v. salbutamol early in the course of ARDS was poorly tolerated, is unlikely to be beneficial and could worsen outcomes. Further trials of β-agonists in patients with ARDS are unlikely to be conducted. Some questions remain, such as whether or not there may be benefit at a different dose or in specific populations, but any studies investigating these would require a very strong rationale. TRIAL REGISTRATION: Current Controlled Trials ISRCTN38366450. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Summary Background Little is known about the effectiveness of treatments for acute whiplash injury. We aimed to estimate whether training of staff in emergency departments to provide active management consultations was more effective than usual consultations (Step 1) and to estimate whether a physiotherapy package was more effective than one additional physiotherapy advice session in patients with persisting symptoms (Step 2). Methods Step 1 was a pragmatic, cluster randomised trial of 12 NHS Trust hospitals including 15 emergency departments who treated patients with acute whiplash associated disorder of grades I–III. The hospitals were randomised by clusters to either active management or usual care consultations. In Step 2, we used a nested individually randomised trial. Patients were randomly assigned to receive either a package of up to six physiotherapy sessions or a single advice session. Randomisation in Step 2 was stratified by centre. Investigator-masked outcomes were obtained at 4, 8, and 12 months. Masking of clinicians and patients was not possible in all steps of the trial. The primary outcome was the Neck Disability Index (NDI). Analysis was intention to treat, and included an economic evaluation. The study is registered ISRCTN33302125. Findings Recruitment ran from Dec 5, 2005 to Nov 30, 2007. Follow-up was completed on Dec 19, 2008. In Step 1, 12 NHS Trusts were randomised, and 3851 of 6952 eligible patients agreed to participate (1598 patients were assigned to usual care and 2253 patients were assigned to active management). 2704 (70%) of 3851 patients provided data at 12 months. NDI score did not differ between active management and usual care consultations (difference at 12 months 0·5, 95% CI −1·5 to 2·5). In Step 2, 599 patients were randomly assigned to receive either advice (299 patients) or a physiotherapy package (300 patients). 479 (80%) patients provided data at 12 months. The physiotherapy package at 4 months showed a modest benefit compared to advice (NDI difference −3·7, −6·1 to −1·3), but not at 8 or 12 months. Active management consultations and the physiotherapy package were more expensive than usual care and single advice session. No treatment-related serious adverse events or deaths were noted. Interpretation Provision of active management consultation did not show additional benefit. A package of physiotherapy gave a modest acceleration to early recovery of persisting symptoms but was not cost effective from a UK NHS perspective. Usual consultations in emergency departments and a single physiotherapy advice session for persistent symptoms are recommended. Funding NIHR Health Technology Assessment programme.

