School-based high-intensity interval training programs in children and adolescents: A systematic review and meta-analysis.

PURPOSE: 1) To investigate the effectiveness of school-based high-intensity interval training (HIIT) interventions in promoting health outcomes of children and adolescents compared with either a control group or other exercise modality; and 2) to explore the intervention characteristics and process outcomes of published school-based HIIT interventions. METHODS: We searched Medline, Embase, CINAHL, SPORTDiscus, and Web of Science from inception until 31 March 2021. Studies were eligible if 1) participants aged 5-17 years old; 2) a HIIT intervention within a school setting ≥ 2 weeks duration; 3) a control or comparative exercise group; 4) health-related, cognitive, physical activity, nutrition, or program evaluation outcomes; and 5) original research published in English. We conducted meta-analyses between HIIT and control groups for all outcomes with ≥ 4 studies and meta-regressions for all outcomes with ≥ 10 studies. We narratively synthesised results between HIIT and comparative exercise groups. RESULTS: Fifty-four papers met eligibility criteria, encompassing 42 unique studies (35 randomised controlled trials; 36 with a high risk of bias). Meta-analyses indicated significant improvements in waist circumference (mean difference (MD) = -2.5cm), body fat percentage (MD = -1.7%), body mass index (standardised mean difference (SMD) = -1.0), cardiorespiratory fitness (SMD = +1.0), resting heart rate (MD = -5bpm), homeostatic model assessment-insulin resistance (MD = -0.7), and low-density lipoprotein cholesterol (SMD = -0.9) for HIIT compared to the control group. Our narrative synthesis indicated mixed findings between HIIT and other comparative exercise groups. CONCLUSION: School-based HIIT is effective for improving several health outcomes. Future research should address the paucity of information on physical activity and nutrition outcomes and focus on the integration and long-term effectiveness of HIIT interventions within school settings. TRIAL REGISTRATION NUMBER: PROSPERO CRD42018117567.

The cost-effectiveness of antenatal and postnatal education and support interventions for women aimed at promoting breastfeeding in the UK.

BACKGROUND: Breastfeeding is associated with health benefits to mothers and babies and cost-savings to the health service. Breastfeeding rates in the UK are low for various reasons including cultural barriers, inadequate support to initiate and sustain breastfeeding, lack of information, or choice not to breastfeed. Education and support interventions have been developed aiming at promoting breastfeeding rates. The objective of this study was to assess the cost-effectiveness of such interventions for women, initiated antenatally or in the first 8 weeks postnatally, aiming at improving breastfeeding rates, in the UK. METHODS: A decision-analytic model was constructed to compare costs and quality-adjusted life-years (QALYs) of a breastfeeding intervention from the perspective of health and personal social services in England. Data on intervention effectiveness and the benefits of breastfeeding were derived from systematic reviews. Other model input parameters were obtained from published sources, supplemented by expert opinion. RESULTS: The incremental cost-effectiveness ratio (ICER) of the modelled intervention added on standard care versus standard care was £51,946/QALY, suggesting that the intervention is not cost-effective under National Institute for Health and Care Excellence (NICE) criteria in England. Sensitivity analysis suggested that the cost-effectiveness of the intervention improved as its effectiveness increased and intervention cost decreased. At the base-case effect (increase in breastfeeding rates 16-26 weeks after birth by 19%), the intervention was cost-effective (<£20,000/QALY) if its cost per woman receiving the intervention became ≈£40-£45. At the base-case cost (£84), the intervention was cost-effective if it increased breastfeeding rates by at least 35-40%. CONCLUSIONS: Available breastfeeding interventions do not appear to be cost-effective under NICE criteria in England. Future breastfeeding interventions need to have higher effectiveness or lower cost compared with currently available interventions in order to become cost-effective. Public health and other societal interventions that protect, promote and support breastfeeding may be key in improving breastfeeding rates in the UK.

Lung cancer screening by low-dose computed tomography: a cost-effectiveness analysis of alternative programmes in the UK using a newly developed natural history-based economic model.

