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Abstract Background Peripheral artery disease is a common condition caused by narrowing/blockage of the arteries, resulting in reduced blood supply. Peripheral artery disease is associated with an increased risk of vascular complications, but early treatment reduces mortality and morbidity. Leg ulcers are long-lasting wounds, usually treated by compression therapy. Compression therapy is not suitable for people with peripheral artery disease, as it can affect the arterial blood supply. In clinical practice, people with peripheral artery disease are identified by measurement of the ankle–brachial pressure index using a sphygmomanometer and manual Doppler device. However, this method can be uncomfortable for people with leg ulcers and automated devices have been proposed as a more acceptable alternative. The objective of this appraisal was to summarise the clinical and cost-effectiveness evidence on the use of automated devices to detect peripheral artery disease in people with leg ulcers. Methods Clinical effectiveness To identify reports of relevant studies, we searched major electronic databases and scrutinised the information supplied by the manufacturers of the automated devices under investigation. Due to the lack of evidence on people with leg ulcers, we considered evidence from studies of any design assessing automated devices versus an acceptable reference device in any population receiving ankle–brachial pressure index assessment. We summarised information on diagnostic accuracy of the automated devices and level of agreement with the reference device. For each device, when data permit, we pooled data across studies by conducting random-effects meta-analyses using a Hierarchical Summary Receiving Operating Characteristics model. Cost-effectiveness An economic model comprising a decision tree (24 weeks) and Markov models to capture lifetime costs and quality-adjusted life-years associated with venous, arterial and mixed aetiology disease in leg ulcer patients. Analyses were conducted from a United Kingdom National Health Service and Personal Social Services perspective. Costs and quality-adjusted life-years were discounted at 3.5% per year. Deterministic and several probabilistic analyses were used to capture uncertainty surrounding a range of optimistic and pessimistic assumptions about the impact of automated tests on health outcomes (ulcer healing and requirement for invasive management of arterial disease). Results Clinical effectiveness From the 116 records retrieved by the electronic searches, we included 24 studies evaluating five devices (BlueDop Vascular Expert, BOSO ABI-System 100, Dopplex Ability, MESI ankle–brachial pressure index MD and WatchBP Office ABI). Two studies assessing people with leg ulcers found that automated devices often gave higher ankle–brachial pressure index readings than manual Doppler (underestimation of arterial disease). In the 22 studies involving people without leg ulcers, automated devices generally demonstrated good specificity and moderate specificity. Meta-analysis of 12 studies showed a pooled sensitivity of 64% (95% confidence interval 57% to 71%) and a pooled specificity of 96% (95% confidence interval 92% to 98%) for detection of peripheral artery disease. Cost-effectiveness Automated devices cost less than manual Doppler to deliver. However, increased risks of invasive treatment requirements for inappropriately compressed arterial/mixed ulcers due to false-negative results, and increased healing times due to delayed compression of false-positive test results mean that in most scenarios manual Doppler was less costly and had slightly higher quality-adjusted life-years than automated devices. Results are highly uncertain, dependent on many assumptions and should be interpreted cautiously. Limitations and conclusions The limited evidence identified for each automated device, especially in people with leg ulcers, and its clinical heterogeneity precludes any firm conclusions on the diagnostic performance and cost-effectiveness of these devices in clinical practice. Study registration This study is registered as PROSPERO CRD42022327588. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135478) and is published in full in Health Technology Assessment; Vol. 28, No. 37. See the NIHR Funding and Awards website for further award information. Plain language summary Leg ulcers are long-lasting wounds mostly caused by problems in blood flow in the veins, which are treated by applying bandages or stockings to create a ‘compression’ effect. However, compression should not be used in people with a condition called peripheral artery disease. To identify people with peripheral artery disease who should not receive compression therapy, health professionals perform a test called ‘ankle–brachial pressure index’, which involves taking blood pressure of the arms and ankles using a device called ‘Doppler ultrasound’. The procedure is time-consuming and people with leg ulcers often find it uncomfortable. Automated devices have been proposed as a more acceptable option for assessing leg ulcers. However, we need to know whether these devices produce reliable results and represent good value for money for the National Health Service. We found 24 clinical studies that assessed 5 automated devices to measure ankle–brachial pressure index. The type of patients and clinical setting varied between studies. Two studies assessed people with leg ulcers and showed that the automated devices tended to give higher readings than standard Doppler and, therefore, may underestimate the presence of peripheral artery disease. Results of the 22 studies assessing people without leg ulcers showed that the automated devices could correctly identify people who did not have peripheral artery disease but were less precise in identifying people with peripheral artery disease. However, there was not enough evidence to confirm if these devices are reliable enough to be used in clinical practice. Compared to manual Doppler, the automated devices were less costly to deliver in clinical practice but had increased costs due to potentially inaccurate results. Our evaluation required many assumptions about how the devices would be used in practice, and there were no data on their impact on patient outcomes. Results are highly uncertain and should be interpreted cautiously. Given current evidence, it is unlikely that automated tests are a convenient option for the National Health Service. Scientific summary Background Peripheral artery disease (PAD) is a highly prevalent atherosclerotic condition characterised by the narrowing of the peripheral arteries resulting in restriction of blood supply to the affected limb. Although PAD is frequently asymptomatic, it can cause complications that can range from intermittent claudication (pain on walking which is relieved by rest) to critical limb ischaemia. Up to one-quarter of people with symptomatic PAD may require intervention, and amputation may be necessary if it is left untreated. Leg ulcers are defined as wounds that occur below the knee and either on or above the ankle (malleolus). Compression treatment (bandages or stockings) is recommended to treat venous leg ulcers, and there is a robust evidence base to support its effectiveness. However, compression therapy should be avoided in people with leg wounds and symptoms of arterial insufficiency, as compression may cause damage by impairing the arterial supply to the ulcerated leg. To improve PAD diagnosis and decide the most suitable treatment, people with leg ulcers are assessed using ankle–brachial pressure index (ABPI) measurements. ABPI is usually measured using a sphygmomanometer and manual Doppler device, which requires expertise from the relevant operator/healthcare professional. The procedure can be protracted and unpleasant for those with leg ulcers. Automated devices may be advantageous in reducing the length of time taken to assess ABPI and, thereby, any associated discomfort for the patient. In addition, automated devices may potentially be more accurate than manual processes in detecting PAD, thus conferring additional benefits such as reduced time to treatment and improved outcomes for people with leg ulcers. Objectives The specific objectives of this assessment were to: Determine the diagnostic performance and clinical utility of automated devices available in United Kingdom (UK) clinical practice [BlueDop Vascular Expert (BlueDop Medical), boso ABI-system 100 (BOSCH + SOHN), WatchBP Office ABI (Microlife), WatchBP Office Vascular (Microlife)], MESI ABPI MD (MESI), MESI mTABLET ABI (MESI), Dopplex Ability Automatic ABI System (Huntleigh Healthcare) for assessing the presence of PAD in people with leg ulcers. Develop an economic model to assess the cost-effectiveness of the automated devices available in UK clinical practice for assessing the presence of PAD in people with leg ulcers. Methods Clinical effectiveness Comprehensive electronic searches of databases including MEDLINE, EMBASE, Cochrane Library Web of Science and CINAHL were conducted to identify relevant reports of published studies. Evidence was considered from studies of any design assessing the relevant automated devices versus standard clinical assessment using a manual Doppler device. Initially, the population of interest was people with leg ulcers requiring measurement of ABPI, but, due to the dearth of available evidence, it was broadened to any population receiving ABPI measurement. Data on the diagnostic performance of the automated devices including data on the level of agreement between ABPI readings from automated devices and those from the reference device were extracted from the included studies. Information on the use of the devices in clinical practice was also recorded. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies – version 2 (QUADAS-2), QUADAS-C and the Review Body for Interventional Procedures (ReBIP) checklists, according to the type of study design. For each device, when sufficient data were available, we conducted random-effects meta-analyses using a Hierarchical Summary Receiving Operating Characteristic (HSROC) model. A two-stage, de novo decision analysis model was developed to assess cost-effectiveness. The first part was a decision tree model, which used a linked-evidence approach to capture the impact of test diagnostic accuracy on expected costs and quality-adjusted life-years (QALYs) for the first 24 weeks following test use. This included delayed venous ulcer healing due to false-positive (FP) test results (indicating PAD when the ulcer was venous) and increased risk of requiring invasive arterial treatment for inappropriately compressed arterial/mixed ulcers following a false-negative (FN) test result (indicating venous when underlying disease was arterial/mixed). It was assumed that any inaccurate tests would be identified within the 24-week time horizon of the decision tree. The surviving proportion of the cohort then entered arterial, mixed or venous ulcer Markov models depending on their true underlying disease classification. The venous disease model included five mutually exclusive health states, centred around ulcer healing (healed index ulcer, unhealed index ulcer, recurrence, healed post recurrence and death). The arterial and mixed disease models included four health states, focusing on the long-term outcomes of the arterial component of disease [critical limb ischaemia (CLI), healed post CLI, amputation and death]. The decision to structure the mixed Markov model similarly to the arterial-only model was based on discussion with clinical experts who explained that, in clinical practice, the arterial component of disease is likely to take priority in the patient’s care pathway. Costs were based on National Health Service and Personal Social Service perspective costs (2021 values) and included: micro-costing of the automated and manual Doppler devices costs of applying compression for the unhealed duration of a venous ulcer costs of referral to vascular services for test-positive patients, including the additional costs of unnecessary referral for patients with a FP test result costs of treating arterial disease, including endovascular and bypass procedures as well as follow-up nursing care long-term follow-up costs in the Markov model included the cost of managing recurrent venous ulcers, recurrent CLI and long-term health and social care costs of amputation. Health state utility values were obtained from the literature and were based on EuroQol-5 Dimensions data, valued using the UK value set where possible. Utilities were combined with mortality estimates for each health state to calculate QALYs. In the decision tree, utilities were dependent on the duration of ulcer healing time for venous ulcers, and whether patients had CLI for those with arterial/mixed disease. All utilities were adjusted for UK age- and sex-specific general population norms, allowing the cohort to experience reduced utility as they aged over subsequent model cycles. Expected costs and QALYs were accumulated over a lifetime horizon, in 6-monthly cycles and an annual discount rate of 3.5% per annum was applied to future costs and QALYs. Probabilistic analyses (Monte Carlo simulation with 1000 draws for each parameter) were conducted for a range of pessimistic and optimistic alternative base-case scenarios. A full range of deterministic scenarios explored the impact of alternative sources of model inputs and assumptions on cost-effectiveness results. Results Nature, description and quality of the available evidence The database searches identified 110 unique records, 79 records were supplied by the respective companies and 2 further studies were identified from reference lists. Twenty-four studies, published in 26 papers, were included in the systematic review of clinical effectiveness. Two studies enrolled specifically people with leg ulcers (167 participants in total) while the remaining studies (4258 participants in total) included people from primary care practices, cardiovascular risk services, vascular services and from epidemiological/general population-based studies. All studies used an ABPI threshold of 0.9. In healthy people, ABPI would be expected to be > 0.9. Most of the studies assessed the performance of a single automated device with only one study comparing two devices (WatchBP and MESI ABPI MD). Regarding the type of automated devices, two studies provided data on the BlueDop Vascular Expert device, four studies on the BOSO ABI-System 100, six studies on the Dopplex Ability, eight studies on the MESI ABPI MD and five studies on the WatchBP Office. No studies assessed the performance of the WatchBP Office Vascular and the MESI mTABLET ABI devices. Apart from one study conducted in New Zealand, all included studies were conducted in Europe (six in the UK). The risk of bias of included studies was assessed using the QUADAS-2 tool. Most studies were judged at low risk for the index test domain and at unclear risk for the patient selection, reference standard and flow and timing domains. The risk of applicability concerns was low in most studies. Summary of benefits and risks The two studies assessing people with leg ulcers did not provide sensitivity and specificity estimates but reported that automated devices gave generally higher readings than manual Doppler. The results of the 22 studies assessing people without leg ulcers varied. Seventeen studies reported sensitivity and specificity estimates for the detection of PAD and showed that the automated devices had good sensitivity but only moderate sensitivity indicating that a proportion of people with PAD would be missed. Sensitivity of BlueDop Vascular Expert ranged from 66% to 95% and specificity from 90% to 94% in two studies; sensitivity of the BOSO ABI-System 100 ranged from 61% to 77% and specificity from 94% to 98% in three studies; sensitivity of Dopplex Ability_ranged from 20% to 79% and specificity from 86% to 96% in four studies; sensitivity of the MESI ABPI MD ranged from 57% to 75% and specificity from 67% to 99% in five studies; sensitivity of the WatchBP Office ABI ranged from 44% to 83% and specificity from 97% to 100% in four studies; We were able to combine results across 12 studies (2004 participants in total) and 3 automated devices. The pooled sensitivity and specificity for PAD diagnosis using automated ABPI were 64% [95% confidence interval (CI) 57% to 71%] and 96% (95% CI 92% to 98%), respectively. Regarding the performance of individual devices, the pooled sensitivity for MESI ABPI MD was 67% (95% CI 59% to 74%) and the pooled specificity 94% (95% CI 83% to 98%); the pooled sensitivity for WatchBP Office ABI was 53% (95% CI 37% to 69%) and the pooled specificity 98% (95% CI 96% to 99%). For the remaining devices, we could not conduct meaningful meta-analyses due to the limited number of available studies. Summary of cost-effectiveness, including sensitivity analyses The uncertainties in the diagnostic accuracy evidence base and the unclear link between test results and patient management mean it is difficult to draw any firm conclusions on cost-effectiveness. A lack of evidence on the impact of the tests on important patient outcomes, the extent to which inaccurate test results would be identified in practice and the implications of acting on inaccurate test results contribute further uncertainty to the assessment of cost-effectiveness. Automated tests were less costly to deliver due to shorter testing times, but in most modelling scenarios, these cost savings were quickly offset by any additional risks and costs associated with withholding compression (FP) or inappropriately applying compression (FN). Given the current evidence base, it is unlikely that the automated tests would generate QALY gains or cost savings, unless a high proportion of FP and FN tests could be reliably identified in clinical practice through holistic patient assessment, and automated tests could deliver improvements in patient referral over manual Doppler testing. Discussion Strengths, limitations of the analyses and uncertainties The methods used to conduct this assessment were detailed, thorough and in line with current methodological standards. We identified only two studies assessing the performance of automated devices in determining ABPI in people with leg ulcers. Given the current lack of evidence in people with leg ulcers, we decided to widen our target population to include studies assessing the use of automated devices for measuring ABPI in different settings. We identified and summarised 22 studies focusing on people without leg ulcers. The main limitations of the clinical effectiveness assessment are summarised below. Lack of evidence on people with leg ulcers to draw any meaningful conclusion about this clinical population. Considerable clinical heterogeneity – in terms of characteristics of the patient population, setting and testing procedures – across studies that focused on people without leg ulcers. Suboptimal agreement between readings of the automated devices and those of the manual Doppler with a systematic tendency towards higher automated readings. Use of manual Doppler as the reference standard for detection of PAD. Variation in the prevalence of PAD across studies. Limited data on the performance of the automated devices in relevant subgroups of patients (e.g. diabetes patients). Uncertainty about the optimal threshold for automated ABPI measurement. Uncertainty about the potential role of automated devices in clinical practice (screening tool, alternative/adjuvant tool to current manual Doppler). Lack of data on the impact of the routine use of automated devices on health outcomes (e.g. the consequences of a delayed diagnosis because of FN results). No data on the WatchBP Office Vascular and MESI mTABLET ABI devices. With regard to the economic modelling, we identified the following areas of uncertainties that complement those identified for the review of clinical effectiveness evidence and raise doubt about the robustness of the cost-effectiveness results: A lack of data regarding the impact of different tests on patient-relevant outcomes such as ulcer healing. It is unclear whether automated tests could achieve tangible benefits in terms of a reduced time to compression therapy in patients with venous disease. Any benefits would rely on a lack of skills to complete manual Doppler assessment in the community, and it is unclear how widespread such a skill shortage might be. Uncertainty around whether inaccurate test results might be identified during clinical evaluation of patients during a testing appointment, and thus the extent to which inaccurate results would be acted upon in clinical practice [i.e. if tests would lead to inappropriate compression of arterial ulcers (FNs), or delayed time to compression (FPs)]. Limited data regarding the costs and outcomes specifically for mixed ulcer disease. Generalisability of the findings It is unclear how the results of studies assessing the accuracy of automated devices for measuring APBI in people without leg ulcers could be generalised to people with leg ulcers. Conclusions Future research is needed to evaluate the use of automated devices within specific populations (people with leg ulcers) and relevant settings. For the broader use of automated devices in clinical practice, more robust evidence is required to establish whether the use of automated devices is appropriate and cost-effective for the general screening of clinical populations with any vascular concerns. In addition, evidence is needed to support the use of automated devices as an alternative or adjunct to manual Doppler in people with symptoms of PAD. Study registration This study is registered as PROSPERO CRD42022327588. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135478) and is published in full in Health Technology Assessment; Vol. 28, No. 37. See the NIHR Funding and Awards website for further award information.