OBJECTIVES: To examine the clinical effectiveness of a stepped care approach over a 12-month period after an acute whiplash injury; to estimate the costs and cost-effectiveness of each strategy including treatments and subsequent health-care costs; and to gain participants' perspective on experiencing whiplash injury, NHS treatment, and recovery within the context of the Managing Injuries of the Neck Trial (MINT). DESIGN: Two linked, pragmatic, randomised controlled trials. In Step 1, emergency departments (EDs) were cluster randomised to usual care advice (UCA) or The Whiplash Book advice (WBA)/active management advice. In Step 2, participants were individually randomised to either a single session of advice from a physiotherapist or a physiotherapy package of up to six sessions. An economic evaluation and qualitative study were run in parallel with the trial. SETTING: Twelve NHS trusts in England comprising 15 EDs. PARTICIPANTS: People who attended EDs with an acute whiplash injury of whiplash-associated disorder grades I-III were eligible for Step 1. People who had attended EDs with whiplash injuries and had persistent symptoms 3 weeks after ED attendance were eligible for Step 2. INTERVENTIONS: In Step 1, the control intervention was UCA and the experimental intervention was a psycho-educational intervention (WBA/active management advice). In Step 2 the control treatment was reinforcement of the advice provided in Step 1 and the experimental intervention was a package of up to six physiotherapy treatments. MAIN OUTCOME: The primary outcome was the Neck Disability Index (NDI), which measures severity and frequency of pain and symptoms, and a range of activities including self-care, driving, reading, sleeping and recreation. Secondary outcomes included the mental and physical health-related quality-of-life (HRQoL) subscales of the Short Form questionnaire-12 items (SF-12) and the number of work days lost. RESULTS: A total of 3851 patients were recruited to Step 1 of the trial. 1598 patients attending EDs were randomised to UCA, and 2253 were randomised to WBA/active management. Outcome data were obtained at 12 months for 70% and 80% of participants at Step 1 and Step 2, respectively. The majority of people recovered from the injury. Eighteen per cent of the Step 1 cohort had late whiplash syndrome. There was no statistically or clinically significant difference observed in any of the outcomes for participants attending EDs randomised to UCA or active management advice [difference in NDI 0.5, 95% confidence interval (CI) -1.8 to 2.8]. In Step 2 the physiotherapy package resulted in improvements in neck disability at 4 months compared with a single advice session, but these effects were small at the population level (difference in NDI -3.2, 95% CI -5.8 to -0.7). The physiotherapy package was accompanied by a significant reduction in the number of work days lost at 4-month follow-up (difference -40.2, 95% CI -44.3 to -35.8). CONCLUSIONS: MINT suggests that enhanced psycho-educational interventions in EDs are no more effective than UCA in reducing the burden of acute whiplash injuries. A physiotherapy package provided to people who have persisting symptoms within the first 6 weeks of injury produced additional short-term benefits in neck disability compared with a single physiotherapy advice session. However, from a health-care perspective, the physiotherapy package was not cost-effective at current levels of willingness to pay. Both experimental treatments were associated with increased cost with no discernible gain in health-related quality of life. However, an important benefit of the physiotherapy package was a reduction in work days lost; consequently, the intervention may prove cost-effective at the societal level. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33302125. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 49. See the HTA programme website for further project information.

PURPOSE: The objective of this study was to evaluate the reproducibility of the cervical range of motion device when measuring both active and passive range of motion in a group of individuals with sub-acute Whiplash Associated Disorders (WAD). METHODS: Participants were recruited as part of a large multi-centre Randomised Controlled Trial from UK emergency departments. Experienced research physiotherapists measured active and passive cervical spine movements in all directions. Both intra- and inter-observer reliability and agreement were assessed using the intra-class correlation coefficient, standard error of measurement and limits of agreement methods. RESULTS: Different groups of 39 and 19 subjects were included in the intra and inter-observer studies, respectively. The CROM device demonstrated substantial intra- and inter-observer reliability and agreement for all the active and passive half-cycle movements (ICC range 0.82-0.99) with the exception of one (passive right lateral flexion for inter-observer; ICC 0.77). CONCLUSIONS: The CROM device has proven to be a reproducible measurement method for a symptomatic WAD population using the measurement protocol described and can be used with confidence to differentiate individuals according to a single measurement.

