Long-term impact of pre-incision antibiotics on children born by caesarean section: a longitudinal study based on UK electronic health records.

BACKGROUND: Since changes in the national guidance in 2011, prophylactic antibiotics for women undergoing caesarean section are recommended prior to skin incision, rather than after the baby's umbilical cord has been clamped. Evidence from randomised controlled trials conducted outside the UK has shown that this reduces maternal infectious morbidity; however, the prophylactic antibiotics also cross the placenta, meaning that babies are exposed to them around the time of birth. Antibiotics are known to affect the gut microbiota of the babies, but the long-term effects of exposure to high-dose broad-spectrum antibiotics around the time of birth on allergy and immune-related diseases are unknown. OBJECTIVES: We aimed to examine whether or not in-utero exposure to antibiotics immediately prior to birth compared with no pre-incisional antibiotic exposure increases the risk of (1) asthma and (2) eczema in children born by caesarean section. DESIGN: This was a controlled interrupted time series study. SETTING: The study took place in primary and secondary care. PARTICIPANTS: Children born in the UK during 2006-18 delivered by caesarean section were compared with a control cohort delivered vaginally. INTERVENTIONS: In-utero exposure to antibiotics immediately prior to birth. MAIN OUTCOME MEASURES: Asthma and eczema in children in the first 5 years of life. Additional secondary outcomes, including other allergy-related conditions, autoimmune diseases, infections, other immune system-related diseases and neurodevelopmental conditions, were also assessed. DATA SOURCES: The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) primary care databases and the Hospital Episode Statistics (HES) database. Previously published linkage strategies were adapted to link anonymised data on mothers and babies in these databases. Duplicate practices contributing to both THIN and the CPRD databases were removed to create a THIN-CPRD data set. RESULTS: In the THIN-CPRD and HES data sets, records of 515,945 and 3,945,351 mother-baby pairs were analysed, respectively. The risk of asthma was not significantly higher in children born by caesarean section exposed to pre-incision antibiotics than in children whose mothers received post-cord clamping antibiotics, with an incidence rate ratio of 0.91 (95% confidence interval 0.78 to 1.05) for diagnosis of asthma in primary care and an incidence rate ratio of 1.05 (95% confidence interval 0.99 to 1.11) for asthma resulting in a hospital admission. We also did not find an increased risk of eczema, with an incidence rate ratio of 0.98 (95% confidence interval 0.94 to1.03) and an incidence rate ratio of 0.96 (95% confidence interval 0.71 to 1.29) for diagnosis in primary care and hospital admissions, respectively. LIMITATIONS: It was not possible to ascertain the exposure to pre-incision antibiotics at an individual level. The maximum follow-up of children was 5 years. CONCLUSIONS: There was no evidence that the policy change from post-cord clamping to pre-incision prophylactic antibiotics for caesarean sections during 2006-18 had an impact on the incidence of asthma and eczema in early childhood in the UK. FUTURE WORK: There is a need for further research to investigate if pre-incision antibiotics have any impact on developing asthma and other allergy and immune-related conditions in older children. STUDY REGISTRATION: This study is registered as researchregistry3736. 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. 30. See the NIHR Journals Library website for further project information.

WHAT WAS THE QUESTION?: Women giving birth by caesarean section are at risk of developing infections (such as wound infections) and are offered antibiotics at the time of their operation to reduce this risk. In 2011, the national guidelines changed from recommending antibiotics after cord clamping to giving them before the operation to further reduce the risk of maternal infection. During birth, the newborn gut is colonised by microbes. Antibiotics given to the mother before caesarean section can reach the baby through the placenta and disrupt the normal microbes that colonise the gut. These microbes are believed to play a role in the development of the immune system and altering the normal development of these microbes has been linked to children developing allergic conditions, such as asthma and eczema. This study investigated whether or not giving antibiotics before the caesarean section had a longer-term impact on children's health. WHAT DID WE DO?: We used routine NHS information already collected by hospitals and general practitioners about women who gave birth in the UK between 2006 and 2018, and their children. We compared the risk of asthma, eczema and other health conditions in the first 5 years after birth in children born by caesarean section before and after the change in hospital policies. We also compared their health with children born vaginally. WHAT DID WE FIND?: We found that there was no increased risk of asthma or eczema for children born by caesarean section after the policy decision in 2011 to give the mother antibiotics before the operation. WHAT DOES THIS MEAN?: The study findings provide further evidence for the current recommendation to give preventative antibiotics to women shortly before the caesarean section to reduce the overall risk of infections after birth.

Long term tapering versus standard prednisolone treatment for first episode of childhood nephrotic syndrome: phase III randomised controlled trial and economic evaluation.