Objectives To identify and prioritise interventions, from the perspectives of parents and health professionals, which may be alternatives to current unscheduled paediatric urgent care pathways.Design FLAMINGO (FLow of AdMissions in chIldren and youNG peOple) is a sequential mixed-methods study, with public and patient involvement (PPI) throughout. Data linkage for urgent admissions and three referral sources: emergency department, out of hours service and general practice, was followed by qualitative interviews with parents and professionals. Findings were presented and discussed at a stakeholder intervention prioritisation event.Setting National Health Service in Scotland, UK.Participants Quantitative data: children with urgent medical admission to hospital from 2015 to 2017. Qualitative interviews: parents and health professionals with experiences of urgent short stay hospital admissions of children. PPI engagement was conducted with nine parent–toddler groups and a university-based PPI advisory group. Stakeholder event: parents, health professionals and representatives from Scottish Government, academia, charities and PPI attended.Results Data for 171 039 admissions which included 92 229 short stay admissions were analysed and 48 health professionals and 21 parents were interviewed. The stakeholder event included 7 parents, 12 health professionals and 28 other stakeholders. Analysis and synthesis of all data identified seven interventions which were prioritised at the stakeholder event: (1) addressing gaps in acute paediatric skills of health professionals working in community settings; (2) assessment and observation of acutely unwell children in community settings; (3) creation of holistic children’s ‘hubs’; (4) adoption of ‘hospital at home’ models; and three specialised care pathways for subgroups of children; (5) convulsions; (6) being aged