BACKGROUND: The World Health Organization recommends routine vitamin A supplementation during pregnancy or lactation in areas with endemic vitamin A deficiency (where night blindness occurs), based on the expectation that supplementation will improve maternal and newborn outcomes including mortality, morbidity and prevention of anaemia or infection. OBJECTIVES: To review the effects of supplementation of vitamin A, or one of its derivatives, during pregnancy, alone or in combination with other vitamins and micronutrients, on maternal and newborn clinical outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 March 2015) and reference lists of retrieved studies. SELECTION CRITERIA: All randomised or quasi‐randomised trials, including cluster‐randomised trials, evaluating the effect of vitamin A supplementation in pregnant women. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: We reviewed 106 reports of 35 trials, published between 1931 and 2015. We included 19 trials including over 310,000 women, excluded 15 trials and one is ongoing. Overall, seven trials were judged to be of low risk of bias, three were high risk of bias and for nine it was unclear. 1) Vitamin A alone versus placebo or no treatment Overall, when trial results are pooled, vitamin A supplementation does not affect the risk of maternal mortality (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.65 to 1.20; four trials Ghana, Nepal, Bangladesh, UK, high quality evidence), perinatal mortality (RR 1.01, 95% CI 0.95 to 1.07; one study, high quality evidence), neonatal mortality, stillbirth, neonatal anaemia, preterm birth (RR 0.98, 95% CI 0.94 to 1.01, five studies, high quality evidence), or the risk of having a low birthweight baby. Vitamin A supplementation reduces the risk of maternal night blindness (RR 0.79, 95% CI 0.64 to 0.98; two trials). There is evidence that vitamin A supplements may reduce maternal clinical infection (RR 0.45, 95% CI 0.20 to 0.99, five trials; South Africa, Nepal, Indonesia, Tanzania, UK, low quality evidence) and maternal anaemia (RR 0.64, 95% CI 0.43 to 0.94; three studies, moderate quality evidence). 2) Vitamin A alone versus micronutrient supplements without vitamin A Vitamin A alone compared to micronutrient supplements without vitamin A does not decrease maternal clinical infection (RR 0.99, 95% CI 0.83 to 1.18, two trials, 591 women). No other primary or secondary outcomes were reported 3) Vitamin A with other micronutrients versus micronutrient supplements without vitamin A Vitamin A supplementation (with other micronutrients) does not decrease perinatal mortality (RR 0.51, 95% CI 0.10 to 2.69; one study, low quality evidence), maternal anaemia (RR 0.86, 95% CI 0.68 to 1.09; three studies, low quality evidence), maternal clinical infection (RR 0.95, 95% CI 0.80 to 1.13; I² = 45%, two studies, low quality evidence) or preterm birth (RR 0.39, 95% CI 0.08 to 1.93; one study, low quality evidence). In HIV‐positive women vitamin A supplementation given with other micronutrients was associated with fewer low birthweight babies (< 2.5 kg) in the supplemented group in one study (RR 0.67, 95% CI 0.47 to 0.96; one study, 594 women). AUTHORS' CONCLUSIONS: The pooled results of three large trials in Nepal, Ghana and Bangladesh (with over 153,500 women) do not currently suggest a role for antenatal vitamin A supplementation to reduce maternal or perinatal mortality. However, the populations studied were probably different with regard to baseline vitamin A status and there were problems with follow‐up of women. There is good evidence that antenatal vitamin A supplementation reduces maternal night blindness, maternal anaemia for women who live in areas where vitamin A deficiency is common or who are HIV‐positive. In addition the available evidence suggests a reduction in maternal infection, but these data are not of a high quality.

The effectiveness of antenatal corticosteroids to prevent neonatal lung disease in women at risk of preterm birth was established by systematic reviews. In addition, subgroup analyses suggested that treatment was most effective in babies born one to seven days after administration. This belief led to widespread use of repeated courses of corticosteroids in women who did not deliver within a week or two of initial treatment. However, the notion that effectiveness declines after seven days may be incorrect, as the analyses that it is based on are unreliable. Here, we discuss the methodological problems of these analyses and their relevance to current randomised controlled trials of repeated versus single courses.

Purpose of review: It is recognised that the quality of CPR is an important predictor of outcome from cardiac arrest yet studies consistently demonstrate that the quality of CPR performed in real life is frequently sub-optimal. Mechanical chest compression devices provide an alternative to manual CPR. This review will consider the evidence and current indications for the use of these devices. Recent findings: Physiological and animal data suggest that mechanical chest compression devices are more effective than manual CPR. However there is no high quality evidence showing improved outcomes in humans. There are specific circumstances where it may not be possible to perform manual CPR effectively e.g. during ambulance transport to hospital, en-route to and during cardiac catheterisation, prior to organ donation and during diagnostic imaging where using these devices may be advantageous. Summary: There is insufficient evidence to recommend the routine use of mechanical chest compression devices. There may be specific circumstances when CPR is difficult or impossible where mechanical devices may play an important role in maintaining circulation. There is an urgent need for definitive clinical and cost effectiveness trials to confirm or refute the place of mechanical chest compression devices during resuscitation.