OBJECTIVE: To determine whether extending initial prednisolone treatment from eight to 16 weeks in children with idiopathic steroid sensitive nephrotic syndrome improves the pattern of disease relapse. DESIGN: Double blind, parallel group, phase III randomised placebo controlled trial, including a cost effectiveness analysis. SETTING: 125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres. PARTICIPANTS: 237 children aged 1-14 years with a first episode of steroid sensitive nephrotic syndrome. INTERVENTIONS: Children were randomised to receive an extended 16 week course of prednisolone (total dose 3150 mg/m2) or a standard eight week course of prednisolone (total dose 2240 mg/m2). The drug was supplied as 5 mg tablets alongside matching placebo so that participants in both groups received the same number of tablets at any time point in the study. A minimisation algorithm ensured balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). MAIN OUTCOME MEASURES: The primary outcome measure was time to first relapse over a minimum follow-up of 24 months. Secondary outcome measures were relapse rate, incidence of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome, use of alternative immunosuppressive treatment, rates of adverse events, behavioural change using the Achenbach child behaviour checklist, quality adjusted life years, and cost effectiveness from a healthcare perspective. Analysis was by intention to treat. RESULTS: No significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P=0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P=0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P=0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P=0.81). Total prednisolone dose after completion of the trial drug was 6674 mg for the extended course versus 5475 mg for the standard course (P=0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P=0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval -0.005 to 0.037) and cost savings (difference -£1673 ($2160; €1930), 95% confidence interval -£3455 to £109). CONCLUSIONS: Clinical outcomes did not improve when the initial course of prednisolone treatment was extended from eight to 16 weeks in UK children with steroid sensitive nephrotic syndrome. However, evidence was found of a short term health economic benefit through reduced resource use and increased quality of life. TRIAL REGISTRATION: ISRCTN16645249; EudraCT 2010-022489-29.

Interferon gamma release assays for Diagnostic Evaluation of Active tuberculosis (IDEA): test accuracy study and economic evaluation.

BACKGROUND: Interferon gamma release assays (IGRAs) are blood tests recommended for the diagnosis of tuberculosis (TB) infection. There is currently uncertainty about the role and clinical utility of IGRAs in the diagnostic workup of suspected active TB in routine NHS clinical practice. OBJECTIVES: To compare the diagnostic accuracy and cost-effectiveness of T-SPOT.TB® (Oxford Immunotec, Abingdon, UK) and QuantiFERON® TB GOLD In-Tube (Cellestis, Carnegie, VIC, Australia) for diagnosis of suspected active TB and to estimate the diagnostic accuracy of second-generation IGRAs. DESIGN: Prospective within-patient comparative diagnostic accuracy study. SETTING: Secondary care. PARTICIPANTS: Adults (aged ≥ 16 years) presenting as inpatients or outpatients at 12 NHS hospital trusts in London, Slough, Oxford, Leicester and Birmingham with suspected active TB. INTERVENTIONS: The index tests [T-SPOT.TB and QuantiFERON GOLD In-Tube (QFT-GIT)] and new enzyme-linked immunospot assays utilising novel Mycobacterium tuberculosis antigens (Rv3615c, Rv2654, Rv3879c and Rv3873) were verified against a composite reference standard applied by a panel of clinical experts blinded to IGRA results. MAIN OUTCOME MEASURES: Sensitivity, specificity, predictive values and likelihood ratios were calculated to determine diagnostic accuracy. A decision tree model was developed to calculate the incremental costs and incremental health utilities [quality-adjusted life-years (QALYs)] of changing from current practice to using an IGRA as an initial rule-out test. RESULTS: A total of 363 patients had active TB (culture-confirmed and highly probable TB cases), 439 had no active TB and 43 had an indeterminate final diagnosis. Comparing T-SPOT.TB and QFT-GIT, the sensitivities [95% confidence interval (CI)] were 82.3% (95% CI 77.7% to 85.9%) and 67.3% (95% CI 62.1% to 72.2%), respectively, whereas specificities were 82.6% (95% CI 78.6% to 86.1%) and 80.4% (95% CI 76.1% to 84.1%), respectively. T-SPOT.TB was more sensitive than QFT-GIT (relative sensitivity 1.22, 95% CI 1.14 to 1.31; p < 0.001), but the specificities were similar (relative specificity 1.02, 95% CI 0.97 to 1.08; p = 0.3). For both IGRAs the sensitivity was lower and the specificity was higher for human immunodeficiency virus (HIV)-positive than for HIV-negative patients. The most promising novel antigen was Rv3615c. The added value of Rv3615c to T-SPOT.TB was a 9% (95% CI 5% to 12%) relative increase in sensitivity at the expense of specificity, which had a relative decrease of 7% (95% CI 4% to 10%). The use of current IGRA tests for ruling out active TB is unlikely to be considered cost-effective if a QALY was valued at £20,000 or £30,000. For T-SPOT.TB, the probability of being cost-effective for a willingness to pay of £20,000/QALY was 26% and 21%, when patients with indeterminate test results were excluded or included, respectively. In comparison, the QFT-GIT probabilities were 8% and 6%. Although the use of IGRAs is cost saving, the health detriment is large owing to delay in diagnosing active TB, leading to prolonged illness. There was substantial between-patient variation in the tests used in the diagnostic pathway. LIMITATIONS: The recruitment target for the HIV co-infected population was not achieved. CONCLUSIONS: Although T-SPOT.TB was more sensitive than QFT-GIT for the diagnosis of active TB, the tests are insufficiently sensitive for ruling out active TB in routine clinical practice in the UK. Novel assays offer some promise. FUTURE WORK: The novel assays require evaluation in distinct clinical settings and in immunosuppressed patient groups. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and the NIHR Health Protection Research Unit in Respiratory Infections, Imperial College London, London, UK.

