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Objective To derive a new maternity early warning score (MEWS) from prospectively collected data on maternity vital signs and to design clinical response pathways with a Delphi consensus exercise.Design Centile based score development and Delphi informed escalation pathways.Setting Pregnancy Physiology Pattern Prediction (4P) prospective UK cohort study, 1 August 2012 to 28 December 2016.Participants Pregnant people from the 4P study, recruited before 20 weeks' gestation at three UK maternity centres (Oxford, Newcastle, and London). 841, 998, and 889 women provided data in the early antenatal, antenatal, and postnatal periods.Main outcome measures Development of a new national MEWS, assigning numerical weights to measurements in the lower and upper extremes of distributions of individual vital signs from the 4P prospective cohort study. Comparison of escalation rates of the new national MEWS with the Scottish and Irish MEWS systems from 18 to 40 weeks' gestation. Delphi consensus exercise to agree clinical responses to raised scores.Results A new national MEWS was developed by assigning numerical weights to measurements in the lower and upper extremes (5%, 1%) of distributions of vital signs, except for oxygen saturation where lower centiles (10%, 2%) were used. For the new national MEWS, in a healthy population, 56% of observation sets resulted in a total score of 0 points, 26% a score of 1 point, 12% a score of 2 points, and 18% a score of ≥2 points (escalation of care is triggered at a total score of ≥2 points). Corresponding values for the Irish MEWS were 37%, 25%, 22%, and 38%, respectively; and for the Scottish MEWS, 50%, 18%, 21%, and 32%, respectively. All three MEWS were similar at the beginning of pregnancy, averaging 0.7-0.9 points. The new national MEWS had a lower mean score for the rest of pregnancy, with the mean score broadly constant (0.6-0.8 points). The new national MEWS had an even distribution of healthy population alerts across the antenatal period. In the postnatal period, heart rate threshold values were adjusted to align with postnatal changes. The centile based score derivation approach meant that each vital sign component in the new national MEWS had a similar alert rate. Suggested clinical responses to different MEWS values were agreed by consensus of an independent expert panel.Conclusions The centile based MEWS alerted escalation of care evenly across the antenatal period in a healthy population, while reducing alerts in healthy women compared with other MEWS systems. How well the tool predicted adverse outcomes, however, was not assessed and therefore external validation studies in large datasets are needed. Unlike other MEWS systems, the new national MEWS was developed with prospectively collected data on vital signs and used a systematic, expert informed process to design an associated escalation protocol.

BackgroundEarly warning scores (EWS) are routinely used in hospitals to assess a patient’s risk of deterioration. EWS are traditionally recorded on paper observation charts but are increasingly recorded digitally. In either case, evidence for the clinical effectiveness of such scores is mixed, and previous studies have not considered whether EWS leads to changes in how deteriorating patients are managed. ObjectiveThis study aims to examine whether the introduction of a digital EWS system was associated with more frequent observation of patients with abnormal vital signs, a precursor to earlier clinical intervention. MethodsWe conducted a 2-armed stepped-wedge study from February 2015 to December 2016, over 4 hospitals in 1 UK hospital trust. In the control arm, vital signs were recorded using paper observation charts. In the intervention arm, a digital EWS system was used. The primary outcome measure was time to next observation (TTNO), defined as the time between a patient’s first elevated EWS (EWS ≥3) and subsequent observations set. Secondary outcomes were time to death in the hospital, length of stay, and time to unplanned intensive care unit admission. Differences between the 2 arms were analyzed using a mixed-effects Cox model. The usability of the system was assessed using the system usability score survey. ResultsWe included 12,802 admissions, 1084 in the paper (control) arm and 11,718 in the digital EWS (intervention) arm. The system usability score was 77.6, indicating good usability. The median TTNO in the control and intervention arms were 128 (IQR 73-218) minutes and 131 (IQR 73-223) minutes, respectively. The corresponding hazard ratio for TTNO was 0.99 (95% CI 0.91-1.07; P=.73). ConclusionsWe demonstrated strong clinical engagement with the system. We found no difference in any of the predefined patient outcomes, suggesting that the introduction of a highly usable electronic system can be achieved without impacting clinical care. Our findings contrast with previous claims that digital EWS systems are associated with improvement in clinical outcomes. Future research should investigate how digital EWS systems can be integrated with new clinical pathways adjusting staff behaviors to improve patient outcomes.