BACKGROUND: A systematic review of economic evaluations for lung cancer identified no economic models of the UK setting based on disease natural history. We first sought to develop a new model of natural history for population screening, then sought to explore the cost-effectiveness of multiple alternative potential programmes. METHODS: An individual patient model (ENaBL) was constructed in MS Excel® and calibrated against data from the US National Lung Screening Trial. Costs were taken from the UK Lung Cancer Screening Trial and took the perspective of the NHS and PSS. Simulants were current or former smokers aged between 55 and 80 years and so at a higher risk of lung cancer relative to the general population. Subgroups were defined by further restricting age and risk of lung cancer as predicted by patient self-questionnaire. Programme designs were single, triple, annual and biennial arrangements of LDCT screens, thereby examining number and interval length. Forty-eight distinct screening strategies were compared to the current practice of no screening. The primary outcome was incremental cost-effectiveness of strategies (additional cost per QALY gained). RESULTS: LDCT screening is predicted to bring forward the stage distribution at diagnosis and reduce lung cancer mortality, with decreases versus no screening ranging from 4.2 to 7.7% depending on screen frequency. Overall healthcare costs are predicted to increase; treatment cost savings from earlier detection are outweighed by the costs of over-diagnosis. Single-screen programmes for people 55-75 or 60-75 years with ≥ 3% predicted lung cancer risk may be cost-effective at the £30,000 per QALY threshold (respective ICERs of £28,784 and £28,169 per QALY gained). Annual and biennial screening programmes were not predicted to be cost-effective at any cost-effectiveness threshold. LIMITATIONS: LDCT performance was unaffected by lung cancer type, stage or location and the impact of a national screening programme of smoking behaviour was not included. CONCLUSION: Lung cancer screening may not be cost-effective at the threshold of £20,000 per QALY commonly used in the UK but may be cost-effective at the higher threshold of £30,000 per QALY.

Recurrent and Subsequent Injuries in Professional and Elite Sport: a Systematic Review.

BACKGROUND: Injury surveillance in professional sport categorises injuries as either "new" or "recurrent". In an attempt to make categorisation more specific, subsequent injury categorisation models have been developed, but it is not known how often these models are used. The aim was to assess how recurrent and subsequent injuries are reported within professional and elite sport. METHODS: Online databases were searched using a search strategy. Studies needed to prospectively report injury rates within professional or elite sports that have published consensus statements for injury surveillance. RESULTS: A total of 1322 titles and abstract were identified and screened. One hundred and ninety-nine studies were screened at full text resulting in 81 eligible studies. Thirty studies did not report recurrent injuries and were excluded from data extraction. Within the studies that reported recurrent injuries, 21 reported the number and percentage; 13 reported only the proportion within all injuries; three reported only the number; five reported the number, percentage and incidence; and two only reported the incidence. Seven studies used subsequent injury terminology, with three reporting subsequent injury following concussion, one using an amended subsequent injury model and three using specific subsequent injury categorisation models. The majority of subsequent injuries (ranging from 51 to 80%) were categorised as different and unrelated to the index injury. The proportion of recurrent injuries (exact same body area and nature related to index injury) ranged from 5 to 21%. CONCLUSIONS: Reporting recurrent or subsequent injuries remains inconsistent, and few studies have utilised subsequent injury models. There is limited understanding of subsequent injury risk, which may affect the development of injury prevention strategies. TRIAL REGISTRATION: CRD42019119264.

Established search filters may miss studies when identifying randomized controlled trials.

OBJECTIVES: The authors were becoming increasingly aware of studies reporting randomized controlled trial (RCT), which reported trial phase but did not mention study design or randomization in the title or abstract. The objective of this study was to determine if established RCT literature search filters should include terms for trial phase. STUDY DESIGN AND SETTING: This study is a case study. A search filter for trial phase (the P3 filter) was developed, and its sensitivity, efficiency, and value were determined when compared with two established RCT literature search filters (The Cochrane Highly Sensitive Search Strategies [HSSS] and the Royle and Waugh Brief RCT Search Strategy [BRSS]) in the year 2015-improved sensitivity was determined where the P3 filter identified studies missed by either of the established filters; efficiency was determined by the number needed to read; and the Cochrane risk of bias tool was used to determine study quality as a proxy for value. RESULTS: Both established filters missed studies. The HSSS missed one RCT and four follow-up RCT studies. The BRSS missed one RCT and five follow-up RCT studies. Study quality was unclear. CONCLUSION: Established RCT literature search filters may miss studies where trial phase is reported instead of terms for study design or randomization. The P3 filter can be incorporated to improve sensitivity.

Correction to: Effect of Immobilisation on Neuromuscular Function In Vivo in Humans: A Systematic Review.

The following sections 3.5.1 to 3.5.3.2, which previously read.