Background Survival after out-of-hospital cardiac arrest is closely linked to the quality of CPR, but in real life, resuscitation during prehospital care and ambulance transport is often suboptimal. Mechanical chest compression devices deliver consistent chest compressions, are not prone to fatigue and could potentially overcome some of the limitations of manual chest compression. However, there is no high-quality evidence that they improve clinical outcomes, or that they are cost effective. The Prehospital Randomised Assessment of a Mechanical Compression Device In Cardiac Arrest (PARAMEDIC) trial is a pragmatic cluster randomised study of the LUCAS-2 device in adult patients with non-traumatic out-of-hospital cardiac arrest. Methods/design The primary objective of this trial is to evaluate the effect of chest compression using LUCAS-2 on mortality at 30 days post out-of-hospital cardiac arrest, compared with manual chest compression. Secondary objectives of the study are to evaluate the effects of LUCAS-2 on survival to 12 months, cognitive and quality of life outcomes and cost-effectiveness. Methods: Ambulance service vehicles will be randomised to either manual compression (control) or LUCAS arms. Adult patients in out-of-hospital cardiac arrest, attended by a trial vehicle will be eligible for inclusion. Patients with traumatic cardiac arrest or who are pregnant will be excluded. The trial will recruit approximately 4000 patients from England, Wales and Scotland. A waiver of initial consent has been approved by the Research Ethics Committees. Consent will be sought from survivors for participation in the follow-up phase. Conclusion The trial will assess the clinical and cost effectiveness of the LUCAS-2 mechanical chest compression device. Trial Registration: The trial is registered on the International Standard Randomised Controlled Trial Number Registry (ISRCTN08233942).

This article draws on findings from a recent Cochrane systematic review of midwife-led care and discusses its contribution to the safety and quality of women's care in the domains of safety, effectiveness, woman-centeredness, and efficiency. According to the Cochrane review, women who received models of midwife-led care were nearly eight times more likely to be attended at birth by a known midwife, were 21% less likely to experience fetal loss before 24 weeks' gestation, 19% less likely to have regional analgesia, 14% less likely to have instrumental birth, 18% less likely to have an episiotomy, and significantly more likely to have a spontaneous vaginal birth, initiate breastfeeding, and feel in control. In addition to normalizing and humanizing birth, the contribution of midwife-led care to the quality and safety of health care is substantial. The implications are that policymakers who wish to improve the quality and safety of maternal and infant care, particularly around normalizing and humanizing birth, should consider midwife-led models of care and how financing of midwife-led services can support this. Suggestions for future research include exploring why fetal loss is reduced under 24 weeks' gestation in midwife-led models of care, and ensuring that the effectiveness of midwife-led models of care on mothers' and infants' health and well-being are assessed in the longer postpartum period.

Objective: To undertake a national survey to determine current practice for the management of whiplash injuries in UK emergency departments (ED).\ud \ud Methods: Postal questionnaire survey. 316 lead consultants from all UK ED with annual new attendances of over 50 000 people were asked to indicate the use of a range of treatments and the frequency with which these treatments were used. Samples of written advice were requested and content analysis was conducted and compared with survey responses.\ud \ud Results: The response rate was 79% (251/316). The intervention most frequently used was verbal advice to exercise, reported by 84% of respondents for most or all cases, and advice against the use of a collar (83%). Other treatments reported as being used frequently were written advice and anti-inflammatory medication. 106 consultants (42%) provided a sample of written materials. Reference to expected recovery and encouragement for early return to activities were included in less than 6%. Nearly 50% of written materials contained information on how to use a soft collar and 61% contained information on solicitors and pursuing a personal injury claim. There were important differences between reported verbal behaviours and written advice.\ud \ud Conclusion: Verbal advice is the primary method for managing whiplash injuries in ED and is usually supplemented by written advice. Within individual hospitals there is a lack of consistency between verbal and written advice. The promotion of personal injury claims is a common feature of written advice. Research is required to develop effective and consistent models of advice.