Background The frequency at which patients should have their vital signs (e.g. blood pressure, pulse, oxygen saturation) measured on hospital wards is currently unknown. Current National Health Service monitoring protocols are based on expert opinion but supported by little empirical evidence. The challenge is finding the balance between insufficient monitoring (risking missing early signs of deterioration and delays in treatment) and over-observation of stable patients (wasting resources needed in other aspects of care). Objective Provide an evidence-based approach to creating monitoring protocols based on a patient’s risk of deterioration and link these to nursing workload and economic impact. Design Our study consisted of two parts: (1) an observational study of nursing staff to ascertain the time to perform vital sign observations; and (2) a retrospective study of historic data on patient admissions exploring the relationships between National Early Warning Score and risk of outcome over time. These were underpinned by opinions and experiences from stakeholders. Setting and participants Observational study: observed nursing staff on 16 randomly selected adult general wards at four acute National Health Service hospitals. Retrospective study: extracted, linked and analysed routinely collected data from two large National Health Service acute trusts; data from over 400,000 patient admissions and 9,000,000 vital sign observations. Results Observational study found a variety of practices, with two hospitals having registered nurses take the majority of vital sign observations and two favouring healthcare assistants or student nurses. However, whoever took the observations spent roughly the same length of time. The average was 5:01 minutes per observation over a ‘round’, including time to locate and prepare the equipment and travel to the patient area. Retrospective study created survival models predicting the risk of outcomes over time since the patient was last observed. For low-risk patients, there was little difference in risk between 4 hours and 24 hours post observation. Conclusions We explored several different scenarios with our stakeholders (clinicians and patients), based on how ‘risk’ could be managed in different ways. Vital sign observations are often done more frequently than necessary from a bald assessment of the patient’s risk, and we show that a maximum threshold of risk could theoretically be achieved with less resource. Existing resources could therefore be redeployed within a changed protocol to achieve better outcomes for some patients without compromising the safety of the rest. Our work supports the approach of the current monitoring protocol, whereby patients’ National Early Warning Score 2 guides observation frequency. Existing practice is to observe higher-risk patients more frequently and our findings have shown that this is objectively justified. It is worth noting that important nurse–patient interactions take place during vital sign monitoring and should not be eliminated under new monitoring processes. Our study contributes to the existing evidence on how vital sign observations should be scheduled. However, ultimately, it is for the relevant professionals to decide how our work should be used. Study registration This study is registered as ISRCTN10863045. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 17/05/03) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 6. See the NIHR Funding and Awards website for further award information. Plain language summary Patient recovery in hospital is tracked by measuring heart rate, blood pressure and other ‘vital signs’ and converting them into a score. These are ‘observed’ regularly by nursing staff so that deterioration can be spotted early. However, taking observations can disturb patients, and taking them too often causes extra work for staff. More frequent monitoring is recommended for higher scores, but evidence is lacking. To work out how often patients should be monitored, we needed to know how likely it is for patients to become more unwell between observations. We analysed over 400,000 patient records from two hospitals to understand how scores change with time. We looked at three of the most serious risks for patients in hospital. These risks are dying, needing intensive care or having a cardiac arrest. We also looked at the risk that a patient’s condition would deteriorate significantly before their measurements were taken again. We identified early signs of deterioration and how changes in vital signs affected the risk of a patient’s condition becoming worse. From this we calculated a maximum risk of deterioration. We then calculated different monitoring schedules that keep individual patients below this risk level. Some of those would consume less staff time than current National Health Service guidelines suggest. We also watched staff record patients’ vital signs. We learnt it takes about 5 minutes to take these measurements from each patient. This information helped us calculate how costs would change if patients’ vital signs were taken more or less often. We found that patients with a low overall score could have their vital signs monitored less often without being in danger of serious harm. This frees up nursing time so that patients with a higher score can be monitored more often. Importantly, this can be achieved without employing more staff. Scientific summary Background The frequency that patients in hospital should have their vital signs (e.g. blood pressure, pulse, oxygen saturations) measured is currently unknown. Current monitoring protocols (from NHS England) are based on expert opinion supported by little empirical evidence. The challenge is to find the balance between insufficient monitoring of patients (which risks missing early signs of deterioration and delays in treatment) and over-observation of stable patients (which wastes resources needed in other aspects of patient care). Guidance suggests monitoring frequency should be determined by a patient’s severity of illness – often measured using risk scores. One such score is the National Early Warning Score (NEWS), which provides a simple integer value showing how much a patient’s vital signs are outside normal ranges. A high NEWS score means the patient is at high risk of deterioration, prompting a range of responses from increasing observations to review by a doctor and changes to treatment. While there is evidence that NEWS can predict patient risk of adverse outcomes [such as death or transfer to the intensive care unit (ICU)], there is no evidence to suggest the appropriate monitoring frequency based on that risk. With so much discussion about pressures on NHS resources, especially workforce issues, this is an important topic. Objectives This study aimed to fill the evidence gap and guide development of future monitoring protocols taking into account the risk of deterioration and the impact on nursing workload and associated cost. We addressed the following research questions: What is the current practice for recording a patient’s vital signs? Who typically takes vital sign observations? How long does it take to record a set of vital signs required to calculate a NEWS score? And how do nursing staff fit observation in alongside other clinical work? Can we predict a patient’s risk of deterioration over time based on their NEWS score? Can we use these risk predictions to identify acceptable monitoring frequencies for each NEWS value? Can we estimate the economic impact and cost-effectiveness of new monitoring protocols to identify whether these are feasible for use in practice? Methods Our study consisted of two parts: (1) an observational study of nursing staff to ascertain the time it takes to perform vital sign observations; and (2) a retrospective study of historic data on patient admissions to explore the relationships between NEWS and risk of outcome over time. These were underpinned by opinions and experiences from stakeholders. Observational study We observed nursing staff on 16 randomly selected adult general wards at 4 acute general NHS hospitals. All wards included in this study used NEWS2, the 2017 update to NEWS. Three hospitals used electronic systems to record vital signs and automate NEWS2 calculation. In one hospital, vital signs were recorded on paper charts at the patient’s bedside and NEWS2 was calculated manually. We observed each ward for a total of 8 hours, spread across four sessions, with a total of 715 sets of vital sign measurements observed. Data were collected in real time by non-participating observers using bespoke software on a tablet computer. They also collected contextual data, including the total number of patients on the ward and the numbers of registered nurses (RNs), healthcare assistants (HCAs) and student nurses on shift during the observation session. Further, they recorded factors influencing the measurement and recording of vital signs, including reasons for, and the nature of, interruptions. After each observation session, data were uploaded onto a server managed by the raters’ institution. We did not store any personal data. We quantified the time it took to record a set of vital signs using three different estimates: (1) length of the round per number of vital signs observation sets, (2) time at the patient’s bedside and (3) variants of (1) and (2) removing interruptions. We used an iterative approach and thematic coding to group the different activities that delayed or interrupted vital sign observations. Retrospective study We extracted, linked and analysed routinely collected data from two large NHS trusts providing acute care: Portsmouth Hospitals University NHS Trust (PHU) and Oxford University Hospitals NHS Foundation Trust (OUH). Data sets included information on: patient demographics; vital sign observations; admission-specific data including admission specialty, whether the patient died, had a cardiac arrest or was transferred to ICU; information on treatment such as visit to operating theatre, receiving blood transfusions or chemotherapy. Data were extracted by each trust’s data team and pseudonymised prior to transfer to the research team. Patient records were filtered to remove people who had registered with the NHS national opt-out. In both hospitals, vital signs were monitored electronically. At PHU, NEWS was automatically calculated at the bedside, while OUH used a different score and NEWS values were calculated retrospectively. Monitoring protocols also varied across the different sites. For analysis and modelling, three study cohorts were created: Development data set: admissions to PHU 1 January 2014 to 30 June 2017 Internal validation data set: admissions to PHU 1 July 2017 to 30 June 2019 External validation data set: admissions to OUH 1 July 2017 to 30 June 2019 We excluded data from vital sign observations outside recorded admission and discharge periods, incomplete vital sign sets, surgical day admissions and admissions to maternity or paediatric specialties. We analysed patient subgroups separately to identify whether these patients had different monitoring requirements: admissions to medical, surgical and ‘elderly medicine’ specialties, admissions with and without visit to operating theatre, elective admissions, emergency admissions, admissions with and without an observation in the last 24 hours, patients aged 80 or older, patients aged 30 or younger. We considered the following adverse events as outcomes: DEATH: in-hospital death. COMB: combined outcome of either in-hospital death or cardiac arrest or unexpected admission to a high-care ward, whichever comes first. NEWS7: any of the events included in COMB or a NEWS value greater than 6. NEWSINC: combined outcome or NEWS > 6 or a NEWS increase of 2 or more. For each data set and patient subgroup, we summarised patient demographics, admission characteristics, observation frequency, average NEWS values and outcomes. We further investigated changes in NEWS over the course of a hospital admission, by tracking the mean NEWS in the days following admission and the days leading up to an event. Using the development data set, we created survival models to predict the risk of each outcome at 15-minute intervals over a 24-hour period based on NEWS from the time of observation. We randomly sampled each data set 2000 times to avoid bias towards admissions that had more vital sign observations, and then calculated average predicted risk. The model was validated internally (including patient subgroups) and externally by assessing model calibration and discrimination. Monitoring protocols were created by setting a consistent risk threshold before which the next observation should be taken, based on predicted risk for a given NEWS value. In generating alternative monitoring schedules, we considered relative workloads and the proportion of observations that will be missed. We explored the effect of three alternative monitoring regimes on risk thresholds, nursing workload and associated cost. Possible observation intervals were limited to integer hour (1 hour, 2 hour, 4 hour, 6 hour, 8 hour, 12 hour) values. Combining the expected number of observations and the average time taken to complete each, we calculated the nursing time required and the nursing cost per patient-day under each alternative protocol. Staffing costs were estimated by applying representative unit costs for RNs and HCAs, weighted to reflect the proportion of vital signs observations undertaken by each, based on observational study data. Stakeholder involvement and engagement We organised stakeholder events to identify factors relevant to the selection of an optimal monitoring protocol. Stakeholders included patients and their carers, and healthcare staff who were responsible for taking vital signs, escalating patients for more senior clinical review or introducing monitoring systems into one or more institutions. Their experiences of current practices influenced decisions made in the retrospective study, particularly when considering the practicalities of alternative observation frequencies. Results Observational study Across the four hospitals we studied, we found a variety of practices, with two hospitals having RNs take the majority of vital sign observations, while the other two hospitals favoured HCAs or student nurses. However, whoever took the observations spent roughly the same length of time. The average of 5:01 minutes per observation over a ‘round’ included the preparation time associated with locating and preparing the equipment and travelling to the patient’s area. An average of 3:45 was spent at each patient’s bedside (excluding interruptions not related to the vital sign taking), rising to 4:24 at the bedside with all interruptions included. Interruptions included jobs needing to be done at a set time of day, jobs convenient to do at the same time as vital sign observations, communication with other health professionals, emergencies, work prompted by the proximity to the patient, and absence or unavailability of patient. Other clinical work seemed to take priority during core time (9 a.m.–5 p.m.) but staff made up for this by scheduling the main rounds of observations around the main shift-change times (early morning and early evening) when there were fewer competing tasks. Any future protocol reducing the frequency of observations might support timely recording during core times, though they would probably still be prioritised below fixed-time activities. Any change to existing protocols might have knock-on effects on proximity-related care. For example, reducing the frequency of observations would reduce the opportunities for the patient to ask a question or benefit from other interaction with the nurse. Correspondingly, increasing the frequency could improve the quality of care provided. Our stakeholders proposed that ‘social interaction’ could be separated from vital sign observations, with a short ‘check-in’ approach adopted for lower-risk patients. In conclusion, while individual components of observation work are quite small, when aggregated over many patients and multiple observations per patient per day, they add up to a substantial amount of daily nursing workload that has to be integrated, prioritised and resourced. Retrospective study Our analysis included data from over 400,000 patient admissions and 9,000,000 vital sign observations. Differences in the distribution of NEWS values suggested there was a difference in case-mix between the two hospital trusts in the study. While patient demographics were broadly comparable, length of stay and mortality rates were higher at PHU (mortality 3.9%) than at OUH (2.6%). Rates for outcomes NEWS7 and NEWSINC were more consistent across the two sites. Elective patients, admissions without an observation in the last 24 hours and patients receiving blood transfusions or chemotherapy were identified as patient subgroups where outcomes and/or monitoring frequency were different to others. Daily patterns of observations showed peak activity at four different times: 06:00, 11:00, 16:00 and 20:00, with more distinct peaks at OUH than PHU. This is consistent with findings from the observational study that showed staff batch observations to avoid meal times and fit observations in with other regular activities. As expected, average NEWS values increased in the days prior to adverse outcome, with trends of deterioration starting up to 9 days prior to the event. Patients with the worst outcomes (death, unanticipated ICU admission) averaged the highest NEWS scores and had the earliest increases. Patients who were discharged without an adverse outcome had higher initial average NEWS values compared to those with outcomes NEWS7 or NEWSINC but showed a steady reduction in the last 5 days prior to discharge. Consistent with previous studies, breathing rate and oxygen saturation were identified as the vital signs most predictive of deterioration. We created survival models that predicted the risk of outcomes over time since the patient was last observed. For low-risk patients, there was not much difference in risk between 4 hours and 24 hours post observation. Model validation showed acceptable performance in both PHU and OUH validation cohorts. The tendency of the model to overestimate risk of outcome in the OUH cohort can be explained by lower observed outcome rates. These results suggest that a single monitoring protocol might be appropriate for the general adult hospital population, offering significant operational advantages. We explored a number of different scenarios with our stakeholders, based on how ‘risk’ could be managed in different ways. Vital sign observations are often done more frequently than necessary from a bald assessment of the patient’s risk. A changed protocol could redeploy existing resources to achieve better outcomes for some patients without compromising the safety of the rest. However, reducing the risk to some patients (by observing them more frequently) is offset by a theoretical increase in risk to others (by observing them less frequently). We cannot be certain that the net effect is positive (though it is likely). Stakeholders felt an increased risk for patients at low risk was acceptable to reduce the risk for high-risk patients. As an observational study, our analysis could not evaluate the actual impact of new monitoring protocols on outcomes. Nevertheless, our approach did assess protocol cost-effectiveness, allowing us to rule out any protocols that would require unfeasible changes in outcomes or costs and so help identify plausible candidate protocols whose performance could be assessed in clinical trials. For example, theoretically a 61% reduction in nursing resource could be achieved without raising any patient’s risk above the current maximum. A 34% saving could be achieved while halving the maximum risk, but both scenarios increase the risk for all low-risk patients (the majority). A 65% increase in resource would reduce the patient risk threshold by a factor of 10. Conclusions We developed a framework using clinical data to propose new observation protocols and a way of evaluating them both clinically (in terms of patient outcome) and economically (possible cost-effectiveness). Our work supports the approach of the current monitoring protocol, whereby patients’ NEWS2 scores guide observation frequency. Existing practice is to observe higher-risk patients more frequently and our findings have shown that this is objectively justified. It is worth noting that important nurse–patient interactions take place during vital sign monitoring and should not be eliminated under new monitoring processes. Our study contributes to the existing evidence on scheduling vital sign observations, but our retrospective design did not allow us to take into account all factors impacting monitoring frequency. Ultimately, it is for relevant professionals to collectively decide how our work should be used: nationally this could be the Royal College of Physicians reviewing NEWS; locally, it could be clinicians/managers determining local practice. Study registration This study is registered as ISRCTN10863045. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 17/05/03) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 6. See the NIHR Funding and Awards website for further award information.