Objectives The aim of this sequential mixed-methods study was to describe and understand how paediatric short stay admission (SSA) rates vary across Health Board regions of Scotland.Design Exploratory sequential mixed-methods study. Routinely acquired data for the annual (per capita) SSA to hospital were compared across the 11 regions. Five diverse regions with different SSA per capita formed cases for qualitative interviews with health professionals and parents to explore how care pathways, service features and geography may influence decisions to admit.Setting Scotland.Participants All children admitted to hospital 2015–2017. Healthcare staff (n=48) and parents (n=15) were interviewed.Results Of 171 039 urgent hospital admissions, 92 229 were SSAs, with a fivefold variation between 14 and 69/1000 children/year across regions. SSAs were higher for children in the most deprived compared with the least deprived communities. When expressed as a ratio of highest to lowest SSA/1000 children/year for diagnosed conditions between regions, the ratio was highest (10.1) for upper respiratory tract infection and lowest (2.8) for convulsions. Readmissions varied between 0.80 and 2.52/1000/year, with regions reporting higher SSA rates more likely to report higher readmission rates (r=0.70, p=0.016, n=11). Proximity and ease of access to services, local differences in service structure and configuration, national policy directives and disparities in how an SSA is defined were recognised by interviewees as explaining the observed regional variations in SSAs. Socioeconomic deprivation was seldom spontaneously raised by professionals when reflecting on reasons to refer or admit a child. Instead, greater emphasis was placed on the wider social circumstances and parents’ capacity to cope with and manage their child’s illness at home.Conclusion SSA rates for children vary quantitatively by region, condition and area deprivation and our interviews identify reasons for this. These findings can usefully inform future care pathway interventions.

BackgroundNonmuscle invasive bladder cancer (NMIBC) accounts for 75% of bladder cancers. It is common and costly. Cost and detriment to patient outcomes and quality of life are driven by high recurrence rates and the need for regular invasive surveillance and repeat treatments. There is evidence that the quality of the initial surgical procedure (transurethral resection of bladder tumor [TURBT]) and administration of postoperative bladder chemotherapy significantly reduce cancer recurrence rates and improve outcomes (cancer progression and mortality). There is surgeon-reported evidence that TURBT practice varies significantly across surgeons and sites. There is limited evidence from clinical trials of intravesical chemotherapy that NMIBC recurrence rate varies significantly between sites and that this cannot be accounted for by differences in patient, tumor, or adjuvant treatment factors, suggesting that how the surgery is performed may be a reason for the variation. ObjectiveThis study primarily aims to determine if feedback on and education about surgical quality indicators can improve performance and secondarily if this can reduce cancer recurrence rates. Planned secondary analyses aim to determine what surgeon, operative, perioperative, institutional, and patient factors are associated with better achievement of TURBT quality indicators and NMIBC recurrence rates. MethodsThis is an observational, international, multicenter study with an embedded cluster randomized trial of audit, feedback, and education. Sites will be included if they perform TURBT for NMIBC. The study has four phases: (1) site registration and usual practice survey; (2) retrospective audit; (3) randomization to audit, feedback, and education intervention or to no intervention; and (4) prospective audit. Local and national ethical and institutional approvals or exemptions will be obtained at each participating site. ResultsThe study has 4 coprimary outcomes, which are 4 evidence-based TURBT quality indicators: a surgical performance factor (detrusor muscle resection); an adjuvant treatment factor (intravesical chemotherapy administration); and 2 documentation factors (resection completeness and tumor features). A key secondary outcome is the early cancer recurrence rate. The intervention is a web-based surgical performance feedback dashboard with educational and practical resources for TURBT quality improvement. It will include anonymous site and surgeon-level peer comparison, a performance summary, and targets. The coprimary outcomes will be analyzed at the site level while recurrence rate will be analyzed at the patient level. The study was funded in October 2020 and began data collection in April 2021. As of January 2023, there were 220 hospitals participating and over 15,000 patient records. Projected data collection end date is June 30, 2023. ConclusionsThis study aims to use a distributed collaborative model to deliver a site-level web-based performance feedback intervention to improve the quality of endoscopic bladder cancer surgery. The study is funded and projects to complete data collection in June 2023. Trial RegistrationClinicalTrials.org NCT05154084; https://clinicaltrials.gov/ct2/show/NCT05154084 International Registered Report Identifier (IRRID)DERR1-10.2196/42254