Background: Midwives are primary providers of care for childbearing women around the world. However, there is a lack of synthesised information to establish whether there are differences in morbidity and mortality, effectiveness and psychosocial outcomes between midwife-led and other models of care. Objectives: To compare midwife-led models of care with other models of care for childbearing women and their infants. Search strategy: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (January 2008), Cochrane Effective Practice and Organisation of Care Group's Trials Register (January 2008), Current Contents (1994 to January 2008), CINAHL (1982 to August 2006), Web of Science, BIOSIS Previews, ISI Proceedings, (1990 to 2008), and the WHO Reproductive Health Library, No. 9. Selection criteria: All published and unpublished trials in which pregnant women are randomly allocated to midwife-led or other models of care during pregnancy, and where care is provided during the ante-and intrapartum period in the midwife-led model. Data collection and analysis: All authors evaluated methodological quality. Two authors independently checked the data extraction. Main results: We included 11trials (12,276 women). Women who had midwife-led models of care were less likely to experience antenatal hospitalisation, risk ratio (RR) 0.90, 95% confidence interval (CI) 0.81 to 0.99), the use of regional analgesia (RR 0.81, 95% CI 0.73 to 0.91), episiotomy (RR 0.82, 95% CI 0.77 to 0.88), and instrumental delivery (RR 0.86, 95% CI 0.78 to 0.96) and were more likely to experience no intrapartum analgesia/ anaesthesia (RR 1.16, 95% CI 1.05 to 1.29), spontaneous vaginal birth (RR 1.04, 95% CI 1.02 to 1.06), to feel in control during labour and childbirth (RR 1.74, 95% CI .32 to 2.30), attendance at birth by a known midwife (RR 7.84, 95% CI 4.15 to 14.81) and initiate breastfeeding (RR 1.35, 95% CI 1.03 to 1.76). In addition, women who were randomised to receive midwife-led care were less likely to experience fetal loss before 24 weeks' gestation (RR 0.79, 95% CI 0.65 to 0.97), and their babies were more likely to have a shorter length of hospital stay (mean difference -2.00, 95% CI -2.15 to -1.85). There were no statistically significant differences between groups for overall fetal loss/neonatal death (RR 0.83, 95% CI 0.70 to 1.00), or fetal loss/neonatal death of at least 24 weeks (RR 1.01, 95% CI 0.67 to 1.53). Authors' conclusions: All women should be offered midwife-led models of care and women should be encouraged to ask for this option.

We performed a Cochrane review to assess which of the treatments for twin-twin transfusion syndrome (TTTS) improves fetal, childhood and maternal outcomes. This article represents a version of the review which includes additional data to the published version. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2007) and the Cochrane Central Register of Controlled Trials (The Cochrane Library, October 2007) for randomized and quasi-randomized studies of amnioreduction, laser coagulation and septostomy and compared their outcomes. We also searched conference proceedings and contacted the authors of published trials for clarification and additional data. No trials compared intervention with no intervention. Three studies (253 women) were included. Laser coagulation resulted in less overall death (48% vs. 59%; relative risk (RR), 0.81; 95% CI, 0.65-1.01 adjusted for clustering; two trials, 364 fetuses), perinatal death (26% vs. 44%; RR, 0.59; 95% CI, 0.40-0.87 adjusted for clustering; one trial, 284 fetuses) and neonatal death (8% vs. 26%; RR, 0.29; 95% CI, 0.14-0.61 adjusted for clustering; one trial, 284 fetuses) when compared with amnioreduction. There was no difference in perinatal outcome between amnioreduction and septostomy. More babies were alive without neurological abnormality at the age of 6 months in the laser group than in the amnioreduction group (52% vs. 31%; RR, 1.66; 95% CI, 1.17-2.35 adjusted for clustering; one trial). There was no difference in the proportion of babies alive at 6 months that had undergone treatment for major neurological abnormality between the laser coagulation and the amnioreduction groups (4% vs. 7%; RR, 0.58; 95% CI, 0.18-1.86 adjusted for clustering; one trial). The results suggest that endoscopic laser coagulation of anastomotic vessels should be considered in the treatment of all stages of TTTS to improve perinatal and neonatal outcome.