Tuberculosis (TB) is one of the world's most important infectious diseases. In 2014, 1.5 million deaths were caused by the disease ­ about one death every 25 seconds. Traditional diagnosis of TB is based partly on the tuberculin skin test. Blood tests such as QuantiFERON GOLD In-Tube (QFT-GIT; Cellestis, Carnegie, VIC, Australia) and T-SPOT.TB^® (Oxford Immunotec, Abingdon, UK) are now available. However, these two tests are not used as part of current NHS practice because of the lack of evidence about how well the tests perform when diagnosing symptomatic (active) TB in routine clinical practice. The purpose of our study was to compare the ability of QFT-GIT and T-SPOT.TB to differentiate people with active TB from those without active TB in a population suspected of the disease. We also assessed new blood tests that are currently being developed for diagnosis of active TB. We recruited 1074 patients with suspected TB from 14 NHS hospitals in London, Slough, Oxford, Leicester and Birmingham into our study. We found that T-SPOT.TB correctly detected more people with active TB than QFT-GIT; T-SPOT.TB would miss about 18 people out of every 100, whereas QFT-GIT would miss about 33 people out of every 100 with active TB. For this reason, neither test is good enough for routine clinical use because the number of people with active TB who are incorrectly diagnosed as not having active TB is unacceptably high. In addition, neither test is good value for money. However, we did find that some of the newer blood tests performed better than T-SPOT.TB and their usefulness should be further investigated.

Model-based economic evaluations of diagnostic point of care tests were rarely fit for purpose.

OBJECTIVES: Linked evidence models are recommended to predict health benefits and cost-effectiveness of diagnostic tests. We considered how published models accounted for changes in patient pathways that occur with point of care tests (POCTs) and their impact on patient health and costs. STUDY DESIGN AND SETTING: Model-based evaluations of diagnostic POCTs published from 2004 to 2017 were identified from searching six databases. For each model, we assessed the outcomes considered, and whether reduced time to diagnosis and increased access to testing affected patient health and costs. RESULTS: Seventy-four model-based evaluations were included: 95% incorporated evidence on test accuracy, but 34% only assessed intermediate outcomes such as rates of correct diagnosis. Of 54 models where POCTs reduced testing time, 39% addressed the economic and 37% addressed the health benefits of faster diagnosis. No model considered differences in access to tests. CONCLUSION: Many models fail to capture the effects of POCTs in increasing access, advancing speed of diagnosis and treatment, and reducing anxiety and the associated costs. Many only consider the impact of testing from changes in accuracy. Ensuring models incorporate changes in patient pathways from faster and more accessible testing will lead to economic evaluations that better reflect the impact of POCTs.

Two interferon gamma release assays for predicting active tuberculosis: the UK PREDICT TB prognostic test study.

BACKGROUND: Despite a recent decline in the annual incidence of tuberculosis (TB) in the UK, rates remain higher than in most Western European countries. The detection and treatment of latent TB infection (LTBI) is an essential component of the UK TB control programme. OBJECTIVES: To assess the prognostic value and cost-effectiveness of the current two interferon gamma release assays (IGRAs) compared with the standard tuberculin skin test (TST) for predicting active TB among untreated individuals at increased risk of TB: (1) contacts of active TB cases and (2) new entrants to the UK from high-TB-burden countries. DESIGN: A prospective cohort study and economic analysis. PARTICIPANTS AND SETTING: Participants were recruited in TB clinics, general practices and community settings. Contacts of active TB cases and migrants who were born in high-TB-burden countries arriving in the UK were eligible to take part if they were aged ≥ 16 years. MAIN OUTCOME MEASURES: Outcomes include incidence rate ratios comparing the incidence of active TB in those participants with a positive test result and those with a negative test result for each assay, and combination of tests and the cost per quality-adjusted life-year (QALY) for each screening strategy. RESULTS: A total of 10,045 participants were recruited between May 2010 and July 2015. Among 9610 evaluable participants, 97 (1.0%) developed active TB. For the primary analysis, all test data were available for 6380 participants, with 77 participants developing active TB. A positive result for TSTa (positive if induration is ≥ 5 mm) was a significantly poorer predictor of progression to active TB than a positive result for any of the other tests. Compared with TSTb [positive if induration is ≥ 6 mm without prior bacillus Calmette-Guérin (BCG) alone, T-SPOT®.TB (Oxford Immunotec Ltd, Oxford, UK), TSTa + T-SPOT.TB, TSTa + IGRA and the three combination strategies including TSTb were significantly superior predictors of progression. Compared with the T-SPOT.TB test alone, TSTa + T-SPOT.TB, TSTb + QuantiFERON® TB Gold In-Tube (QFT-GIT; QIAGEN GmbH, Hilden, Germany) and TSTb + IGRA were significantly superior predictors of progression and, compared with QFT-GIT alone, T-SPOT.TB, TSTa + T-SPOT.TB, TSTa + QFT-GIT, TSTa + IGRA, TSTb + T-SPOT.TB, TSTb + QFT-GIT and TSTb + IGRA were significantly superior predictors of progression. When evaluating the negative predictive performance of tests and strategies, negative results for TSTa + QFT-GIT were significantly poorer predictors of non-progression than negative results for TSTa, T-SPOT.TB and TSTa + IGRA. The most cost-effective LTBI testing strategies are the dual-testing strategies. The cost and QALY differences between the LTBI testing strategies were small; in particular, QFT-GIT, TSTb + T-SPOT.TB and TSTb + QFT-GIT had very similar incremental net benefit estimates. CONCLUSION: This study found modest differences between tests, or combinations of tests, in identifying individuals who would go on to develop active TB. However, a two-step approach that combined TSTb with an IGRA was the most cost-effective testing option. IMPLICATIONS FOR PRACTICE AND FUTURE RESEARCH: The two-step TSTb strategy, which stratified the TST by prior BCG vaccination followed by an IGRA, was the most cost-effective approach. The limited ability of current tests to predict who will progress limits the clinical utility of tests. The implications of these results for the NHS England/Public Health England national TB screening programme for migrants should be investigated. STUDY REGISTRATION: This study is registered as NCT01162265. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Prognostic value of interferon-γ release assays and tuberculin skin test in predicting the development of active tuberculosis (UK PREDICT TB): a prospective cohort study.