Abstract Background Return of gastrointestinal (GI) function is fundamental to patient recovery after colorectal surgery and is required before patients can be discharged from hospital safely. Up to 40% of patients suffer delayed return of GI function after colorectal surgery, causing nausea, vomiting and abdominal discomfort, resulting in longer hospital stay. Small, randomised studies have suggested perioperative intravenous (IV) lidocaine, which has analgesic and anti-inflammatory effects, may accelerate return of GI function after colorectal surgery. The ALLEGRO trial is a pragmatic effectiveness study to assess the benefit of perioperative IV lidocaine in improving return of GI function after elective minimally invasive (laparoscopic or robotic) colorectal surgery. Methods United Kingdom (UK) multi-centre double blind placebo-controlled randomised controlled trial in 562 patients undergoing elective minimally invasive colorectal resection. IV lidocaine or placebo will be infused for 6–12 h commencing at the start of surgery as an adjunct to usual analgesic/anaesthetic technique. The primary outcome will be return of GI function. Discussion A 6–12-h perioperative intravenous infusion of 2% lidocaine is a cheap addition to usual anaesthetic/analgesic practice in elective colorectal surgery with a low incidence of adverse side-effects. If successful in achieving quicker return of gut function for more patients, it would reduce the rate of postoperative ileus and reduce the duration of inpatient recovery, resulting in reduced pain and discomfort with faster recovery and discharge from hospital. Since colorectal surgery is a common procedure undertaken in every acute hospital in the UK, a reduced length of stay and reduced rate of postoperative ileus would accrue significant cost savings for the National Health Service (NHS). Trial registration EudraCT Number 2017-003835-12; REC Number 17/WS/0210 the trial was prospectively registered (ISRCTN Number: ISRCTN52352431 ); date of registration 13 June 2018; date of enrolment of first participant 14 August 2018.

Abstract Background Early and accurate acute kidney injury (AKI) detection may improve patient outcomes and reduce health service costs. This study evaluates the diagnostic accuracy and cost-effectiveness of NephroCheck and NGAL (urine and plasma) biomarker tests used alongside standard care, compared with standard care to detect AKI in hospitalised UK adults. Methods A 90-day decision tree and lifetime Markov cohort model predicted costs, quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) from a UK NHS perspective. Test accuracy was informed by a meta-analysis of diagnostic accuracy studies. Clinical trial and observational data informed the link between AKI and health outcomes, health state probabilities, costs and utilities. Value of information (VOI) analysis informed future research priorities. Results Under base case assumptions, the biomarker tests were not cost-effective with ICERs of £105,965 (NephroCheck), £539,041 (NGAL urine BioPorto), £633,846 (NGAL plasma BioPorto) and £725,061 (NGAL urine ARCHITECT) per QALY gained compared to standard care. Results were uncertain, due to limited trial data, with probabilities of cost-effectiveness at £20,000 per QALY ranging from 0 to 99% and 0 to 56% for NephroCheck and NGAL tests respectively. The expected value of perfect information (EVPI) was £66 M, which demonstrated that additional research to resolve decision uncertainty is worthwhile. Conclusions Current evidence is inadequate to support the cost-effectiveness of general use of biomarker tests. Future research evaluating the clinical and cost-effectiveness of test guided implementation of protective care bundles is necessary. Improving the evidence base around the impact of tests on AKI staging, and of AKI staging on clinical outcomes would have the greatest impact on reducing decision uncertainty.

Summary: Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17–1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81–1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92–1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82–1·15]; p=0·69), smoking status (interaction 1·68 [0·41–6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89–4·82; p=0·025) were not associated with cardiovascular risk. Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Funding: National Institute for Health Research Health Technology Assessment Programme.

Background: Relapse is a major determinant of outcome for people with a diagnosis of schizophrenia. Early warning signs frequently precede relapse. A recent Cochrane Review found low-quality evidence to suggest a positive effect of early warning signs interventions on hospitalisation and relapse. Objective: How feasible is a study to investigate the clinical effectiveness and cost-effectiveness of a digital intervention to recognise and promptly manage early warning signs of relapse in schizophrenia with the aim of preventing relapse? Design: A multicentre, two-arm, parallel-group cluster randomised controlled trial involving eight community mental health services, with 12-month follow-up. Settings: Glasgow, UK, and Melbourne, Australia. Participants: Service users were aged > 16 years and had a schizophrenia spectrum disorder with evidence of a relapse within the previous 2 years. Carers were eligible for inclusion if they were nominated by an eligible service user. Interventions: The Early signs Monitoring to Prevent relapse in psychosis and prOmote Wellbeing, Engagement, and Recovery (EMPOWER) intervention was designed to enable participants to monitor changes in their well-being daily using a mobile phone, blended with peer support. Clinical triage of changes in well-being that were suggestive of early signs of relapse was enabled through an algorithm that triggered a check-in prompt that informed a relapse prevention pathway, if warranted. Main outcome measures: The main outcomes were feasibility of the trial and feasibility, acceptability and usability of the intervention, as well as safety and performance. Candidate co-primary outcomes were relapse and fear of relapse. Results: We recruited 86 service users, of whom 73 were randomised (42 to EMPOWER and 31 to treatment as usual). Primary outcome data were collected for 84% of participants at 12 months. Feasibility data for people using the smartphone application (app) suggested that the app was easy to use and had a positive impact on motivations and intentions in relation to mental health. Actual app usage was high, with 91% of users who completed the baseline period meeting our a priori criterion of acceptable engagement (> 33%). The median time to discontinuation of > 33% app usage was 32 weeks (95% confidence interval 14 weeks to ∞). There were 8 out of 33 (24%) relapses in the EMPOWER arm and 13 out of 28 (46%) in the treatment-as-usual arm. Fewer participants in the EMPOWER arm had a relapse (relative risk 0.50, 95% confidence interval 0.26 to 0.98), and time to first relapse (hazard ratio 0.32, 95% confidence interval 0.14 to 0.74) was longer in the EMPOWER arm than in the treatment-as-usual group. At 12 months, EMPOWER participants were less fearful of having a relapse than those in the treatment-as-usual arm (mean difference –4.29, 95% confidence interval –7.29 to –1.28). EMPOWER was more costly and more effective, resulting in an incremental cost-effectiveness ratio of £3041. This incremental cost-effectiveness ratio would be considered cost-effective when using the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year gained. Limitations: This was a feasibility study and the outcomes detected cannot be taken as evidence of efficacy or effectiveness. Conclusions: A trial of digital technology to monitor early warning signs that blended with peer support and clinical triage to detect and prevent relapse is feasible. Future work: A main trial with a sample size of 500 (assuming 90% power and 20% dropout) would detect a clinically meaningful reduction in relapse (relative risk 0.7) and improvement in other variables (effect sizes 0.3–0.4). Trial registration: This trial is registered as ISRCTN99559262. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 27. See the NIHR Journals Library website for further project information. Funding in Australia was provided by the National Health and Medical Research Council (APP1095879).