Study Design. Systematic Review. Objective. To summarize evidence concerning physical prognostic factors for development of Late Whiplash Syndrome (LWS). Summary of Background Data. There have been 3 previous systematic reviews of prognosis of whiplash with conflicting findings. The Quebec Task Force concluded that high priority should be given to determining prognostic factors. Subsequently their review was updated by Cote et al (Spine 2001; 26: E445-58) and most recently by Scholten-Peeters et al (Pain 2003; 104: 303-22). Methods. We searched electronic databases from their inception to August 2006 using a prespecified search strategy. We included prospective cohort and case control studies that studied physical prognostic factors at baseline. Two independent reviewers selected articles, extracted data, and assessed quality. Meta-analysis was not performed due to the heterogeneity between studies. Instead, levels of evidence were generated by grouping similar findings from cohorts. Results. Thirty-eight articles from 26 cohorts were reviewed. The majority of articles (25 of 38) were rated as low quality. No studies were rated as high quality. Only a minority of studies used validated prognostic measures and/or outcome measures. High initial neck pain intensity, neck pain related disability, and cold hyperalgesia all had moderate evidence for an association with the development of LWS. No factor was rated as having strong evidence. Conclusion. Pain has a central role to play as a prognostic factor for the development of LWS. Other physical factors commonly used in the clinical setting showed inconclusive evidence for their influence on prognosis. There is a need for improved quality of studies with consistent use of validated measures of all categories of prognostic factors and outcome. This may then provide a clearer understanding of prognosis of Whiplash Associated Disorders and therefore facilitate effective management of this costly problem.

Background: A substantial proportion of patients with whiplash injuries develop chronic symptoms. However, the best treatment of acute injuries to prevent long-term problems is uncertain. A stepped care treatment pathway has been proposed, in which patients are given advice and education at their initial visit to the emergency department (ED), followed by review at three weeks and physiotherapy for those with persisting symptoms. MINT is a two-stage randomised controlled trial to evaluate two components of such a pathway: 1. use of The Whiplash Book versus usual advice when patients first attend the emergency department; 2. referral to physiotherapy versus reinforcement of advice for patients with continuing symptoms at three weeks. Methods: Evaluation of the Whiplash Book versus usual advice uses a cluster randomised design in emergency departments of eight NHS Trusts. Eligible patients are identified by clinicians in participating emergency departments and are sent a study questionnaire within a week of their ED attendance. Three thousand participants will be included. Patients with persisting symptoms three weeks after their ED attendance are eligible to join an individually randomised study of physiotherapy versus reinforcement of the advice given in ED. Six hundred participants will be randomised. Follow-up is at 4, 8 and 12 months after their ED attendance. Primary outcome is the Neck Disability Index (NDI), and secondary outcomes include quality of life and time to return to work and normal activities. An economic evaluation is being carried out. Conclusion: This paper describes the protocol and operational aspects of a complex intervention trial based in NHS emergency and physiotherapy departments, evaluating two components of a stepped-care approach to the treatment of whiplash injuries. The trial uses two randomisations, with the first stage being cluster randomised and the second individually randomised.