Effect of Immobilisation on Neuromuscular Function In Vivo in Humans: A Systematic Review.

BACKGROUND: Muscle strength loss following immobilisation has been predominantly attributed to rapid muscle atrophy. However, this cannot fully explain the magnitude of muscle strength loss, so changes in neuromuscular function (NMF) may be involved. OBJECTIVES: We systematically reviewed literature that quantified changes in muscle strength, size and NMF following periods of limb immobilisation in vivo in humans. METHODS: Studies were identified following systematic searches, assessed for inclusion, data extracted and quality appraised by two reviewers. Data were tabulated and reported narratively. RESULTS: Forty eligible studies were included, 22 immobilised lower and 18 immobilised upper limbs. Limb immobilisation ranged from 12 h to 56 days. Isometric muscle strength and muscle size declined following immobilisation; however, change magnitude was greater for strength than size. Evoked resting twitch force decreased for lower but increased for upper limbs. Rate of force development either remained unchanged or slowed for lower and typically slowed for upper limbs. Twitch relaxation rate slowed for both lower and upper limbs. Central motor drive typically decreased for both locations, while electromyography amplitude during maximum voluntary contractions decreased for the lower and presented mixed findings for the upper limbs. Trends imply faster rates of NMF loss relative to size earlier in immobilisation periods for all outcomes. CONCLUSIONS: Limb immobilisation results in non-uniform loss of isometric muscle strength, size and NMF over time. Different outcomes between upper and lower limbs could be attributed to higher degrees of central neural control of upper limb musculature. Future research should focus on muscle function losses and mechanisms following acute immobilisation. REGISTRATION: PROSPERO reference: CRD42016033692.

Evaluating the effectiveness, efficiency, cost and value of contacting study authors in a systematic review: a case study and worked example.

BACKGROUND: Studies find that identifying additional study data is possible by contacting study authors or experts. What is less certain is the time taken, costs involved and value found by using this supplementary search method. The purpose of this study is to determine the effectiveness, efficiency, cost and value of contacting study authors by e-mail, updating the evidence available for this search method. METHODS: Eighty-eight study authors, whose studies met title/abstract inclusion in a. systematic review, were contacted by e-mail. * effectiveness was assessed by comparing the number of study authors contacted. compared to the number of replies received; * efficiency was assessed by recording the time taken to contact study authors; * cost was assessed by comparing the efficiency of contacting authors with the. effectiveness; and * value was assessed by reading and comparing the published studies with the replies received to see if any unique data was identified. RESULTS: Contacting study authors took 6 h, 54 min and 25 s across 7 weeks. 38 answers (46%) were received from 83 possible contacts. Contacting study authors cost £80.33 or £2.11 per reply. We identified unique data from author replies when compared with data reported in published studies, determining this method as 'valuable'. CONCLUSIONS: Whilst our effectiveness findings differ from other studies, we believe that this study demonstrates the effectiveness of contacting study authors. By linking effectiveness to value and cost, we offer a new way to interpret the 'effectiveness' of this supplementary search method.

Three biomarker tests to help diagnose preterm labour: a systematic review and economic evaluation.