Background There is debate whether the use of more arterial grafts during coronary artery bypass graft surgery provides advantages to the standard operation using the left internal thoracic artery plus vein grafts. We review data from the Arterial Revascularisation Trial to determine whether there is support for the multiple arterial graft hypothesis. Methods Patients undergoing coronary artery bypass graft for clinical reasons and who provided written informed consent were randomised to standard coronary artery bypass graft using the single internal thoracic artery or use of bilateral internal thoracic arteries. Additional vein grafts could be used. The primary outcome was all-cause mortality at 10 years and exploratory analyses were carried out to test the multiple arterial graft hypothesis. Results A total of 3102 patients were enrolled (1548 bilateral internal thoracic artery and 1554 single internal thoracic artery). Follow-up to 10 years for vital status was 98% complete. In the bilateral group, 14% of patients received a single internal thoracic artery only and use of radial artery grafts occurred in about 20% of patients in both groups. Aspirin was used in 81% of the patients, beta-blockers in 74%, statins in 90% and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in 73%. At 10 years, death rates were 20.3% and 21.2% in the bilateral internal thoracic artery and single internal thoracic artery groups, respectively (hazard ratio 0.96, 95% confidence intervals 0.82 to 1.12; p = 0.62) and composite of all-cause mortality, myocardial infarction or stroke 24.9% and 27.3%, respectively (hazard ratio 0.90, 95% confidence interval 0.79 to 1.03; p = 0.12). Exploratory analyses using the ‘as-treated’ approach indicate that outcomes were better in patients who received multiple arterial grafts (adding the right internal thoracic and/or radial arteries) compared with a single arterial graft. This effect appeared to be greater in patients with diabetes and those aged 70 years or less. Use of total arterial grafting without vein grafts may provide the best outcomes. Limitations The elevated cross-over rate between bilateral internal thoracic artery and single internal thoracic artery and the non-randomised use of radial artery grafts may have contributed to a loss of power to detect a difference in mortality between the two groups. Moreover, secondary analyses are prone to bias as they compare non-randomised groups. Conclusions The Arterial Revascularisation Trial is one of the largest long-term studies in cardiac surgery. The primary analysis did not show a mortality benefit for bilateral internal thoracic artery at 10 years, perhaps due to high crossover rates in the bilateral internal thoracic artery group and concomitant use of the radial artery. Secondary analyses suggest a mortality benefit for patients receiving multiple arterial grafts compared with single arterial graft with possible greater effects in patients with diabetes and separately in patients aged 70 years or above. The trial will follow patients to 15 years and the continuing Randomized Comparison of the Clinical Outcome of Single versus Multiple Arterial Grafts trial will further test the multiple arterial graft hypothesis. Trial registration This trial is registered as ISRCTN46552265. Funding This project was funded by the British Heart Foundation, the UK. Medical Research Council and the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 7. See the NIHR Journals Library website for further project information. Plain language summary Introduction Coronary artery bypass grafting is a surgical procedure aimed at improving blood flow in narrowed or blocked coronary (heart) arteries. The cardiac surgeon typically uses an artery from inside the chest wall (the internal thoracic artery) and veins from the leg to bypass the effected coronary arteries. Growing evidence suggests that using two internal thoracic arteries may be better than one. The main question in the Arterial Revascularisation Trial was ‘would the use of two internal thoracic arteries allow patients to live longer after coronary artery bypass graft than those who received a single internal thoracic artery?’ Methods The Arterial Revascularisation Trial was carried out in 28 hospitals in 7 countries. Patients scheduled to have coronary artery bypass graft and willing to participate in the trial were allocated at random (like tossing a coin) to grafting with either a single or a double internal thoracic artery. Additional vein or arterial grafts were used as considered necessary for that patient. Patients enrolled into the Arterial Revascularisation Trial were then followed-up for 10 years. Results A total of 3102 patients were enrolled in the trial; 1548 received bilateral internal thoracic artery and 1554 single internal thoracic artery grafts. Ninety-eight per cent of the patients were followed-up for up to 10 years and no statistical difference in survival was detected between the two groups at this timepoint (20.3% in the bilateral group vs. 21.2% in the single internal thoracic artery group). Additional analyses suggested that using more than one arterial graft, including the radial artery (from the arm), compared with using a single arterial graft, may be better, but this needs to be confirmed by further research. Limitations Some patients received a single internal thoracic artery when they should have received bilateral internal thoracic arteries, which could have reduced the efficiency of the trial to detect a difference between the two groups. Discussion The Arterial Revascularisation Trial is one of the largest long-term studies in cardiac surgery. This trial did not show that using two internal thoracic arteries during coronary artery bypass graft provides better outcomes for patients than using a single internal thoracic artery. Further results from the trial will be released upon completion of follow-up at 15 years. Scientific summary Objectives The Arterial Revascularisation Trial (ART) was a superiority trial aimed at comparing the outcomes of patients undergoing coronary artery bypass grafting (CABG) with either a bilateral internal thoracic artery (BITA) or single internal thoracic artery (SITA). The main secondary questions were whether using multiple arterial grafting (MAG) was associated with improved clinical outcomes and whether additional factors influence the efficacy of MAG such as diabetes and age. Methods Patients with multivessel coronary artery disease (CAD) involving at least the left anterior descending artery and the circumflex artery undergoing CABG were included and randomised equally to BITA or SITA. Emergency patients (refractory myocardial ischaemia/cardiogenic shock) and those requiring single grafts or redo CABG were excluded. After surgery, patients were followed-up on annual basis. Based on power calculation, 2928 patients were needed to be enrolled to detect an absolute 5% difference in mortality between the two groups with 90% power at the 5% significance level. The primary outcome of the trial was all-cause mortality and the secondary outcomes were the composite of death from any cause, myocardial infarction (MI), or stroke (in a time-to-event analysis), rate of repeat revascularisation and safety outcomes (including bleeding and sternal wound complications). The primary research question used the log rank method to compare survival in the BITA and SITA groups based on the intention to treat principle and censored patients at 10 years of follow-up after the date of randomisation. Secondary analyses used the as-treated principle and applied propensity score-based methods as appropriate to reduce confounding. Results A total of 3102 patients were enrolled in the trial: 1548 received BITA and 1554 SITA. Complete follow-up data for the primary outcome were available for 98% of patients at 10 years. Aspirin was used in 80%, beta-blockers 74%, statins 90% and angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers in 71%. The death rate at 10 years was 20.3% in the BITA group and 21.2% in the SITA group [hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.82 to 1.12; p = 0.62] while the composite of all-cause mortality, MI or stroke occurred in 24.9% in BITA compared with 27.3% in SITA (HR 0.97; 95% CI 0.83 to 1.14; p = 0.12). In those randomised to BITA, 86% actually received BITA grafts while in the SITA group, 97.5% received SITA. Additional radial artery grafts were used in 19% of patients in BITA and 22% in SITA. In a secondary analysis exploring the effect of multiple (MAG) and total arterial grafting (TAG), there was a significant trend toward a reduction in 10-year mortality in the MAG and TAG groups compared with single arterial grafting (SAG) (test for trend = 0.04). TAG was associated with a reduction in all-cause death when compared with SAG (P = 0.03). The benefit of TAG was also confirmed for the composite endpoint including death, MI, stroke or repeat revascularisation (P = 0.02) compared with SAG. When investigating the effect of diabetes, MAG was associated with a survival benefit in both the diabetic and non-diabetic groups compared with SAG. Similarly, MAG was associated with lower rates of the composite endpoint of death, MI and stroke in the diabetic and non-diabetic groups. However, MAG was associated with higher rates of deep sternal wound infection compared with SAG in both the diabetic and non-diabetic groups. Patients with insulin-dependent diabetes receiving MAG experienced the highest absolute rate of sternal wound infection (9.6%). Use of BITA was found to be associated with higher rates of sternal wound infection. Limitations The elevated crossover rate between BITA and SITA and the non-randomised use of RA grafts may have contributed to a loss of power to detect a difference in mortality between the two groups. Moreover, secondary analyses are prone to bias as they compare non-randomised groups. Conclusions The ART has shown that is possible to run pragmatic long-term trials in cardiac surgery. Overall, the study has not shown that use of BITA is associated with reduced mortality compared to SITA. Secondary analyses support the potential benefit of MAG and TAG. More information is needed to understand the interaction of graft patency and clinical outcomes after CABG, and routine computed tomography coronary angiography may be a useful option. Trial registration This trial is registered as ISRCTN46552265. Funding This project was funded by the British Heart Foundation, the UK Medical Research Council and the National Institute of Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 7. See the NIHR Journals Library website for further project information.