BACKGROUND: Tackling tuberculosis requires testing and treatment of latent tuberculosis in high-risk groups. The aim of this study was to estimate the predictive values of the tuberculin skin test (TST) and two interferon-γ release assays (IGRAs) for the development of active tuberculosis in high-risk groups-ie, people in recent contact with active tuberculosis cases and from high-burden countries. METHOD: In this prospective cohort study, we recruited participants from 54 centres (eg, clinics, community settings) in London, Birmingham, and Leicester in the UK. Participants were eligible if they were aged 16 years or older and at high risk for latent tuberculosis infection (ie, recent contact with someone with active tuberculosis [contacts] or a migrant who had arrived in the UK in the past 5 years from-or who frequently travelled to-a country with a high burden of tuberculosis [migrants]). Exclusion criteria included prevalent cases of tuberculosis, and participants who were treated for latent tuberculosis after a positive test result in this study. Each participant received three tests (QuantiFERON-TB Gold-In Tube, T-SPOT.TB, and a Mantoux TST). A positive TST result was reported using three thresholds: 5 mm (TST-5), 10 mm (TST-10), and greater than 5 mm in BCG-naive or 15 mm in BCG-vaccinated (TST-15) participants. Participants were followed up from recruitment to development of tuberculosis or censoring. Incident tuberculosis cases were identified by national tuberculosis databases, telephone interview, and review of medical notes. Our primary objective was to estimate the prognostic value of IGRAs compared with TST, assessed by the ratio of incidence rate ratios and predictive values for tuberculosis development. The study was registered with ClinicalTrials.gov, NCT01162265, and is now complete. FINDINGS: Between May 4, 2010, and June 1, 2015, 10 045 people were recruited, of whom 9610 were eligible for inclusion. Of this cohort, 4861 (50·6%) were contacts and 4749 (49·4%) were migrants. Participants were followed up for a median of 2·9 years (range 21 days to 5·9 years). 97 (1·0%) of 9610 participants developed active tuberculosis (77 [1·2%] of 6380 with results for all three tests). In all tests, annual incidence of tuberculosis was very low in those who tested negatively (ranging from 1·2 per 1000 person-years, 95% CI 0·6-2·0 for TST-5 to 1·9 per 1000 person-years, 95% CI 1·3-2·7, for QuantiFERON-TB Gold In-Tube). Annual incidence in participants who tested positively were highest for T-SPOT.TB (13·2 per 1000 person-years, 95% CI 9·9-17·4), TST-15 (11·1 per 1000 person-years, 8·3-14·6), and QuantiFERON-TB Gold In-Tube (10·1 per 1000 person-years, 7·4-13·4). Positive results for these tests were significantly better predictors of progression than TST-10 and TST-5 (eg, ratio of test positivity rates in those progressing to tuberculosis compared with those not progressing T-SPOT.TB vs TST-5: 1·99, 95% CI 1·68-2·34; p<0·0001). However, TST-5 identified a higher proportion of participants who progressed to active tuberculosis (64 [83%] of 77 tested) than all other tests and TST thresholds (≤75%). INTERPRETATION: IGRA-based or BCG-stratified TST strategies appear most suited to screening for potential disease progression among high-risk groups. Further work will be needed to assess country-specific cost-effectiveness of each screening test, and in the absence of highly specific diagnostic tests, cheap non-toxic treatments need to be developed that could be given to larger groups of people at potential risk. FUNDING: National Institute for Health Research Health Technology Assessment Programme 08-68-01.

MRI versus laparoscopy to diagnose the main causes of chronic pelvic pain in women: a test-accuracy study and economic evaluation.