Background: Urinary stone disease affects 2–3% of the general population. Ureteric stones are associated with severe pain and can have a significant impact on a patient’s quality of life. Most ureteric stones are expected to pass spontaneously with supportive care; however, between one-fifth and one-third of patients require an active intervention. The two standard interventions are shockwave lithotripsy and ureteroscopic stone treatment. Both treatments are effective, but they differ in terms of invasiveness, anaesthetic requirement, treatment setting, number of procedures, complications, patient-reported outcomes and cost. There is uncertainty around which is the more clinically effective and cost-effective treatment. Objectives: To determine if shockwave lithotripsy is clinically effective and cost-effective compared with ureteroscopic stone treatment in adults with ureteric stones who are judged to require active intervention. Design: A pragmatic, multicentre, non-inferiority, randomised controlled trial of shockwave lithotripsy as a first-line treatment option compared with primary ureteroscopic stone treatment for ureteric stones. Setting: Urology departments in 25 NHS hospitals in the UK. Participants: Adults aged ≥ 16 years presenting with a single ureteric stone in any segment of the ureter, confirmed by computerised tomography, who were able to undergo either shockwave lithotripsy or ureteroscopic stone treatment and to complete trial procedures. Intervention: Eligible participants were randomised 1 : 1 to shockwave lithotripsy (up to two sessions) or ureteroscopic stone treatment. Main outcome measures: The primary clinical outcome measure was resolution of the stone episode (stone clearance), which was operationally defined as ‘no further intervention required to facilitate stone clearance’ up to 6 months from randomisation. This was determined from 8-week and 6-month case report forms and any additional hospital visit case report form that was completed by research staff. The primary economic outcome measure was the incremental cost per quality-adjusted life-year gained at 6 months from randomisation. We estimated costs from NHS resources and calculated quality-adjusted life-years from participant completion of the EuroQol-5 Dimensions, three-level version, at baseline, pre intervention, 1 week post intervention and 8 weeks and 6 months post randomisation. Results: In the shockwave lithotripsy arm, 67 out of 302 (22.2%) participants needed further treatment. In the ureteroscopic stone treatment arm, 31 out of 302 (10.3%) participants needed further treatment. The absolute risk difference was 11.4% (95% confidence interval 5.0% to 17.8%); the upper bound of the 95% confidence interval ruled out the prespecified margin of non-inferiority (which was 20%). The mean quality-adjusted life-year difference (shockwave lithotripsy vs. ureteroscopic stone treatment) was –0.021 (95% confidence interval 0.033 to –0.010) and the mean cost difference was –£809 (95% confidence interval –£1061 to –£551). The probability that shockwave lithotripsy is cost-effective is 79% at a threshold of society’s willingness to pay for a quality-adjusted life-year of £30,000. The CEAC is derived from the joint distribution of incremental costs and incremental effects. Most of the results fall in the south-west quadrant of the cost effectiveness plane as SWL always costs less but is less effective. Limitations: A limitation of the trial was low return and completion rates of patient questionnaires. The study was initially powered for 500 patients in each arm; however, the total number of patients recruited was only 307 and 306 patients in the ureteroscopic stone treatment and shockwave lithotripsy arms, respectively. Conclusions: Patients receiving shockwave lithotripsy needed more further interventions than those receiving primary ureteroscopic retrieval, although the overall costs for those receiving the shockwave treatment were lower. The absolute risk difference between the two clinical pathways (11.4%) was lower than expected and at a level that is acceptable to clinicians and patients. The shockwave lithotripsy pathway is more cost-effective in an NHS setting, but results in lower quality of life. Future work: (1) The generic health-related quality-of-life tools used in this study do not fully capture the impact of the various treatment pathways on patients. A condition-specific health-related quality-of-life tool should be developed. (2) Reporting of ureteric stone trials would benefit from agreement on a core outcome set that would ensure that future trials are easier to compare. Trial registration: This trial is registered as ISRCTN92289221. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 19. See the NIHR Journals Library website for further project information.

Background: Convulsive status epilepticus is defined as ≥ 5 minutes of either continuous seizure activity or repetitive seizures without regaining consciousness. It is regarded as an emergency condition that requires prompt treatment to avoid hospitalisation and to reduce morbidity and mortality. Rapid pre-hospital first-line treatment of convulsive status epilepticus is currently benzodiazepines, administered either by trained caregivers in the community (e.g. buccal midazolam, rectal diazepam) or by trained health professionals via intramuscular or intravenous routes (e.g. midazolam, lorazepam). There is a lack of clarity about the optimal treatment for convulsive status epilepticus in the pre-hospital setting. Objectives: To assess the current evidence on the clinical effectiveness and cost-effectiveness of treatments for adults with convulsive status epilepticus in the pre-hospital setting. Data sources: We searched major electronic databases, including MEDLINE, EMBASE, PsycInfo®, CINAHL, CENTRAL, NHS Economic Evaluation Database, Health Technology Assessment Database, Research Papers in Economics, and the ISPOR Scientific Presentations Database, with no restrictions on publication date or language of publication. Final searches were carried out on 21 July 2020. Review methods: Systematic review of randomised controlled trials assessing adults with convulsive status epilepticus who received treatment before or on arrival at the emergency department. Eligible treatments were any antiepileptic drugs offered as first-line treatments, regardless of their route of administration. Primary outcomes were seizure cessation, seizure recurrence and adverse events. Two reviewers independently screened all citations identified by the search strategy, retrieved full-text articles, extracted data and assessed the risk of bias of the included trials. Results were described narratively. Results: Four trials (1345 randomised participants, of whom 1234 were adults) assessed the intravenous or intramuscular use of benzodiazepines or other antiepileptic drugs for the pre-hospital treatment of convulsive status epilepticus in adults. Three trials at a low risk of bias showed that benzodiazepines were effective in stopping seizures. In particular, intramuscular midazolam was non-inferior to intravenous lorazepam. The addition of levetiracetam to clonazepam did not show clear advantages over clonazepam alone. One trial at a high risk of bias showed that phenobarbital plus optional phenytoin was more effective in terminating seizures than diazepam plus phenytoin. The median time to seizure cessation from drug administration varied from 1.6 minutes to 15 minutes. The proportion of people with recurrence of seizures ranged from 10.4% to 19.1% in two trials reporting this outcome. Across trials, the rates of respiratory depression among participants receiving active treatments were generally low (from 6.4% to 10.6%). The mortality rate ranged from 2% to 7.6% in active treatment groups and from 6.2% to 15.5% in control groups. Only one study based on retrospective observational data met the criteria for economic evaluation; therefore, it was not possible to draw any robust conclusions on cost-effectiveness. Limitations: The limited number of identified trials and their differences in terms of treatment comparisons and outcomes hindered any meaningful pooling of data. None of the included trials was conducted in the UK and none assessed the use of buccal midazolam or rectal diazepam. The review of economic evaluations was hampered by lack of suitable data. Conclusions: Both intravenous lorazepam and intravenous diazepam administered by paramedics are more effective than a placebo in the treatments of adults with convulsive status epilepticus, and intramuscular midazolam is non-inferior to intravenous lorazepam. Large well-designed clinical trials are needed to establish which benzodiazepines are more effective and preferable in the pre-hospital setting. Study registration: This study is registered as PROSPERO CRD42020201953. Funding: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 26, No. 20. See the NIHR Journals Library website for further project information.