BackgroundThe Alberta Stroke Program Early CT Score (ASPECTS) is used to quantify the extent of injury to the brain following acute ischemic stroke (AIS) and to inform treatment decisions. The e-ASPECTS software uses artificial intelligence methods to automatically process non-contrast CT (NCCT) brain scans from patients with AIS affecting the middle cerebral artery (MCA) territory and generate an ASPECTS. This study aimed to evaluate the impact of e-ASPECTS (Brainomix, Oxford, UK) on the performance of US physicians compared to a consensus ground truth.MethodsThe study used a multi-reader, multi-case design. A total of 10 US board-certified physicians (neurologists and neuroradiologists) scored 54 NCCT brain scans of patients with AIS affecting the MCA territory. Each reader scored each scan on two occasions: once with and once without reference to the e-ASPECTS software, in random order. Agreement with a reference standard (expert consensus read with reference to follow-up imaging) was evaluated with and without software support.ResultsA comparison of the area under the curve (AUC) for each reader showed a significant improvement from 0.81 to 0.83 (p = 0.028) with the support of the e-ASPECTS tool. The agreement of reader ASPECTS scoring with the reference standard was improved with e-ASPECTS compared to unassisted reading of scans: Cohen's kappa improved from 0.60 to 0.65, and the case-based weighted Kappa improved from 0.70 to 0.81.ConclusionDecision support with the e-ASPECTS software significantly improves the accuracy of ASPECTS scoring, even by expert US neurologists and neuroradiologists.