BACKGROUND: Chronic pelvic pain (CPP) symptoms in women are variable and non-specific; establishing a differential diagnosis can be hard. A diagnostic laparoscopy is often performed, although a prior magnetic resonance imaging (MRI) scan may beneficial. OBJECTIVES: To estimate the accuracy and added value of MRI in making diagnoses of (1) idiopathic CPP and (2) the main gynaecological causes of CPP. To quantify the impact MRI can have on decision-making with respect to triaging for therapeutic laparoscopy and to conduct an economic evaluation. DESIGN: Comparative test-accuracy study with cost-effectiveness modelling. SETTING: Twenty-six UK-based hospitals. PARTICIPANTS: A total of 291 women with CPP. METHODS: Pre-index information concerning the patient's medical history, previous pelvic examinations and ultrasound scans was collected. Women reported symptoms and quality of life at baseline and 6 months. MRI scans and diagnostic laparoscopy (undertaken and interpreted blind to each other) were the index tests. For each potential cause of CPP, gynaecologists indicated their level of certainty that the condition was causing the pelvic pain. The analysis considered both diagnostic laparoscopy as a reference standard for observing structural gynaecological causes and consensus from a two-stage expert independent panel for ascertaining the cause of CPP. The stage 1 consensus was based on pre-index, laparoscopy and follow-up data; for stage 2, the MRI scan report was also provided. The primary analysis involved calculations of sensitivity and specificity for the presence or absence of each structural gynaecological cause of pain. A decision-analytic model was developed, with a 6-month time horizon. Two strategies, laparoscopy or MRI, were considered and populated with study data. RESULTS: Using reference standards of laparoscopic and expert panel diagnoses, MRI scans had high specificity but poor sensitivity for observing deep-infiltrating endometriosis, endometrioma, adhesions and ovarian cysts. MRI scans correctly identified 56% [95% confidence interval (CI) 48% to 64%] of women judged to have idiopathic CPP, but missed 46% (95% CI 37% to 55%) of those considered to have a gynaecological structural cause of CPP. MRI added significant value, over and above the pre-index information, in identifying deep-infiltrating endometriosis (p = 0.006) and endometrioma (p = 0.02) as the cause of pain, but not for other gynaecological structural causes or for identifying idiopathic CPP (p = 0.08). Laparoscopy was significantly more accurate than MRI in diagnosing idiopathic CPP (p < 0.0001), superficial peritoneal endometriosis (p < 0.0001), deep-infiltrating endometriosis (p < 0.0001) and endometrioma of the ovary (p = 0.02) as the cause of pelvic pain. The accuracy of laparoscopy appeared to be able to rule in these diagnoses. Using MRI to identify women who require therapeutic laparoscopy would lead to 369 women in a cohort of 1000 receiving laparoscopy unnecessarily, and 136 women who required laparoscopy not receiving it. The economic analysis highlighted the importance of the time horizon, the prevalence of CPP and the cut-off values to inform the sensitivity and specificity of MRI and laparoscopy on the model results. MRI was not found to be a cost-effective diagnostic approach in any scenario. CONCLUSIONS: MRI was dominated by laparoscopy in differential diagnosis of women presenting to gynaecology clinics with CPP. It did not add value to information already gained from history, examination and ultrasound about idiopathic CPP and various gynaecological conditions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13028601. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 40. See the NIHR Journals Library website for further project information.

Association between use of systematic reviews and national policy recommendations on screening newborn babies for rare diseases: systematic review and meta-analysis.

OBJECTIVE: To understand whether international differences in recommendations of whether to screen for rare diseases using the newborn blood spot test might in part be explained by use of systematic review methods. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Website searches of 26 national screening organisations. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Journal articles, papers, legal documents, presentations, conference abstracts, or reports relating to a national recommendation on whether to screen for any condition using the newborn blood spot test, with no restrictions on date or language. DATA EXTRACTION: Two reviewers independently assessed whether the recommendation for or against screening included systematic reviews, and data on test accuracy, benefits of early detection, and potential harms of overdiagnosis. ANALYSIS: The odds of recommending screening according to the use of systematic review methods was estimated across conditions using meta-analysis. RESULTS: 93 reports were included that assessed 104 conditions across 14 countries, totalling 276 recommendations (units of analysis). Screening was favoured in 159 (58%) recommendations, not favoured in 98 (36%), and not recommended either way in 19 (7%). Only 60 (22%) of the recommendations included a systematic review. Use of a systematic review was associated with a reduced probability of screening being recommended (23/60 (38%) v 136/216 (63%), odds ratio 0.17, 95% confidence interval 0.07 to 0.43). Of the recommendations, evidence for test accuracy, benefits of early detection, and overdiagnosis was not considered in 115 (42%), 83 (30%), and 211 (76%), respectively. CONCLUSIONS: Using systematic review methods is associated with a reduced probability of screening being recommended. Many national policy reviews of screening for rare conditions using the newborn blood spot test do not assess the evidence on the key benefits and harms of screening.

Outcomes important to burns patients during scar management and how they compare to the concepts captured in burn-specific patient reported outcome measures.