BACKGROUND: Preterm birth may result in short- and long-term health problems for the child. Accurate diagnoses of preterm births could prevent unnecessary (or ensure appropriate) admissions into hospitals or transfers to specialist units. OBJECTIVES: The purpose of this report is to assess the test accuracy, clinical effectiveness and cost-effectiveness of the diagnostic tests PartoSure™ (Parsagen Diagnostics Inc., Boston, MA, USA), Actim® Partus (Medix Biochemica, Espoo, Finland) and the Rapid Fetal Fibronectin (fFN)® 10Q Cassette Kit (Hologic, Inc., Marlborough, MA, USA) at thresholds ≠50 ng/ml [quantitative fFN (qfFN)] for women presenting with signs and symptoms of preterm labour relative to fFN at 50 ng/ml. METHODS: Systematic reviews of the published literature were conducted for diagnostic test accuracy (DTA) studies of PartoSure, Actim Partus and qfFN for predicting preterm birth, the clinical effectiveness following treatment decisions informed by test results and economic evaluations of the tests. A model-based economic evaluation was also conducted to extrapolate long-term outcomes from the results of the diagnostic tests. The model followed the structure of the model that informed the 2015 National Institute for Health and Care Excellence guidelines on preterm labour diagnosis and treatment, but with antenatal steroids use, as opposed to tocolysis, driving health outcomes. RESULTS: Twenty studies were identified evaluating DTA against the reference standard of delivery within 7 days and seven studies were identified evaluating DTA against the reference standard of delivery within 48 hours. Two studies assessed two of the index tests within the same population. One study demonstrated that depending on the threshold used, qfFN was more or less accurate than Actim Partus, whereas the other indicated little difference between PartoSure and Actim Partus. No study assessing qfFN and PartoSure in the same population was identified. The test accuracy results from the other included studies revealed a high level of uncertainty, primarily attributable to substantial methodological, clinical and statistical heterogeneity between studies. No study compared all three tests simultaneously. No clinical effectiveness studies evaluating any of the three biomarker tests were identified. One partial economic evaluation was identified for predicting preterm birth. It assessed the number needed to treat to prevent a respiratory distress syndrome case with a 'treat-all' strategy, relative to testing with qualitative fFN. Because of the lack of data, our de novo model involved the assumption that management of pregnant women fully adhered to the results of the tests. In the base-case analysis for a woman at 30 weeks' gestation, Actim Partus had lower health-care costs and fewer quality-adjusted life-years (QALYs) than qfFN at 50 ng/ml, reducing costs at a rate of £56,030 per QALY lost compared with qfFN at 50 ng/ml. PartoSure is less costly than Actim Partus while being equally effective, but this is based on diagnostic accuracy data from a small study. Treatment with qfFN at 200 ng/ml and 500 ng/ml resulted in lower cost savings per QALY lost relative to fFN at 50 ng/ml than treatment with Actim Partus. In contrast, qfFN at 10 ng/ml increased QALYs, by 0.002, and had a cost per QALY gained of £140,267 relative to fFN at 50 ng/ml. Similar qualitative results were obtained for women presenting at different gestational ages. CONCLUSION: There is a high degree of uncertainty surrounding the test accuracy and cost-effectiveness results. We are aware of four ongoing UK trials, two of which plan to enrol > 1000 participants. The results of these trials may significantly alter the findings presented here. STUDY REGISTRATION: The study is registered as PROSPERO CRD42017072696. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Infants may suffer from health problems if they are born early. If a mother has symptoms of labour before her baby is due, a test could be used to predict if the symptoms are real or a false alarm. A test could help the doctor to decide whether the mother needs treatment or to move to a specialist hospital or if she could be sent home (if it is a false alarm). Our report compares three tests [PartoSure™ (Parsagen Diagnostics Inc., Boston, MA, USA), Actim^® Partus (Medix Biochemica, Espoo, Finland) and the Fetal Fibronectin (fFN) Test (Hologic, Inc., Marlborough, MA, USA)] on how well they predict an early birth and how the costs and the long-term health outcomes of the child compare between and among tests. All the published literature reporting the accuracy of the three tests and their costs was reviewed. We developed a new cost-effectiveness model, which estimated the long-term health outcomes of the child based on the test results. Twenty of the studies reviewed looked at how good the tests were at predicting an early birth within the next 7 days, and six looked at predicting birth within 48 hours. The designs of the studies and the women taking part in the studies varied greatly. This meant that comparing the accuracy of the tests was very difficult and it would be unfair to decide which test was the best. Our model suggested no firm conclusions for the cost-effectiveness of fFN compared with Actim Partus. PartoSure appears to be less costly than Actim Partus and equally good at predicting preterm birth, but this is based on a study of very few patients. There were no data that allowed us to compare all three tests together. The accuracy of the results is uncertain, mainly because all the studies are very different. We are aware of four related UK trials that are currently ongoing that plan to include large numbers of women.

Do we know enough about the effect of low-dose computed tomography screening for lung cancer on survival to act? A systematic review, meta-analysis and network meta-analysis of randomised controlled trials.