Background: Patients with diabetes and obesity are at higher risk of adverse long-term outcomes following coronary artery bypass grafting. The use of bilateral internal thoracic arteries (BITA) can potentially offer survival benefit in higher risk patients compared to single internal thoracic artery (SITA), but BITA is not routinely used due to lack of clear evidence of efficacy and concerns over sternal wound complications. Methods: Medline, Embase and the Cochrane Library were searched for studies comparing the efficacy and safety of BITA and SITA grafting in patients with diabetes and obesity. Meta-analysis of mortality and sternal wound complications was performed. Results: We identified eight observational and ten propensity matched studies, and one RCT, comparing BITA and SITA which included patients with diabetes (n = 19,589); two propensity matched studies and one RCT which included patients with obesity (n = 6,972); mean follow up was 10.5 and 11.3 years respectively. Meta-analysis demonstrated a mortality reduction for BITA compared to SITA in patients with diabetes (risk ratio [RR] 0.79; 95% confidence interval [CI] 0.70–0.90; p = 0.0003). In patients with obesity there was a non-significant reduction in mortality in the BITA group (RR 0.73, 95% CI 0.47–1.12; p = 0.15). There was a significantly higher rate of sternal wound complications following BITA observed in patients with diabetes (RR 1.53, 95% CI 1.23–1.90; p = 0.0001) and obesity (RR 2.24, 95% CI 1.63–3.07; p

Abstract Background There is level 1 evidence for cerebral thrombectomy with thrombolysis in acute large vessel occlusion. Many hospitals are now contemplating setting up this life-saving service. For the hospital, however, the first treatment is associated with an initial high cost to cover the procedure. Whilst the health economic benefit of treating stroke is documented, this is the only study to date performing matched-pair, patient-level costing to determine treatment cost within the first hospital episode and up to 90 days post-event. Methods We conducted a retrospective coarsened exact matched-pair analysis of 50 acute stroke patients eligible for thrombectomy. Results Thrombectomy resulted in significantly more good outcomes (mRS 0–2) compared to matched controls (56% vs 8%, p = 0.001). More patients in the thrombectomy group could be discharged home (60% vs 28%), fewer were discharged to nursing homes (4% vs 16%), residential homes (0% vs 12%) or rehabilitation centres (8% vs 20%). Thrombectomy patients had fewer serious adverse events (n = 30 vs 86) and were, on average, discharged 36 days earlier. They required significantly fewer physiotherapy sessions (18.72 vs 46.49, p = 0.0009) resulting in a median reduction in total rehabilitation cost of £4982 (p = 0.0002) per patient. The total cost of additional investigations was £227 lower (p = 0.0369). Overall, the median cost without thrombectomy was £39,664 per case vs £22,444, resulting in median savings of £17,221 (p = 0.0489). Conclusions Mechanical thrombectomy improved patient outcome, reduced length of hospitalisation and, even without procedural reimbursement, significantly reduced cost to the thrombectomy providing hospital.

BackgroundShort- and long-term outcomes from endovascular thrombectomy (EVT) for large vessel occlusion stroke remain variable. Numerous relevant predictors have been identified, including severity of neurological deficits, age, and imaging features. The latter is typically defined as acute changes (most commonly Alberta Stroke Programme Early CT Score, ASPECTS, at presentation), but there is little information on the impact of imaging assessment of premorbid brain health as a determinant of outcome.AimsTo examine the impact of automated measures of stroke severity and underlying brain frailty on short- and long-term outcomes in acute stroke treated with EVT.MethodsIn 215 patients with anterior circulation stroke, who subsequently underwent EVT, automated analysis of presenting non-contrast CT scans was used to determine acute ischemic volume (AIV) and e-ASPECTS as markers of stroke severity, and cerebral atrophy as a marker of brain frailty. Univariate and multivariate logistic regression were used to identify significant predictors of NIHSS improvement, modified Rankin scale (mRS) at 90 and 30 days, mortality at 90 days and symptomatic intracranial hemorrhage (sICH) following successful EVT.ResultsFor long-term outcome, atrophy and presenting NIHSS were significant predictors of mRS 0–2 and death at 90 days, whereas age did not reach significance in multivariate analysis. Conversely, for short-term NIHSS improvement, AIV and age were significant predictors, unlike presenting NIHSS. The interaction between age and NIHSS was similar to the interaction of AIV and atrophy for mRS 0–2 at 90 days.ConclusionCombinations of automated software-based imaging analysis and clinical data can be useful for predicting short-term neurological outcome and may improve long-term prognostication in EVT. These results provide a basis for future development of predictive tools built into decision-aiding software in stroke.