BackgroundNumbers of urgent short stay admissions (SSAs) of children to UK hospitals are rising rapidly. This paper reports on experiences of SSAs from the perspective of parents accessing urgent care for their acutely unwell child and of health professionals referring, caring for, or admitting children.MethodsA qualitative interview study was conducted by a multi-disciplinary team with patient and public involvement (PPI) to explore contextual factors relating to SSAs and better understand pre-hospital urgent care pathways. Purposive sampling of Health Board areas in Scotland, health professionals with experience of paediatric urgent care pathways and parents with experience of a SSA for their acutely unwell child was undertaken to ensure maximal variation in characteristics such as deprivation, urban-rural and hospital structure. Interviews took place between Dec 2019 and Mar 2021 and thematic framework analysis was applied.ResultsTwenty-one parents and forty-eight health professionals were interviewed. In the context of an urgent SSA, the themes were centred around shared outcomes of care that matter. The main outcome which was common to both parents and health professionals was the importance of preserving the child's safety. Additional shared outcomes by parents and health professionals were a desire to reduce worries and uncertainty about the illness trajectory, and provide reassurance with sufficient time, space and personnel to undertake a period of skilled observation to assess and manage the acutely unwell child. Parents wanted easy access to urgent care and, preferably, with input from paediatric-trained staff. Healthcare professionals considered that it was important to reduce the number of children admitted to hospital where safe and appropriate to do so.ConclusionsThe shared outcomes of care between parents and health professionals emphasises the potential merit of adopting a partnership approach in identifying, developing and testing interventions to improve the acceptability, safety, efficiency, and cost-effectiveness of urgent care pathways between home and hospital.

Background: Acute kidney injury is a serious complication that occurs in the context of an acute critical illness or during a postoperative period. Earlier detection of acute kidney injury may facilitate strategies to preserve renal function, prevent further disease progression and reduce mortality. Acute kidney injury diagnosis relies on a rise in serum creatinine levels and/or fall in urine output; however, creatinine is an imperfect marker of kidney function. There is interest in the performance of novel biomarkers used in conjunction with existing clinical assessment, such as NephroCheck® (Astute Medical, Inc., San Diego, CA, USA), ARCHITECT® urine neutrophil gelatinase-associated lipocalin (NGAL) (Abbott Laboratories, Abbott Park, IL, USA), and urine and plasma BioPorto NGAL (BioPorto Diagnostics A/S, Hellerup, Denmark) immunoassays. If reliable, these biomarkers may enable earlier identification of acute kidney injury and enhance management of those with a modifiable disease course. Objective: The objective was to evaluate the role of biomarkers for assessing acute kidney injury in critically ill patients who are considered for admission to critical care. Data sources: Major electronic databases, conference abstracts and ongoing studies were searched up to June 2019, with no date restrictions. MEDLINE, EMBASE, Health Technology Assessment Database, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Web of Science, World Health Organization Global Index Medicus, EU Clinical Trials Register, International Clinical Trials Registry Platform and ClinicalTrials.gov were searched. Review methods: A systematic review and meta-analysis were conducted to evaluate the performance of novel biomarkers for the detection of acute kidney injury and prediction of other relevant clinical outcomes. Random-effects models were adopted to combine evidence. A decision tree was developed to evaluate costs and quality-adjusted life-years accrued as a result of changes in short-term outcomes (up to 90 days), and a Markov model was used to extrapolate results over a lifetime time horizon. Results: A total of 56 studies (17,967 participants), mainly prospective cohort studies, were selected for inclusion. No studies addressing the clinical impact of the use of biomarkers on patient outcomes, compared with standard care, were identified. The main sources of bias across studies were a lack of information on blinding and the optimal threshold for NGAL. For prediction studies, the reporting of statistical details was limited. Although the meta-analyses results showed the potential ability of these biomarkers to detect and predict acute kidney injury, there were limited data to establish any causal link with longer-term health outcomes and there were considerable clinical differences across studies. Cost-effectiveness results were highly uncertain, largely speculative and should be interpreted with caution in the light of the limited evidence base. To illustrate the current uncertainty, 15 scenario analyses were undertaken. Incremental quality-adjusted life-years were very low across all scenarios, ranging from positive to negative increments. Incremental costs were also small, in general, with some scenarios generating cost savings with tests dominant over standard care (cost savings with quality-adjusted life-year gains). However, other scenarios generated results whereby the candidate tests were more costly with fewer quality-adjusted life-years, and were thus dominated by standard care. Therefore, it was not possible to determine a plausible base-case incremental cost-effectiveness ratio for the tests, compared with standard care. Limitations: Clinical effectiveness and cost-effectiveness results were hampered by the considerable heterogeneity across identified studies. Economic model predictions should also be interpreted cautiously because of the unknown impact of NGAL-guided treatment, and uncertain causal links between changes in acute kidney injury status and changes in health outcomes. Conclusions: Current evidence is insufficient to make a full appraisal of the role and economic value of these biomarkers and to determine whether or not they provide cost-effective improvements in the clinical outcomes of acute kidney injury patients. Future work: Future studies should evaluate the targeted use of biomarkers among specific patient populations and the clinical impact of their routine use on patient outcomes and management. Study registration: This study is registered as PROSPERO CRD42019147039. Funding: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 26, No. 7. See the NIHR Journals Library website for further project information.