BACKGROUND: Diagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early. METHODS: Our objective was to estimate the effect of LDCT lung cancer screening on mortality in high-risk populations. A systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programme (such as chest X-ray (CXR)) was conducted. RCTs of CXR screening were additionally included in the network meta-analysis. Bibliographic sources including MEDLINE, Embase, Web of Science and the Cochrane Library were searched to January 2017. All key review steps were done by two persons. Quality assessment used the Cochrane Risk of Bias tool. Meta-analyses were performed. RESULTS: Four RCTs were included. More will provide data in the future. Meta-analysis demonstrated that LDCT screening with up to 9.80 years of follow-up was associated with a statistically non-significant decrease in lung cancer mortality (pooled relative risk (RR) 0.94, 95% confidence interval (CI) 0.74 to 1.19; p = 0.62). There was a statistically non-significant increase in all-cause mortality. Given the considerable heterogeneity for both outcomes, the results should be treated with caution.Network meta-analysis including the four original RCTs plus two further RCTs assessed the relative effectiveness of LDCT, CXR and usual care. The results showed that in terms of lung cancer mortality reduction LDCT was ranked as the best screening strategy, CXR screening as the worst strategy and usual care intermediate. CONCLUSIONS: LDCT screening may be effective in reducing lung cancer mortality but there is considerable uncertainty: the largest of the RCTs compared LDCT with CXR screening rather than no screening; there is imprecision of the estimates; and there is important heterogeneity between the included study results. The uncertainty about the effect on all-cause mortality is even greater. Maturing trials may resolve the uncertainty.

Low-dose computed tomography for lung cancer screening in high-risk populations: a systematic review and economic evaluation.

BACKGROUND: Diagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early. OBJECTIVES: To estimate the clinical effectiveness and cost-effectiveness of LDCT lung cancer screening in high-risk populations. DATA SOURCES: Bibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library. METHODS: Clinical effectiveness - a systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programmes [such as chest X-ray (CXR)] was conducted. Bibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library. Meta-analyses, including network meta-analyses, were performed. Cost-effectiveness - an independent economic model employing discrete event simulation and using a natural history model calibrated to results from a large RCT was developed. There were 12 different population eligibility criteria and four intervention frequencies [(1) single screen, (2) triple screen, (3) annual screening and (4) biennial screening] and a no-screening control arm. RESULTS: Clinical effectiveness - 12 RCTs were included, four of which currently contribute evidence on mortality. Meta-analysis of these demonstrated that LDCT, with ≤ 9.80 years of follow-up, was associated with a non-statistically significant decrease in lung cancer mortality (pooled relative risk 0.94, 95% confidence interval 0.74 to 1.19). The findings also showed that LDCT screening demonstrated a non-statistically significant increase in all-cause mortality. Given the considerable heterogeneity detected between studies for both outcomes, the results should be treated with caution. Network meta-analysis, including six RCTs, was performed to assess the relative clinical effectiveness of LDCT, CXR and usual care. The results showed that LDCT was ranked as the best screening strategy in terms of lung cancer mortality reduction. CXR had a 99.7% probability of being the worst intervention and usual care was ranked second. Cost-effectiveness - screening programmes are predicted to be more effective than no screening, reduce lung cancer mortality and result in more lung cancer diagnoses. Screening programmes also increase costs. Screening for lung cancer is unlikely to be cost-effective at a threshold of £20,000/quality-adjusted life-year (QALY), but may be cost-effective at a threshold of £30,000/QALY. The incremental cost-effectiveness ratio for a single screen in smokers aged 60-75 years with at least a 3% risk of lung cancer is £28,169 per QALY. Sensitivity and scenario analyses were conducted. Screening was only cost-effective at a threshold of £20,000/QALY in only a minority of analyses. LIMITATIONS: Clinical effectiveness - the largest of the included RCTs compared LDCT with CXR screening rather than no screening. Cost-effectiveness - a representative cost to the NHS of lung cancer has not been recently estimated according to key variables such as stage at diagnosis. Certain costs associated with running a screening programme have not been included. CONCLUSIONS: LDCT screening may be clinically effective in reducing lung cancer mortality, but there is considerable uncertainty. There is evidence that a single round of screening could be considered cost-effective at conventional thresholds, but there is significant uncertainty about the effect on costs and the magnitude of benefits. FUTURE WORK: Clinical effectiveness and cost-effectiveness estimates should be updated with the anticipated results from several ongoing RCTs [particularly the NEderlands Leuvens Longkanker Screenings ONderzoek (NELSON) screening trial]. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016048530. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Everolimus, lutetium-177 DOTATATE and sunitinib for advanced, unresectable or metastatic neuroendocrine tumours with disease progression: a systematic review and cost-effectiveness analysis.