Abstract Background Timely recognition of the deteriorating inpatient remains challenging. Wearable monitoring systems (WMS) may augment current monitoring practices. However, there are many barriers to implementation in the hospital environment, and evidence describing the clinical impact of WMS on deterioration detection and patient outcome remains unclear. Objective To assess the impact of vital-sign monitoring on detection of deterioration and related clinical outcomes in hospitalised patients using WMS, in comparison with standard care. Methods A systematic search was conducted in August 2020 using MEDLINE, Embase, CINAHL, Cochrane Database of Systematic Reviews, CENTRAL, Health Technology Assessment databases and grey literature. Studies comparing the use of WMS against standard care for deterioration detection and related clinical outcomes in hospitalised patients were included. Deterioration related outcomes (primary) included unplanned intensive care admissions, rapid response team or cardiac arrest activation, total and major complications rate. Other clinical outcomes (secondary) included in-hospital mortality and hospital length of stay. Exploratory outcomes included alerting system parameters and clinical trial registry information. Results Of 8706 citations, 10 studies with different designs met the inclusion criteria, of which 7 were included in the meta-analyses. Overall study quality was moderate. The meta-analysis indicated that the WMS, when compared with standard care, was not associated with significant reductions in intensive care transfers (risk ratio, RR 0.87; 95% confidence interval, CI 0.66–1.15), rapid response or cardiac arrest team activation (RR 0.84; 95% CI 0.69–1.01), total (RR 0.77; 95% CI 0.44–1.32) and major (RR 0.55; 95% CI 0.24–1.30) complications prevalence. There was also no statistically significant association with reduced mortality (RR 0.48; 95% CI 0.18–1.29) and hospital length of stay (mean difference, MD − 0.09; 95% CI − 0.43 to 0.44). Conclusion This systematic review indicates that there is no current evidence that implementation of WMS impacts early deterioration detection and associated clinical outcomes, as differing design/quality of available studies and diversity of outcome measures make it difficult to reach a definite conclusion. Our narrative findings suggested that alarms should be adjusted to minimise false alarms and promote rapid clinical action in response to deterioration. PROSPERO Registration number: CRD42020188633 .

Summary: Background: Pleural infection is a common and severe disease with high morbidity and mortality worldwide. The knowledge of pleural infection bacteriology remains incomplete, as pathogen detection methods based on culture have insufficient sensitivity and are biased to selected microbes. We designed a study with the aim to discover and investigate the total microbiome of pleural infection and assess the correlation between bacterial patterns and 1-year survival of patients. Methods: We assessed 243 pleural fluid samples from the PILOT study, a prospective observational study on pleural infection, with 16S rRNA next generation sequencing. 20 pleural fluid samples from patients with pleural effusion due to a non-infectious cause and ten PCR-grade water samples were used as controls. Downstream analysis was done with the DADA2 pipeline. We applied multivariate Cox regression analyses to investigate the association between bacterial patterns and 1-year survival of patients with pleural infection. Findings: Pleural infection was predominately polymicrobial (192 [79%] of 243 samples), with diverse bacterial frequencies observed in monomicrobial and polymicrobial disease and in both community-acquired and hospital-acquired infection. Mixed anaerobes and other Gram-negative bacteria predominated in community-acquired polymicrobial infection whereas Streptococcus pneumoniae prevailed in monomicrobial cases. The presence of anaerobes (hazard ratio 0·46, 95% CI 0·24–0·86, p=0·015) or bacteria of the Streptococcus anginosus group (0·43, 0·19–0·97, p=0·043) was associated with better patient survival, whereas the presence (5·80, 2·37–14·21, p

Introduction Ambulatory monitoring systems (AMS) can facilitate early detection of clinical deterioration, and have the potential to improve hospitalised patient outcomes. The objective of this systematic review is to assess the impact of vital signs monitoring on detection of deterioration and related outcomes in hospitalised patients using AMS, in comparison with standard care.Methods and analysis A systematic search was conducted on 27 August 2020 in MEDLINE, Embase, CINAHL, Cochrane Database of Systematic Reviews, CENTRAL and Health Technology Assessment databases, as well as grey literature. Search results will be reviewed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis checklist for systematic reviews. Studies comparing the use of ambulatory monitoring devices against standard care for deterioration detection and related clinical outcomes in hospitalised patients will be included and further clinical and other outcomes will also be explored. Deterioration-related outcomes may include (but not limited to) unplanned intensive care admissions, rapid response team activation and unscheduled emergency interventions, as defined by the included studies. Two reviewers will independently extract study data and assess the quality and risk of bias of included studies. Where possible, a meta-analysis will be conducted and quantitative results presented. Alternatively, a narrative synthesis will be reported.Ethics and dissemination Ethical approval is not required for this study as no primary data will be collected. This study is part of our virtual High Dependency Unit project and will be disseminated through peer-reviewed publications, public and scientific conference presentations.PROSPERO registration number CRD42020188633.

BackgroundGestational hypertensive and acute hypotensive disorders are associated with maternal morbidity and mortality worldwide. However, physiological blood pressure changes in pregnancy are insufficiently defined. We describe blood pressure changes across healthy pregnancies from the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) Fetal Growth Longitudinal Study (FGLS) to produce international, gestational age-specific, smoothed centiles (third, 10th, 50th, 90th, and 97th) for blood pressure.Methods and findingsSecondary analysis of a prospective, longitudinal, observational cohort study (2009 to 2016) was conducted across 8 diverse urban areas in Brazil, China, India, Italy, Kenya, Oman, the United Kingdom, and the United States of America. We enrolled healthy women at low risk of pregnancy complications. We measured blood pressure using standardised methodology and validated equipment at enrolment at 14 mmHg or diastolic blood pressure by >11 mmHg in fewer than 10% of women at any gestational age. Fewer than 10% of women increased their systolic blood pressure by >24 mmHg or diastolic blood pressure by >18 mmHg at any gestational age. The study's main limitations were the unavailability of prepregnancy blood pressure values and inability to explore circadian effects because time of day was not recorded for the blood pressure measurements.ConclusionsOur findings provide international, gestational age-specific centiles and limits of acceptable change to facilitate earlier recognition of deteriorating health in pregnant women. These centiles challenge the idea of a clinically significant midpregnancy drop in blood pressure.