BACKGROUND: Pressure garment therapy (PGT) is an established treatment for the prevention and treatment of hypertrophic scarring; however, there is limited evidence for its effectiveness. Burn survivors often experience multiple issues many of which are not adequately captured in current PGT trial measures. To assess the effectiveness of PGT it is important to understand what outcomes matter to patients and to consider whether patient-reported outcome measures (PROMs) can be used to ascertain the effect of treatments on patients' health-related quality of life. This study aimed to (a) understand the priorities and perspectives of adult burns patients and the parents of burns patients who have experienced PGT via in-depth qualitative data, and (b) compare these with the concepts captured within burn-specific PROMs. METHODS: We undertook 40 semi-structured interviews with adults and parents of paediatric and adolescent burns patients who had experienced PGT to explore their priorities and perspectives on scar management. Interviews were audio-recorded, transcribed and thematically analysed. The outcomes interpreted within the interview data were then mapped against the concepts captured within burn-specific PROMs currently in the literature. RESULTS: Eight core outcome domains were identified as important to adult patients and parents: (1) scar characteristics and appearance, (2) movement and function, (3) scar sensation, (4) psychological distress, adjustments and a sense of normality, (5) body image and confidence, (6) engagement in activities, (7) impact on relationships, and (8) treatment burden. CONCLUSIONS: The outcome domains presented reflect a complex holistic patient experience of scar management and treatments such as PGT. Some currently available PROMs do capture the concepts described here, although none assess psychological adjustments and attainment of a sense of normality following burn injury. The routine use of PROMs that represent patient experience and their relative contribution to trial outcome assessment versus clinical measures is now a matter for further research and debate.

BAlloon versus Stenting in severe Ischaemia of the Leg-3 (BASIL-3): study protocol for a randomised controlled trial.

BACKGROUND: Severe limb ischaemia (SLI) is defined as the presence of rest pain and/or tissue loss secondary to lower extremity atherosclerotic peripheral arterial disease. The superficial femoral and popliteal arteries are the most commonly diseased vessels in such patients and are being increasingly treated using endovascular revascularisation techniques. However, it is currently unknown whether drug-eluting stents and drug-coated balloons confer additional clinical benefits over more established techniques using plain balloons and bare metal stents, or whether they represent a cost-effective use of NHS resources. METHODS: The BASIL-3 trial is a UK National Institute for Health Research, Health Technology Assessment Programme-funded, multicentre, randomised controlled trial (RCT) comparing the clinical and cost-effectiveness of plain balloon angioplasty with or without bail-out bare metal stenting, drug-coated balloon angioplasty with or without bail-out bare metal stenting, and primary stenting with drug-eluting stents for SLI secondary to femoro-popliteal disease. Patients with 'multilevel' disease may receive aorto-iliac and/or infrapopliteal treatments concurrently with their randomised femoro-popliteal intervention. The primary clinical outcome is amputation-free survival defined as the time to major (above the ankle) amputation of the index limb or death from any cause. The primary outcome for the economic analysis is cost per quality-adjusted life year. Secondary outcome measures include overall survival, major adverse limb events, major adverse cardiac events, relief of ischaemic pain, healing of tissue loss, and quality of life. The required sample size has been calculated at 861 participants (287 on each arm). These patients will be recruited over 3 years and followed-up for between 2 and 5 years. DISCUSSION: BASIL-3 is a pragmatic RCT designed to reflect current UK clinical practice. The results will inform decision-making regarding the appropriateness of funding the use of drug-coated balloons and drug-eluting stents, by the NHS, for the management of SLI due to femoro-popliteal disease. TRIAL REGISTRATION: ISRCTN Registry, identifier: ISRCTN14469736 . Registered on 22 October 2015.

Testing and Treating Women after Unsuccessful Conservative Treatments for Overactive Bladder or Mixed Urinary Incontinence: A Model-Based Economic Evaluation Based on the BUS Study.

OBJECTIVE: To compare the cost-effectiveness of bladder ultrasonography, clinical history, and urodynamic testing in guiding treatment decisions in a secondary care setting for women failing first line conservative treatment for overactive bladder or urgency-predominant mixed urinary incontinence. DESIGN: Model-based economic evaluation from a UK National Health Service (NHS) perspective using data from the Bladder Ultrasound Study (BUS) and secondary sources. METHODS: Cost-effectiveness analysis using a decision tree and a 5-year time horizon based on the outcomes of cost per woman successfully treated and cost per Quality-Adjusted Life-Year (QALY). Deterministic and probabilistic sensitivity analyses, and a value of information analysis are also undertaken. RESULTS: Bladder ultrasonography is more costly and less effective test-treat strategy than clinical history and urodynamics. Treatment on the basis of clinical history alone has an incremental cost-effectiveness ratio (ICER) of £491,100 per woman successfully treated and an ICER of £60,200 per QALY compared with the treatment of all women on the basis of urodynamics. Restricting the use of urodynamics to women with a clinical history of mixed urinary incontinence only is the optimal test-treat strategy on cost-effectiveness grounds with ICERs of £19,500 per woman successfully treated and £12,700 per QALY compared with the treatment of all women based upon urodynamics. Conclusions remained robust to sensitivity analyses, but subject to large uncertainties. CONCLUSIONS: Treatment based upon urodynamics can be seen as a cost-effective strategy, and particularly when targeted at women with clinical history of mixed urinary incontinence only. Further research is needed to resolve current decision uncertainty.