BACKGROUND: Neuroendocrine tumours (NETs) are a group of heterogeneous cancers that develop in cells in the diffuse neuroendocrine system. OBJECTIVES: To estimate the clinical effectiveness of three interventions [everolimus (Afinitor®; Novartis International AG, Basel, Switzerland), lutetium-177 DOTATATE (177Lu-DOTATATE) (Lutathera®; Imaging Equipment Ltd, Radstock, UK) and sunitinib (Sutent®; Pfizer Inc., New York, NY, USA)] for treating unresectable or metastatic NETs with disease progression and establish the cost-effectiveness of these interventions. DATA SOURCES: The following databases were searched from inception to May 2016: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Daily, Epub Ahead of Print, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science. REVIEW METHODS: We systematically reviewed the clinical effectiveness and cost-effectiveness literature on everolimus, 177Lu-DOTATATE and sunitinib for treating advanced, unresectable or metastatic progressive NETs. The following NET locations were considered separately: pancreas, gastrointestinal (GI) tract and lung, and GI tract (midgut only). We wrote a survival partition cohort-based economic evaluation in Microsoft Excel® 2013 (Microsoft Corporation, Redmond, WA, USA) from the UK NHS and Personal Social Services perspective. This comprised three health states: (1) progression-free survival (PFS), (2) progressed disease and (3) death. RESULTS: Three randomised controlled trials (RCTs), RADIANT-3 [RAD001 in Advanced Neuroendocrine Tumors, Third Trial; pancreatic NETs (pNETs): everolimus vs. best supportive care (BSC)], A6181111 (pNETs: sunitinib vs. BSC) and RADIANT-4 (RAD001 in Advanced Neuroendocrine Tumors, Fourth Trial; GI and lung NETs: everolimus vs. BSC), met the inclusion criteria for the clinical effectiveness systematic review. The risk of bias was low. Although the NETTER-1 (Neuroendocrine Tumors Therapy) RCT, of 177Lu-DOTATATE plus 30 mg of octreotide (Sandostatin®, Novartis) compared with 60 mg of octreotide, was excluded from the review, we nonetheless present the results of this trial, as it informs our estimate of the cost-effectiveness of 177Lu-DOTATATE. The pNETs trials consistently found that the interventions improved PFS and overall survival (OS) compared with BSC. Our indirect comparison found no significant difference in PFS between everolimus and sunitinib. Estimates of OS gain were confounded because of high rates of treatment switching. After adjustment, our indirect comparison suggested a lower, but non-significant, hazard of death for sunitinib compared with everolimus. In GI and lung NETs, everolimus significantly improved PFS compared with BSC and showed a non-significant trend towards improved OS compared with BSC. Adverse events were more commonly reported following treatment with targeted interventions than after treatment with BSC. In the base case for pNETs, assuming list prices, we estimated incremental cost-effectiveness ratios (ICERs) for everolimus compared with BSC of £45,493 per quality-adjusted life-year (QALY) and for sunitinib compared with BSC of £20,717 per QALY. These ICERs increased substantially without the adjustment for treatment switching. For GI and lung NETs, we estimated an ICER for everolimus compared with BSC of £44,557 per QALY. For GI (midgut) NETs, the ICERs were £199,233 per QALY for everolimus compared with BSC and £62,158 per QALY for a scenario analysis comparing 177Lu-DOTATATE with BSC. We judge that no treatment meets the National Institute for Health and Care Excellence's (NICE) end-of-life criteria, although we cannot rule out that sunitinib in the A6181111 trial does. LIMITATIONS: A RCT with included comparators was not identified for 177Lu-DOTATATE. The indirect treatment comparison that our economic analysis was based on was of a simple Bucher type, unadjusted for any differences in the baseline characteristics across the two trials. CONCLUSIONS: Given NICE's current stated range of £20,000-30,000 per QALY for the cost-effectiveness threshold, based on list prices, only sunitinib might be considered good value for money in England and Wales. FUTURE WORK: Further analysis of individual patient data from RADIANT-3 would allow assessment of the robustness of our findings. The data were not made available to us by the company sponsoring the trial. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016041303. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Sex-Specific Changes in Physical Performance Following Military Training: A Systematic Review.