Auricular acupuncture (insertion of acupuncture into a number, usually five, of specific points in the ear) is a widely-used treatment for cocaine dependence.To determine whether auricular acupuncture is an effective treatment for cocaine dependence, and to investigate whether its effectiveness is influenced by the treatment regimen.We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2004); MEDLINE (January 1966 to October 2004) , EMBASE (January 1988 to October 2004); PsycInfo (1985 to October 2004); CINAHL (1982 to October 2004); SIGLE (1980 to October 2004) and reference lists of articles.Randomised controlled trials comparing a therapeutic regimen of auricular acupuncture with sham acupuncture or no treatment for reduction of cocaine use in cocaine dependents.Two authors independently extracted data from published reports and assessed study quality using the Drug and Alcohol CRG checklist. All authors were contacted for additional information; two provided data. Separate meta-analyses were conducted for studies comparing auricular acupuncture with sham acupuncture, and with no treatment. For the main cocaine use outcomes, analyses were conducted by intention to treat, assuming that missing data were treatment failures. Available case analyses, using only individuals who provided data, were also conducted.Seven studies with a total of 1,433 participants were included. All were of generally low methodological quality. No differences between acupuncture and sham acupuncture were found for attition RR 1.05 (95% CI 0.89 to 1.23) or acupuncture and no acupuncture: RR 1.06 (95% CI 0.90 to 1.26) neither for any measure of cocaine or other drug use. However, the number of participants included in meta-analyses was low, and power was limited. Moderate benefit or harm is not ruled out by these results. Methodological limitations of the included studies may have also made the results open to bias.There is currently no evidence that auricular acupuncture is effective for the treatment of cocaine dependence. The evidence is not of high quality and is inconclusive. Further randomised trials of auricular acupuncture may be justified.

Therapeutic communities (TCs) are a popular treatment for the rehabilitation of drug users in the USA and Europe.To determine the effectiveness of TC versus other treatments for substance dependents, and to investigate whether effectiveness is modified by client or treatment characteristics.We searched: Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2005); MEDLINE, EMBASE, Psycinfo, CINAHL, SIGLE from their inception to March 2004. Reference lists of studies were scanned.Randomised controlled trials comparing TC with other treatments, no treatment or another TC.Two authors independently inspected abstracts, the methodological quality was assessed using Drug and Alcohol CRG checklist. When possible, data were summarised using relative risks and differences in means, otherwise results are presented as reported by authors.Seven studies were included. Differences between studies precluded any pooling of data, results are summarised for each trial individually: TC versus community residence: no significant differences for treatment completion; Residential versus day TC: attrition (first two weeks), and abstinence rates at six months significantly lower in the residential treatment group; Standard TC versus enhanced abbreviated TC: number of employed higher in standard TC RR 0.78 (95% CI 0.63, 0.96). Three months versus six months programme within modified TC, and six months versus 12 months programme within standard TC: completion rate higher in the three months programme and retention rate (40 days) significantly greater with the 12 months than 6 months programme. Two trials evaluated TCs within a prison setting: one reported significantly fewer re incarcerated 12 months after release from prison in the TC group compared with no treatment, RR 0.68 (95% CI 057, 0.81). In the other, people treated in prison with TC compared with Mental Health Treatment Programmes showed significantly fewer re incarcerations RR 0.28 (95% CI 0.13, 0.63), criminal activity 0.69 (95% CI 0.52, 0.93) and alcohol and drug offences 0.62 (95% CI 0.43, 0.90) 12 months after release from prison.There is little evidence that TCs offer significant benefits in comparison with other residential treatment, or that one type of TC is better than another. Prison TC may be better than prison on it's own or Mental Health Treatment Programmes to prevent re-offending post-release for in-mates. However, methodological limitations of the studies may have introduced bias and firm conclusions cannot be drawn due to limitations of the existing evidence.