Bladder ultrasonography for diagnosing detrusor overactivity: test accuracy study and economic evaluation.

BACKGROUND: Urodynamics (UDS) has been considered the gold standard test for detrusor overactivity (DO) in women with an overactive bladder (OAB). Bladder ultrasonography to measure bladder wall thickness (BWT) is less invasive and has been proposed as an alternative test. OBJECTIVES: To estimate the reliability, reproducibility, accuracy and acceptability of BWT in women with OAB, measured by ultrasonography, in the diagnosis of DO; to explore the role of UDS and its impact on treatment outcomes; and to conduct an economic evaluation of alternative care pathways. DESIGN: A cross-sectional test accuracy study. SETTING: 22 UK hospitals. PARTICIPANTS: 687 women with OAB. METHODS: BWT was measured using transvaginal ultrasonography, and DO was assessed using UDS, which was performed blind to ultrasonographic findings. Intraobserver and interobserver reproducibility were assessed by repeated measurements from scans in 37 and 57 women, respectively, and by repeated scans in 27 women. Sensitivity and specificity were computed at pre-specified thresholds. The smallest real differences detectable of BWT were estimated using one-way analysis of variance. The pain and acceptability of both tests were evaluated by a questionnaire. Patient symptoms were measured before testing and after 6 and 12 months using the International Consultation on Incontinence modular Questionnaire Overactive Bladder (short form) (ICIQ-OAB) questionnaire and a global impression of improvement elicited at 12 months. Interventions and patient outcomes were analysed according to urodynamic diagnoses and BWT measurements. A decision-analytic model compared the cost-effectiveness of care strategies using UDS, ultrasonography or clinical history, estimating the cost per woman successfully treated and the cost per quality-adjusted life-year (QALY). RESULTS: BWT showed very low sensitivity and specificity at all pre-specified cut-off points, and there was no evidence of discrimination at any threshold (p = 0.25). Extensive sensitivity and subgroup analyses did not alter the interpretation of these findings. The smallest detectable difference in BWT was estimated to be 2 mm. Pain levels following both tests appeared relatively low. The proportion of women who found the test 'totally acceptable' was significantly higher with ultrasonography than UDS (81% vs. 56%; p < 0.001). Overall, subsequent treatment was highly associated with urodynamic diagnosis (p < 0.0001). There was no evidence that BWT had any relationship with the global impression of improvement responses at 20 months (p = 0.4). Bladder ultrasonography was more costly and less effective than the other strategies. The incremental cost-effectiveness ratio (ICER) of basing treatment on the primary clinical presentation compared with UDS was £491,500 per woman successfully treated and £60,200 per QALY. Performing a UDS in those women with a clinical history of mixed urinary incontinence had an ICER of £19,500 per woman successfully treated and £12,700 per QALY compared with the provision of urodynamic to all women. For DO cases detected, UDS was the most cost-effective strategy. CONCLUSION: There was no evidence that BWT had any relationship with DO, regardless of the cut-off point, nor any relationship to symptoms as measured by the ICIQ-OAB. Bladder ultrasonography has no diagnostic or prognostic value as a test in this condition. Furthermore, despite its greater acceptability, BWT measurement was not sufficiently reliable or reproducible. TRIAL REGISTRATION: Current Controlled Trials ISRCTN46820623. 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. 20, No. 7. See the NIHR Journals Library website for further project information.

Systematic review of peer support for breastfeeding continuation: metaregression analysis of the effect of setting, intensity, and timing.

OBJECTIVE: To examine the effect of setting, intensity, and timing of peer support on breast feeding. DESIGN: Systematic review and metaregression analysis of randomised controlled trials. DATA SOURCES: Cochrane Library, Medline, CINAHL, the National Research Register, and British Nursing Index were searched from inception or from 1980 to 2011. Review methods Study selection, data abstraction, and quality assessment were carried out independently and in duplicate. Risk ratios and 95% confidence intervals were calculated for individual studies and pooled. Effects were estimated for studies grouped according to setting (high income countries, low or middle income countries, and the United Kingdom), intensity (<5 and ≥5 planned contacts), and timing of peer support (postnatal period with or without antenatal care), and analysed using metaregression for any and exclusive breast feeding at last study follow-up. RESULTS: Peer support interventions had a significantly greater effect on any breast feeding in low or middle income countries (P<0.001), reducing the risk of not breast feeding at all by 30% (relative risk 0.70, 95% confidence interval 0.60 to 0.82) compared with a reduction of 7% (0.93, 0.87 to 1.00) in high income countries. Similarly, the risk of non-exclusive breast feeding decreased significantly more in low or middle income countries than in high income countries: 37% (0.63, 0.52 to 0.78) compared with 10% (0.90, 0.85 to 0.97); P=0.01. No significant effect on breast feeding was observed in UK based studies. Peer support had a greater effect on any breastfeeding rates when given at higher intensity (P=0.02) and only delivered in the postnatal period (P<0.001), although no differences were observed of its effect on exclusive breastfeeding rates by intensity or timing. CONCLUSION: Although peer support interventions increase breastfeeding continuation in low or middle income countries, especially exclusive breast feeding, this does not seem to apply in high income countries, particularly the United Kingdom, where breastfeeding support is part of routine postnatal healthcare. Peer support of low intensity does not seem to be effective. Policy relating to provision of peer support should be based on more specific evidence on setting and any new peer services in high income countries need to undergo concurrent evaluation.