Background: The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly hospital admissions. Measurement of fetal fibronectin in vaginal fluid is a biochemical test that can indicate impending preterm birth. Objectives: To develop an externally validated prognostic model using quantitative fetal fibronectin concentration, in combination with clinical risk factors, for the prediction of spontaneous preterm birth and to assess its cost-effectiveness. Design: The study comprised (1) a qualitative study to establish the decisional needs of pregnant women and their caregivers, (2) an individual participant data meta-analysis of existing studies to develop a prognostic model for spontaneous preterm birth within 7 days in women with symptoms of preterm labour based on quantitative fetal fibronectin and clinical risk factors, (3) external validation of the prognostic model in a prospective cohort study across 26 UK centres, (4) a model-based economic evaluation comparing the prognostic model with qualitative fetal fibronectin, and quantitative fetal fibronectin with cervical length measurement, in terms of cost per QALY gained and (5) a qualitative assessment of the acceptability of quantitative fetal fibronectin. Data sources/setting: The model was developed using data from five European prospective cohort studies of quantitative fetal fibronectin. The UK prospective cohort study was carried out across 26 UK centres. Participants: Pregnant women at 22+0–34+6 weeks’ gestation with signs and symptoms of preterm labour. Health technology being assessed: Quantitative fetal fibronectin. Main outcome measures: Spontaneous preterm birth within 7 days. Results: The individual participant data meta-analysis included 1783 women and 139 events of spontaneous preterm birth within 7 days (event rate 7.8%). The prognostic model that was developed included quantitative fetal fibronectin, smoking, ethnicity, nulliparity and multiple pregnancy. The model was externally validated in a cohort of 2837 women, with 83 events of spontaneous preterm birth within 7 days (event rate 2.93%), an area under the curve of 0.89 (95% confidence interval 0.84 to 0.93), a calibration slope of 1.22 and a Nagelkerke R2 of 0.34. The economic analysis found that the prognostic model was cost-effective compared with using qualitative fetal fibronectin at a threshold for hospital admission and treatment of ≥ 2% risk of preterm birth within 7 days. Limitations: The outcome proportion (spontaneous preterm birth within 7 days of test) was 2.9% in the validation study. This is in line with other studies, but having slightly fewer than 100 events is a limitation in model validation. Conclusions: A prognostic model that included quantitative fetal fibronectin and clinical risk factors showed excellent performance in the prediction of spontaneous preterm birth within 7 days of test, was cost-effective and can be used to inform a decision support tool to help guide management decisions for women with threatened preterm labour. Future work: The prognostic model will be embedded in electronic maternity records and a mobile telephone application, enabling ongoing data collection for further refinement and validation of the model. Study registration: This study is registered as PROSPERO CRD42015027590 and Current Controlled Trials ISRCTN41598423. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 52. See the NIHR Journals Library website for further project information.

BackgroundTimely interventions in women presenting with preterm labour can substantially improve health outcomes for preterm babies. However, establishing such a diagnosis is very challenging, as signs and symptoms of preterm labour are common and can be nonspecific. We aimed to develop and externally validate a risk prediction model using concentration of vaginal fluid fetal fibronectin (quantitative fFN), in combination with clinical risk factors, for the prediction of spontaneous preterm birth and assessed its cost-effectiveness.Methods and findingsPregnant women included in the analyses were 22+0 to 34+6 weeks gestation with signs and symptoms of preterm labour. The primary outcome was spontaneous preterm birth within 7 days of quantitative fFN test. The risk prediction model was developed and internally validated in an individual participant data (IPD) meta-analysis of 5 European prospective cohort studies (2009 to 2016; 1,783 women; mean age 29.7 years; median BMI 24.8 kg/m2; 67.6% White; 11.7% smokers; 51.8% nulliparous; 10.4% with multiple pregnancy; 139 [7.8%] with spontaneous preterm birth within 7 days). The model was then externally validated in a prospective cohort study in 26 United Kingdom centres (2016 to 2018; 2,924 women; mean age 28.2 years; median BMI 25.4 kg/m2; 88.2% White; 21% smokers; 35.2% nulliparous; 3.5% with multiple pregnancy; 85 [2.9%] with spontaneous preterm birth within 7 days). The developed risk prediction model for spontaneous preterm birth within 7 days included quantitative fFN, current smoking, not White ethnicity, nulliparity, and multiple pregnancy. After internal validation, the optimism adjusted area under the curve was 0.89 (95% CI 0.86 to 0.92), and the optimism adjusted Nagelkerke R2 was 35% (95% CI 33% to 37%). On external validation in the prospective UK cohort population, the area under the curve was 0.89 (95% CI 0.84 to 0.94), and Nagelkerke R2 of 36% (95% CI: 34% to 38%). Recalibration of the model's intercept was required to ensure overall calibration-in-the-large. A calibration curve suggested close agreement between predicted and observed risks in the range of predictions 0% to 10%, but some miscalibration (underprediction) at higher risks (slope 1.24 (95% CI 1.23 to 1.26)). Despite any miscalibration, the net benefit of the model was higher than "treat all" or "treat none" strategies for thresholds up to about 15% risk. The economic analysis found the prognostic model was cost effective, compared to using qualitative fFN, at a threshold for hospital admission and treatment of ≥2% risk of preterm birth within 7 days. Study limitations include the limited number of participants who are not White and levels of missing data for certain variables in the development dataset.ConclusionsIn this study, we found that a risk prediction model including vaginal fFN concentration and clinical risk factors showed promising performance in the prediction of spontaneous preterm birth within 7 days of test and has potential to inform management decisions for women with threatened preterm labour. Further evaluation of the risk prediction model in clinical practice is required to determine whether the risk prediction model improves clinical outcomes if used in practice.Trial registrationThe study was approved by the West of Scotland Research Ethics Committee (16/WS/0068). The study was registered with ISRCTN Registry (ISRCTN 41598423) and NIHR Portfolio (CPMS: 31277).

Background: Urinary incontinence is prevalent in nursing and residential care homes, and has a profound impact on residents’ dignity and quality of life. Treatment options are limited in these care contexts and care homes predominantly use absorbent pads to contain incontinence, rather than actively treat it. Transcutaneous posterior tibial nerve stimulation is a non-invasive, safe, low-cost intervention that is effective in reducing urinary incontinence in adults. Objective: To determine the clinical effectiveness of transcutaneous posterior tibial nerve stimulation to treat urinary incontinence in care home residents and to determine the associated costs of the treatment. Design: A multicentre, pragmatic, participant and outcome assessor-blind, randomised placebo-controlled trial. Setting: A total of 37 UK residential and nursing care homes. Participants: Care home residents with at least weekly urinary incontinence that is contained using absorbent pads and who are able to use a toilet/toilet aid with or without assistance. Interventions: Residents were randomised (1 : 1) to receive 12 30-minute sessions of transcutaneous posterior tibial nerve stimulation or sham stimulation over a 6-week period. Main outcome measures: Primary outcome – change in volume of urine leaked over a 24-hour period at 6 weeks. Secondary outcomes – number of pads used, Perception of Bladder Condition, toileting skills, quality of life and resource use. Results: A total of 408 residents were randomised (transcutaneous posterior tibial nerve stimulation, n = 197; sham stimulation, n = 209); two exclusions occurred post randomisation. Primary outcome data were available for 345 (85%) residents (transcutaneous posterior tibial nerve stimulation, n = 167; sham stimulation, n = 178). Adherence to the intervention protocol was as follows: 78% of the transcutaneous posterior tibial nerve stimulation group and 71% of the sham group received the correct stimulation. Primary intention-to-treat adjusted analysis indicated a mean change of –5 ml (standard deviation 362 ml) urine leakage from baseline in the transcutaneous posterior tibial nerve stimulation group and –66 ml (standard deviation 394 ml) urine leakage in the sham group, which was a statistically significant, but not clinically important, between-group difference of 68-ml urine leakage (95% confidence interval 0 to 136 ml; p = 0.05) in favour of the sham group. Sensitivity analysis supported the primary analysis. No meaningful differences were detected in any of the secondary outcomes. No serious adverse events related to transcutaneous posterior tibial nerve stimulation were reported. Economic evaluation assessed the resources used. The training and support costs for the staff to deliver the intervention were estimated at £121.03 per staff member. Estimated costs for delivery of transcutaneous posterior tibial nerve stimulation during the trial were £81.20 per participant. No significant difference was found between participants’ scores over time, or between transcutaneous posterior tibial nerve stimulation and sham groups at any time point, for resident or proxy quality-of-life measures. Conclusions: The ELECTRIC (ELECtric Tibial nerve stimulation to Reduce Incontinence in Care homes) trial showed, in the care home context (with a high proportion of residents with poor cognitive capacity and limited independent mobility), that transcutaneous posterior tibial nerve stimulation was not effective in reducing urinary incontinence. No economic case for transcutaneous posterior tibial nerve stimulation was made by the cost–consequences analysis; however, the positive reception of learning about urinary incontinence for care home staff supports a case for routine education in this care context. Limitations: Completing 24-hour pad collections was challenging for care home staff, resulting in some missing primary outcome data. Future work: Research should investigate transcutaneous posterior tibial nerve stimulation in residents with urgency urinary incontinence to determine whether or not targeted stimulation is effective. Research should evaluate the effects of continence training for staff on continence care in care homes. Trial registration: Current Controlled Trials ISRCTN98415244 and ClinicalTrials.gov NCT03248362. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 41. See the NIHR Journals Library website for further project information.