Background There is a variety of techniques for closing the abdominal wall during caesarean section. Some methods may be better in terms of postoperative recovery and other important outcomes. Objectives To compare the effects of alternative techniques for closure of the rectus sheath and subcutaneous fat on maternal health and healthcare resource use. Search methods We searched the Cochrane Pregnancy and Childbirth Group trials register (September 2003), MEDLINE (1966 to September 2003), EMBASE (1980 to September 2003), CINAHL (1983 to September 2003) and CAB Health (1973 to September 2003), and the reference lists of included articles. Selection criteria Randomised trials making any of the following comparisons: (a) any suturing technique or material used for closure of the rectus sheath versus any other; (b) closure versus non-closure of subcutaneous fat; (c) any suturing technique or material used for closure of the subcutaneous fat versus any other; (d) any type of needle for repair of the abdominal wall in caesarean section versus any other; (e) any other comparison of methods of abdominal wall closure. Data collection and analysis Both reviewers evaluated trials for eligibility and methodological quality without consideration of their results. Main results Seven studies involving 2056 women were included. The risk of haematoma or seroma was reduced with fat closure compared with non-closure (relative risk (RR) 0.52, 95% confidence interval (CI) 0.33 to 0.82), as was the risk of 'wound complication' (haematoma, seroma, wound infection or wound separation) (RR 0.68, 95% CI 0.52 to 0.88). No difference in the risk of wound infection alone or other short-term outcomes was found. No long-term outcomes were reported. There was no difference in the risk of wound infection between blunt needles and sharp needles in one small study. No studies were found examining suture techniques or materials for closure of the rectus sheath or subcutaneous fat. Authors' conclusions Implications for practice Closure of the subcutaneous fat may reduce wound complications but it is unclear to what extent these differences affect the well-being and satisfaction of the women concerned. Implications for research Further trials are justified to investigate whether the apparent increased risk of haematoma or seroma with non-closure of the subcutaneous fat is real. These should use a broader range of short- and long-term outcomes, and ensure that they are adequately powered to detect clinically important differences. Further research comparing blunt and sharp needles is justified, as are trials evaluating suturing materials and suturing techniques for the rectus sheath.

Summary Background Admission cardiotocography is widely used to identify pregnancies that might benefit from continuous electronic fetal monitoring in labour. We aimed to compare the effect on neonatal outcome of admission cardiotocography versus intermittent auscultation of the fetal heart rate. Methods 8580 women admitted to the delivery ward of a Dublin teaching hospital who were at low risk of fetal distress in labour were randomly assigned admission cardiotocography (20 min) or the unit's usual care (intermittent auscultation only, with continuous cardiotocography only if clinically indicated). The primary outcome was moderate to severe neonatal morbidity, or perinatal mortality in the absence of a major congenital malformation. Analyses were by intention to treat. Findings 44 (1·0%) women assigned admission cardiotocography did not undergo the procedure; 15 (0·4%) assigned usual care had admission cardiotocography. The primary endpoint occurred in 56 (1·3%) of 4298 women assigned admission cardiotocography and 55 (1·3%) of 4282 in the usual-care group (relative risk 1·01; 95% CI 0·70–1·47). Other indices of neonatal morbidity also showed no differences. Despite an increase in use of continuous cardiotocography (1·39; 1·33–1·45) and fetal blood sampling (1·30; 1·14–1·47) with admission cardiotocography, there were no significant differences in the rates of caesarean delivery (1·13; 0·92–1·40), instrumental delivery (1·03; 0·92–1·16), or episiotomy (1·06; 0·99–1·13). Interpretation Routine use of cardiotocography for 20 min on admission to the delivery ward does not improve neonatal outcome. No significant increase in operative delivery was apparent, probably because of liberal use of fetal blood sampling.

Few trials have been conducted by UK ambulance services, and well-known examples of trials experiencing difficulties has led to the perception that prehospital care is a difficult environment for trials. PARAMEDIC is an HTA-funded trial comparing mechanical chest compression (using the LUCAS-2 device) with manual chest compression, during attempted resuscitation after cardiac arrest. It is recruiting 4,344 patients from four ambulance services in the UK; the primary outcome is 30 day survival. The trial uses cluster randomisation, with allocation by vehicles. All eligible cardiac arrests where a trial vehicle was first in attendance are included, which. This ensures minimal chance of differential recruitment between the LUCAS and manual chest compression arms, avoiding one of the main threats to cluster randomised trials. The study has raised a number of interesting methodological challenges, including: 1. How to identify all cardiac arrests attended by trial vehicles from multiple imperfect data sources; 2. Movements of vehicles between ambulance stations; trial vehicles often move away from their base station to a non-participating station, and hence do not recruit to the trial; 3. Device management; devices are easily removed from vehicles, and also need to be located for servicing or product recalls; 4. Compliance; although the crews cannot decide not to recruit a patient, they can decide not to use the LUCAS device; there has been significant non-use of the devices, with important consequences for the analysis of the trial.