Abstract Background Current reference ranges for blood pressure and heart rate throughout pregnancy have a poor evidence base. Methods This is a systematic review and meta-analysis. We included studies measuring blood pressure or heart rate from healthy pregnant women within defined gestational periods of 16 weeks or less. We analysed systolic blood pressure, diastolic blood pressure and heart rate by gestational age. We assessed effects of measurement year and method. Results We included 39 studies undertaken in 1967–2017, containing 124,349 systolic measurements from 36,239 women, 124,291 diastolic measurements from 36,181 women and 10,948 heart rate measurements from 8317 women. Mean (95% CI) systolic blood pressure was lowest at 10 weeks gestation, 110.4 (108.5, 112.3) mmHg, rising to 116.0 (113.6, 118.4) mmHg at 40 weeks, mean (95% CI) change 5.6 (4.0, 7.2) mmHg. Mean (95% CI) diastolic blood pressure was lowest at 21 weeks gestation, 65.9 (64.2, 67.7) mmHg; rising to 72.8 (71.0, 74.6) mmHg at 40 weeks, mean (95% CI) change 6.9 (6.2, 7.5) mmHg. Mean (95% CI) heart rate rose from 79.3 (75.5, 83.1) beats/min at 10 weeks to 86.9 (82.2, 91.6) beats/min at 40 weeks gestation, mean (95% CI) change 7.6 (1.8, 13.4) beats/min. Studies using manual measurement reported higher diastolic blood pressures than studies using automated measurement, mean (95 CI) difference 4.9 (0.8, 8.9) mmHg. Diastolic blood pressure increased by 0.26 (95% CI 0.10–0.43) mmHg/year. Including only higher-quality studies had little effect on findings, with heterogeneity remaining high (I 2 statistic > 50%). Conclusions Significant gestational blood pressure and heart rate changes occur that should be taken into account when assessing pregnant women. Commonly taught substantial decreases in blood pressure mid-pregnancy were not seen and heart rate increases were lower than previously thought. Manual and automated blood pressure measurement cannot be used interchangeably. Increases in diastolic blood pressure over the last half-century and differences between published studies show contemporary data are required to define current normal ranges. Study registration PROSPERO CRD42014009673

Objectives National guidelines for identifying physiological deterioration and sepsis in hospitals depend on thresholds for blood pressure that do not account for age or sex. In populations outside hospital, differences in blood pressure are known to occur with both variables. Whether these differences remain in the hospitalised population is unknown. This database analysis study aims to generate representative centiles to quantify variations in blood pressure by age and sex in hospitalised patients.Design Retrospective cross-sectional observational database analysis.Setting Four near-sea-level hospitals between April 2015 and April 2017Participants 75 342 adult patients who were admitted to the hospitals and had at least one set of documented vital sign observations within 24 hours before discharge were eligible for inclusion. Patients were excluded if they died in hospital, had no vital signs 24 hours prior to discharge, were readmitted within 7 days of discharge, had missing age or sex or had no blood pressure recorded.Results Systolic blood pressure (SBP) for hospitalised patients increases with age for both sexes. Median SBP increases from 122 (CI: 121.1 to 122.1) mm Hg to 132 (CI: 130.9 to 132.2) mm Hg in men, and 114 (CI: 113.1 to 114.4) mm Hg to 135 (CI: 134.5 to 136.2) mm Hg in women, between the ages of 20 and 90 years. Diastolic blood pressure peaked around 50 years for men 76 (CI: 75.5 to 75.9) mm Hg and women 69 (CI: 69.0 to 69.4) mm Hg. The blood pressure criterion for sepsis, systolic

Abstract Background For many vital signs, monitoring methods require contact with the patient and/or are invasive in nature. There is increasing interest in developing still and video image-guided monitoring methods that are non-contact and non-invasive. We will undertake a systematic review of still and video image-based monitoring methods. Methods We will perform searches in multiple databases which include MEDLINE, Embase, CINAHL, Cochrane library, IEEE Xplore and ACM Digital Library. We will use OpenGrey and Google searches to access unpublished or commercial data. We will not use language or publication date restrictions. The primary goal is to summarise current image-based vital signs monitoring methods, limited to heart rate, respiratory rate, oxygen saturations and blood pressure. Of particular interest will be the effectiveness of image-based methods compared to reference devices. Other outcomes of interest include the quality of the method comparison studies with respect to published reporting guidelines, any limitations of non-contact non-invasive technology and application in different populations. Discussion To the best of our knowledge, this is the first systematic review of image-based non-contact methods of vital signs monitoring. Synthesis of currently available technology will facilitate future research in this highly topical area. Systematic review registration PROSPERO CRD42016029167

Abstract Background Temporal changes in the placebo arm of randomized controlled trials (RCTs) have not been thoroughly investigated, despite the fact that results of RCTs depend on the comparison between arms. Methods In this update of our earlier systematic review and meta-analysis, we set out to investigate the effect of assessment time and number of visits on the magnitude of change from baseline in the placebo arm of these trials. We used linear mixed-effects models to account for within-trial correlations. Results Across all 47 trials the magnitude of response in the placebo arm did not change with time (β = -0.0070, 95% CI -0.024, 0.010) or visit (β = -0.033, 95% CI -0.082, 0.017) and remained significantly different from baseline for at least 12 months or seven follow-up visits. Change in the placebo arm in trials with subjective outcomes was large (β0 = 0.68, 95% CI 0.53, 0.82) and relatively constant across time (β = -0.0042, 95% CI -0.024, 0.016) and visit (β = -0.029, 95% CI -0.089, 0.031), whereas in trials with objective outcomes the response was smaller (β0 = 0.28, 95% CI 0.11, 0.46) and diminished with time (β = -0.030, 95% CI -0.050, -0.010), but not with visit (β = -0.099, 95% CI -0.30, 0.11). For trials with assessed outcomes, there was no significant effect of time (β = -0.0071, 95% CI -0.026, 0.011) or visit (β = -0.032, 95% CI -0.33, 0.26); however, these results should be interpreted with caution due to the small number of studies, and high clinical heterogeneity between studies. In trials with pain as an outcome, the improvement was significant (β0 = 0.91, 95% CI 0.75, 1.07), but there was no effect of time (β = -0.013, 95% CI -0.06, 0.03) or visit (β = -0.045, 95% CI -0.16, 0.069), and pain ratings remained significantly different from baseline for 12 months or seven visits. Conclusions These results are consistent with our previous findings. In trials with subjective outcomes response in the placebo arm remains large and relatively constant for at least a year, which is interesting considering that this is an effect of a single application of an invasive procedure. The lack of effect of time and visit number on subjective outcomes raises further questions regarding whether the observed response is the result of placebo effect or the result of bias.