Health promotion in older Chinese: a 12-month cluster randomized controlled trial of pedometry and "peer support".

PURPOSE: Aging, in conjunction with decreasing physical activity, is associated with a range of health problems. Simple, low-maintenance, population-based means of promoting activity to counteract the age-associated decline are required. We therefore assessed the effect of pedometry and buddy support to increase physical activity. METHODS: We undertook a clustered randomized trial (HKCTR-346) of 24 community centers involving 399 older Chinese participants (≥ 60 yr). Centers were randomly allocated to 1) pedometry and buddy, 2) pedometry and no buddy, 3) no pedometry and buddy, and 4) no pedometry and no buddy with a 2 × 2 factorial design. The trial simultaneously tested the individual and combined effects of the interventions. The intervention groups also received monthly organized group activities to provide encouragement and support. Outcome measures were assessed at 6 and 12 months, including physical fitness and activity and cardiovascular disease risk factors (anthropometry and blood pressure). RESULTS: From the 24 centers, 356 volunteers (89.2%) completed the study. Those receiving the interventions had higher mean physical activity levels at 12 months of 1820 (95% confidence interval (CI) = 1360-2290) and 1260 (95% CI = 780-1740) MET·min·wk(-1), respectively relative to the decrease in the control groups. The buddy peer support intervention significantly improved mean aerobic fitness (12% [95% CI = 4%-21%]) and reduced both body fat (-0.6% [95% CI = -1.1% to 0.0%]) and time to complete the 2.5-m get-up-and-go test (-0.27 [95% CI = -0.53 to -0.01] s). No other improvements in the cardiovascular disease risk factors were observed. The combination of motivational tools was no better than the individual interventions. CONCLUSIONS: Both motivational interventions increased physical activity levels, and the buddy style improved fitness. These tools could be useful adjuncts in the prevention of obesity and age-related complications.

QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.

In 2003, the QUADAS tool for systematic reviews of diagnostic accuracy studies was developed. Experience, anecdotal reports, and feedback suggested areas for improvement; therefore, QUADAS-2 was developed. This tool comprises 4 domains: patient selection, index test, reference standard, and flow and timing. Each domain is assessed in terms of risk of bias, and the first 3 domains are also assessed in terms of concerns regarding applicability. Signalling questions are included to help judge risk of bias. The QUADAS-2 tool is applied in 4 phases: summarize the review question, tailor the tool and produce review-specific guidance, construct a flow diagram for the primary study, and judge bias and applicability. This tool will allow for more transparent rating of bias and applicability of primary diagnostic accuracy studies.

Pulse oximetry screening for congenital heart defects in newborn infants (PulseOx): a test accuracy study.

BACKGROUND: Screening for congenital heart defects relies on antenatal ultrasonography and postnatal clinical examination; however, life-threatening defects often are not detected. We prospectively assessed the accuracy of pulse oximetry as a screening test for congenital heart defects. METHODS: In six maternity units in the UK, asymptomatic newborn babies (gestation >34 weeks) were screened with pulse oximetry before discharge. Infants who did not achieve predetermined oxygen saturation thresholds underwent echocardiography. All other infants were followed up to 12 months of age by use of regional and national registries and clinical follow-up. The main outcome was the sensitivity and specificity of pulse oximetry for detection of critical congenital heart defects (causing death or requiring invasive intervention before 28 days) or major congenital heart disease (causing death or requiring invasive intervention within 12 months of age). FINDINGS: 20,055 newborn babies were screened and 53 had major congenital heart disease (24 critical), a prevalence of 2·6 per 1000 livebirths. Analyses were done on all babies for whom a pulse oximetry reading was obtained. Sensitivity of pulse oximetry was 75·00% (95% CI 53·29-90·23) for critical cases and 49·06% (35·06-63·16) for all major congenital heart defects. In 35 cases, congenital heart defects were already suspected after antenatal ultrasonography, and exclusion of these reduced the sensitivity to 58·33% (27·67-84·83) for critical cases and 28·57% (14·64-46·30) for all cases of major congenital heart defects. False-positive results were noted for 169 (0·8%) babies (specificity 99·16%, 99·02-99·28), of which six cases were significant, but not major, congenital heart defects, and 40 were other illnesses that required urgent medical intervention. INTERPRETATION: Pulse oximetry is a safe, feasible test that adds value to existing screening. It identifies cases of critical congenital heart defects that go undetected with antenatal ultrasonography. The early detection of other diseases is an additional advantage. FUNDING: National Institute for Health Research Health Technology Assessment programme.

A simplified 4-site economical intradermal post-exposure rabies vaccine regimen: a randomised controlled comparison with standard methods.

BACKGROUND: The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods. METHODS: Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available. FINDINGS: All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method. CONCLUSIONS: This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN 30087513.