ABSTRACT Background Although pharmacotherapy is to be avoided wherever possible during pregnancy, aggressive pharmacotherapy is required for the treatment of pregnancy associated hypertension, which remains a leading cause of morbidity and mortality in the UK. While the teratogenic effects of angiotensin-converting enzyme inhibitors are well documented, the possible long term effects, on the child, following in utero exposure to other antihypertensive agents remains unknown. Approach The aim of this study was to systematically review all published literature relevant to possible adverse outcomes on the child associated with in utero exposure to antihypertensive medications. OVID (Medline, Embase), Scopus, EBSCO Collections (PsycINFO, CINAHL), The Cochrane Library and Web of Science databases were searched from January 1950 to January 2016 and a total of 688 papers were identified. Following review 43 primary studies and 4 Meta-analyses were eligible for inclusion. The Critical Appraisal Skills Programme (CASP) checklists were used to assess study quality. Results Three studies were of excellent quality the remainder were either mediocre or poor. Increased risk of low birth weight, low size for gestational age, preterm birth and congenital defects following in utero exposure to all antihypertensive agents were identified. The clinical importance of these reported risks is unclear, as many study findings were based on small case numbers. Four studies of mediocre quality reported on the relationship between in utero exposure and neurological adverse effects in offspring. Two studies reported an increased risk of attention deficit hyperactivity disorder following exposure to labetalol, and an increased risk of sleep disorders following exposure to methyldopa and clonidine. The remaining two studies identified no such associations. Conclusions This systematic review demonstrates a lack of published high quality studies. Available published studies indicate an increased risk of adverse child health outcomes, although it is unclear whether these outcomes are clinically significant. This review is the first step in a larger project, which is exploring child health outcomes in Scotland following in utero exposure to antihypertensive and psychotropic medications. Dispensed drug data will be used to identify mothers who have been prescribed antihypertensive or psychotropic medication during pregnancy. National databases (PIS, SMR02, SMR01, etc.) will be used to cross-link mother and child data to identify in utero exposure to the drugs of interest, and the resulting child outcomes. All aspects of child health outcomes will be assessed to identify possible adverse effects from in utero exposure to medications.

ABSTRACT Objective Maternal obesity during pregnancy is a risk factor for increased childhood body mass index (BMI) and the mechanism may be causal or confounded by lifestyle common to mother and child. We studied BMI in siblings and their mothers to test the hypothesis that siblings born after maternal weight gain will have increased BMI compared to older siblings. Approach This was a whole population data linkage study using data from North East Scotland, UK. Databases containing details from pregnant mothers and their five-year-old children born between 1997 and 2005 were linked using the community health index number. Childhood BMI and the difference between siblings BMI were related to maternal weight gain between pregnancies. Covariates included maternal obesity, smoking, socioeconomic status and the child’s birth weight. Results Maternal weight gain between pregnancies was determined for 5,863 mothers in whom 718 had >2 pregnancies. Childhood BMI z score was increased in association with maternal obesity (mean increase 0.47 [95% CI 0.39, 0.56]) and with ≥10% maternal weight gain between pregnancies (mean increase 0.14 [95% CI 0.06, 0.21]), independent of covariates. In contrast, increased BMI z score for younger siblings, compared to older siblings, was not associated with maternal obesity in the earlier pregnancy or maternal weight gain between pregnancies. BMI z score was higher in younger compared to older siblings in association with deprivation (mean difference between most and least affluent categories 0.29 [0.08, 0.37]), persistent or new onset maternal smoking (increased by mean of 0.10[0.00, 0.19] for always smokers and 0.20[0.03, 0.38] for those starting compared to never smoked) and increased birth weight (BMI z score increased by 0.11 for each increase in birth weight z score [0.07, 0.14]). Conclusion When within-family confounding is considered, poverty, persistent and new onset maternal smoking during pregnancy and increased birth weight, but not maternal obesity or weight gain, are independent predictors of increased BMI in young children.

BackgroundA role for Epstein Barr virus (EBV) in multiple sclerosis (MS) has been postulated. Previous systematic reviews found higher prevalences of anti-EBV antibodies in MS patients compared to controls, but many studies have since been published, and there is a need to apply more rigorous systematic review methods.Methodology/principal findingsWe examined the link between EBV and MS by conducting a systematic review and meta-analysis of case-control and cohort studies that examined the prevalence of anti-EBV antibodies in the serum of cases and controls. We searched Medline and Embase databases from 1960 to 2012, with no language restriction. The Mantel-Haenszel odds ratios (OR) for anti-EBV antibodies sero-positivity were calculated, and meta-analysis conducted. Quality assessment was performed using a modified version of the Newcastle Ottawa scale. Thirty-nine studies were included. Quality assessment found most studies reported acceptable selection and comparability of cases and controls. However the majority had poor reporting of ascertainment of exposure. Most studies found a higher sero-prevalence of anti-EBNA IgG and anti-VCA IgG in cases compared to controls. The results for anti-EA IgG were mixed with only half the studies finding a higher sero-prevalence in cases. The meta-analysis showed a significant OR for sero-positivity to anti-EBNA IgG and anti-VCA IgG in MS cases (4.5 [95% confidence interval (CI) 3.3 to 6.6, pConclusion/significanceThese findings support previous systematic reviews, however publication bias cannot be excluded. The methodological conduct of studies could be improved, particularly with regard to reporting and conduct of laboratory analyses.

Vitamin D has been linked with many health outcomes. The aim of this longitudinal study, was to assess predictors of seasonal variation of 25-hydroxy-vitamin D (25(OH)D) (including use of supplements and holidays in sunny destinations) at a northerly latitude in the UK (57°N) in relation to bone health indicators. 365 healthy postmenopausal women (mean age 62.0 y (SD 1.4)) had 25(OH)D measurements by immunoassay, serum C-telopeptide (CTX), estimates of sunlight exposure (badges of polysulphone film), information regarding holidays in sunny destinations, and diet (from food diaries, including use of supplements such as cod liver oil (CLO)) at fixed 3-monthly intervals over 15 months (subject retention 88%) with an additional 25(OH)D assessment in spring 2008. Bone mineral density (BMD) at the lumbar spine (LS) and dual hip was measured in autumn 2006 and spring 2007 (Lunar I-DXA). Deficiency prevalence (25(OH)D