BackgroundThere is still uncertainty about the safety of aprotinin for coronary artery bypass graft surgery. The ART (Arterial Revascularization Trial) was designed to compare survival after bilateral versus single internal thoracic artery grafting. Many of the ART patients (≈30%) received perioperative aprotinin. We investigated the association between perioperative aprotinin administration and short‐term (in‐hospital) and long‐term outcomes by performing a post hoc analysis of the ART. Methods and ResultsAmong patients enrolled in the ART (n=3102) from 2004 to 2007, we excluded those who did not undergo surgery (n=18) and those with no information about use of perioperative aprotinin (n=9). Finally, 836 of 3076 patients (27%) received aprotinin. Propensity matching was used to select 536 pairs for final comparison. Aprotinin was also associated with an increased risk of hospital mortality (9 [1.7%] versus 1 [0.2%]; odds ratio, 9.12; 95% confidence interval [CI], 1.15–72.2; P=0.03), intra‐aortic balloon pump insertion (37 [6.9%] versus 17 [3.2%]; odds ratio, 2.26; 95% CI, 1.26–4.07; P=0.006), and acute kidney injury (102 [19.0%] versus 76 [14.2%]; odds ratio, 1.42; 95% CI, 1.03–1.97; P=0.03). Aprotinin was not associated with a lower incidence of transfusion (37 [6.9%] versus 28 [5.2%]; odds ratio, 1.34; 95% CI, 0.81–2.23; P=0.25) and reexploration (26 [4.9%] versus 19 [3.5%]; hazard ratio, 1.39; 95% CI, 0.76–2.53; P=0.28). At 5 years, all‐cause mortality was significantly increased in the aprotinin group (56 [10.6%] versus 38 [7.3%]; hazard ratio, 1.51; 95% CI, 1.0–2.28; P=0.045). ConclusionsIn the present post hoc ART analysis, aprotinin was associated with a significantly increased risk of early and late mortality. Clinical Trial RegistrationURL: http://www.isrctn.com. Unique identifier: ISRCTN46552265.

BackgroundHeterologous prime-boost vaccination with chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) encoding multiple epitope string thrombospondin-related adhesion protein (ME-TRAP) has shown acceptable safety and promising immunogenicity in African adult and pediatric populations. If licensed, this vaccine could be given to infants receiving routine childhood immunizations. We therefore evaluated responses to ChAd63 MVA ME-TRAP when co-administered with routine Expanded Program on Immunization (EPI) vaccines.MethodsWe enrolled 65 Gambian infants and neonates, aged 16, 8, or 1 week at first vaccination and randomized them to receive either ME-TRAP and EPI vaccines or EPI vaccines only. Safety was assessed by the description of vaccine-related adverse events (AEs). Immunogenicity was evaluated using IFNγ enzyme-linked immunospot, whole-blood flow cytometry, and anti-TRAP IgG ELISA. Serology was performed to confirm all infants achieved protective titers to EPI vaccines.ResultsThe vaccines were well tolerated in all age groups with no vaccine-related serious AEs. High-level TRAP-specific IgG and T cell responses were generated after boosting with MVA. CD8+ T cell responses, previously found to correlate with protection, were induced in all groups. Antibody responses to EPI vaccines were not altered significantly.ConclusionMalaria vectored prime-boost vaccines co-administered with routine childhood immunizations were well tolerated. Potent humoral and cellular immunity induced by ChAd63 MVA ME-TRAP did not reduce the immunogenicity of co-administered EPI vaccines, supporting further evaluation of this regimen in infant populations.Clinical Trial RegistrationThe clinical trial was registered on http://Clinicaltrials.gov (NCT02083887) and the Pan-African Clinical Trials Registry (PACTR201402000749217).

Background: Cognitive–behavioural therapy (CBT) for childhood anxiety disorders is associated with modest outcomes in the context of parental anxiety disorder. Objectives: This study evaluated whether or not the outcome of CBT for children with anxiety disorders in the context of maternal anxiety disorders is improved by the addition of (i) treatment of maternal anxiety disorders, or (ii) treatment focused on maternal responses. The incremental cost-effectiveness of the additional treatments was also evaluated. Design: Participants were randomised to receive (i) child cognitive–behavioural therapy (CCBT); (ii) CCBT with CBT to target maternal anxiety disorders [CCBT + maternal cognitive–behavioural therapy (MCBT)]; or (iii) CCBT with an intervention to target mother–child interactions (MCIs) (CCBT + MCI). Setting: A NHS university clinic in Berkshire, UK. Participants: Two hundred and eleven children with a primary anxiety disorder, whose mothers also had an anxiety disorder. Interventions: All families received eight sessions of individual CCBT. Mothers in the CCBT + MCBT arm also received eight sessions of CBT targeting their own anxiety disorders. Mothers in the MCI arm received 10 sessions targeting maternal parenting cognitions and behaviours. Non-specific interventions were delivered to balance groups for therapist contact. Main outcome measures: Primary clinical outcomes were the child’s primary anxiety disorder status and degree of improvement at the end of treatment. Follow-up assessments were conducted at 6 and 12 months. Outcomes in the economic analyses were identified and measured using estimated quality-adjusted life-years (QALYs). QALYS were combined with treatment, health and social care costs and presented within an incremental cost–utility analysis framework with associated uncertainty. Results: MCBT was associated with significant short-term improvement in maternal anxiety; however, after children had received CCBT, group differences were no longer apparent. CCBT + MCI was associated with a reduction in maternal overinvolvement and more confident expectations of the child. However, neither CCBT + MCBT nor CCBT + MCI conferred a significant post-treatment benefit over CCBT in terms of child anxiety disorder diagnoses [adjusted risk ratio (RR) 1.18, 95% confidence interval (CI) 0.87 to 1.62, p = 0.29; adjusted RR CCBT + MCI vs. control: adjusted RR 1.22, 95% CI 0.90 to 1.67, p = 0.20, respectively] or global improvement ratings (adjusted RR 1.25, 95% CI 1.00 to 1.59, p = 0.05; adjusted RR 1.20, 95% CI 0.95 to 1.53, p = 0.13). CCBT + MCI outperformed CCBT on some secondary outcome measures. Furthermore, primary economic analyses suggested that, at commonly accepted thresholds of cost-effectiveness, the probability that CCBT + MCI will be cost-effective in comparison with CCBT (plus non-specific interventions) is about 75%. Conclusions: Good outcomes were achieved for children and their mothers across treatment conditions. There was no evidence of a benefit to child outcome of supplementing CCBT with either intervention focusing on maternal anxiety disorder or maternal cognitions and behaviours. However, supplementing CCBT with treatment that targeted maternal cognitions and behaviours represented a cost-effective use of resources, although the high percentage of missing data on some economic variables is a shortcoming. Future work should consider whether or not effects of the adjunct interventions are enhanced in particular contexts. The economic findings highlight the utility of considering the use of a broad range of services when evaluating interventions with this client group. Trial registration: Current Controlled Trials ISRCTN19762288. Funding: This trial was funded by the Medical Research Council (MRC) and Berkshire Healthcare Foundation Trust and managed by the National Institute for Health Research (NIHR) on behalf of the MRC–NIHR partnership (09/800/17) and will be published in full in Health Technology Assessment; Vol. 19, No. 38.