INTRODUCTION: Men and women joining the military undergo the same training, often in mixed-sex platoons. Given the inherent physiological and physical performance differences between men and women, it is reasonable to question whether sex differences exist in the adaptation to military training and, therefore, whether sex-specific training should be employed to optimise training adaptations. OBJECTIVE: To systematically review the literature evaluating changes in the physical performance of men and women following military training. METHODS: Six database sources were searched in addition to extensive secondary searching. Primary prospective intervention studies (all designs) evaluating physical training interventions in military populations, reporting pre- to post-training changes in physical fitness outcomes for both women and men, were included. RESULTS: We screened 3966 unique records. Twenty-nine studies (n = 37 study reports) were included, most of which were conducted in the USA and evaluated initial training for military recruits. Positive changes were more consistently observed in aerobic fitness and muscle strength (whole body and upper body) outcomes than lower body strength, muscle power or muscle endurance outcomes, following physical training. Relative pre- to post-training changes for all outcome measures tended to be greater in women than men although few statistically significant sex by outcome/time interactions were observed. CONCLUSION: Improvements in some, but not all, performance components were observed following a period of military training. Largely, these improvements were not significantly different between sexes. Further prospective research is needed to evaluate sex-specific differences in the response to physical training in controlled conditions to improve military physical training outcomes for both sexes.

Defining the process to literature searching in systematic reviews: a literature review of guidance and supporting studies.

BACKGROUND: Systematic literature searching is recognised as a critical component of the systematic review process. It involves a systematic search for studies and aims for a transparent report of study identification, leaving readers clear about what was done to identify studies, and how the findings of the review are situated in the relevant evidence. Information specialists and review teams appear to work from a shared and tacit model of the literature search process. How this tacit model has developed and evolved is unclear, and it has not been explicitly examined before. The purpose of this review is to determine if a shared model of the literature searching process can be detected across systematic review guidance documents and, if so, how this process is reported in the guidance and supported by published studies. METHOD: A literature review. Two types of literature were reviewed: guidance and published studies. Nine guidance documents were identified, including: The Cochrane and Campbell Handbooks. Published studies were identified through 'pearl growing', citation chasing, a search of PubMed using the systematic review methods filter, and the authors' topic knowledge. The relevant sections within each guidance document were then read and re-read, with the aim of determining key methodological stages. Methodological stages were identified and defined. This data was reviewed to identify agreements and areas of unique guidance between guidance documents. Consensus across multiple guidance documents was used to inform selection of 'key stages' in the process of literature searching. RESULTS: Eight key stages were determined relating specifically to literature searching in systematic reviews. They were: who should literature search, aims and purpose of literature searching, preparation, the search strategy, searching databases, supplementary searching, managing references and reporting the search process. CONCLUSIONS: Eight key stages to the process of literature searching in systematic reviews were identified. These key stages are consistently reported in the nine guidance documents, suggesting consensus on the key stages of literature searching, and therefore the process of literature searching as a whole, in systematic reviews. Further research to determine the suitability of using the same process of literature searching for all types of systematic review is indicated.

Revisiting the need for a literature search narrative: A brief methodological note.

In this method note, we question if the primary search strategy in a systematic review should be accompanied by a search narrative. A search narrative could offer a conceptual and contextual report on the search strategy, which we suggest might benefit the peer review of literature searches and increase engagement with, and discussion of, the literature search strategy from review stakeholders, topic experts, and lay users of research. Search narratives would also increase the transparency of decision-making in literature searching.

Cost-effectiveness of diagnostic and therapeutic interventions for chronic hepatitis C: a systematic review of model-based analyses.

BACKGROUND: Decisions about which subgroup of chronic hepatitis C (CHC) patients should be treated with direct acting anti-viral agents (DAAs) have economic importance due to high drug prices. Treat-all DAA strategies for CHC have gained acceptance despite high drug acquisition costs. However, there are also costs associated with the surveillance of CHC to determine a subgroup of patients with significant impairment. The aim of this systematic review was to describe the modelling methods used and summarise results in cost-effectiveness analyses (CEAs) of both CHC treatment with DAAs and surveillance of liver disease. METHODS: Electronic databases including Embase and Medline were searched from inception to May 2015. Eligible studies included models predicting costs and/or outcomes for interventions, surveillance, or management of people with CHC. Narrative and quantitative synthesis were conducted. Quality appraisal was conducted using validated checklists. The review was conducted following principles published by NHS Centre for Research and Dissemination. RESULTS: Forty-one CEAs met the eligibility criteria for the review; 37 evaluated an intervention and four evaluated surveillance strategies for targeting DAA treatment to those likely to gain most benefit. Included studies were of variable quality mostly due to reporting omissions. Of the 37 CEAs, eight models that enabled comparative analysis were fully appraised and synthesized. These models provided non-unique cost-effectiveness estimates in a specific DAA comparison in a specific population defined in terms of genotype, prior treatment status, and presence or absence of cirrhosis. Marked heterogeneity in cost-effectiveness estimates was observed despite this stratification. Approximately half of the estimates suggested that DAAs were cost-effective considering a threshold of US$30,000 and 73% with threshold of US$50,000. Two models evaluating surveillance strategies suggested that treating all CHC patients regardless of the staging of liver disease could be cost-effective. CONCLUSIONS: CEAs of CHC treatments need to better account for variability in their estimates. This analysis suggested that there are still circumstances where DAAs are not cost-effective. Surveillance in place of a treat-all strategy may still need to be considered as an option for deploying DAAs, particularly where acquisition cost is at the limit of affordability for a given health system.

Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England.

BACKGROUND: Combination therapies with cetuximab (Erbitux®; Merck Serono UK Ltd) and panitumumab (Vectibix®; Amgen UK Ltd) are shown to be less effective in adults with metastatic colorectal cancer who have mutations in exons 2, 3 and 4 of KRAS and NRAS oncogenes from the rat sarcoma (RAS) family. OBJECTIVE: The objective of the study was to estimate the cost effectiveness of these drugs in patients with previously untreated RAS wild-type (i.e. non-mutated) metastatic colorectal cancer, not eligible for liver resection at baseline, from the UK National Health Service and Personal Social Services perspective. METHODS: We constructed a partitioned survival model to evaluate the long-term costs and benefits of cetuximab and panitumumab combined with either FOLFOX (folinic acid, fluorouracil and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil and irinotecan) vs. FOLFOX or FOLFIRI alone. The economic analysis was based on three randomised controlled trials. Costs and quality-adjusted life-years were discounted at 3.5% per annum. RESULTS: Based on the evidence available, both drugs fulfil the National Institute for Health and Care Excellence's end-of-life criteria. In the analysis, assuming discount prices for the drugs from patient access schemes agreed by the drug manufacturers with the Department of Health, predicted mean incremental cost-effectiveness ratios for cetuximab + FOLFOX, panitumumab + FOLFOX and cetuximab + FOLFIRI compared with chemotherapy alone appeared cost-effective at the National Institute for Health and Care Excellence's threshold of £50,000 per quality-adjusted life-year gained, applicable to end-of-life treatments. CONCLUSION: Cetuximab and panitumumab were recommended by the National Institute for Health and Care Excellence for patients with previously untreated RAS wild-type metastatic colorectal cancer, not eligible for liver resection at baseline, for use within the National Health Service in England. Both treatments are available via the UK Cancer Drugs Fund.

Immunosuppressive agents in adult kidney transplantation in the National Health Service: a model-based economic evaluation.

BACKGROUND: Immunosuppression is required in kidney transplantation to prevent rejection and prolong graft survival. We conducted an economic evaluation to support England's National Institute for Health and Care Excellence in developing updated guidance on the use of immunosuppression, incorporating new immunosuppressive agents, and addressing changes in pricing and the evidence base. METHODS: A discrete-time state transition model was developed to simulate adult kidney transplant patients over their lifetime. A total of 16 different regimens were modelled to assess the cost-effectiveness of basiliximab and rabbit anti-thymocyte globulin (rabbit ATG) as induction agents (with no antibody induction as a comparator) and immediate-release tacrolimus, prolonged-release tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept as maintenance agents (with ciclosporin and azathioprine as comparators). Graft survival was extrapolated from acute rejection rates, graft function and post-transplant diabetes rates, all estimated at 12 months post-transplantation. National Health Service (NHS) and personal social services costs were included. Cost-effectiveness thresholds of £20 000 and £30 000 per quality-adjusted life year were used. RESULTS: Basiliximab was predicted to be more effective and less costly than rabbit ATG and induction without antibodies. Immediate-release tacrolimus and mycophenolate mofetil were cost-effective as maintenance therapies. Other therapies were either more expensive and less effective or would only be cost-effective if a threshold in excess of £100 000 per quality-adjusted life year were used. CONCLUSIONS: A regimen comprising induction with basiliximab, followed by maintenance therapy with immediate-release tacrolimus and mycophenolate mofetil, is likely to be effective for uncomplicated adult kidney transplant patients and a cost-effective use of NHS resources.

The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation.

BACKGROUND: Colorectal cancer is the fourth most commonly diagnosed cancer in the UK after breast, lung and prostate cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Targeted agents are available, including the antiepidermal growth factor receptor (EGFR) agents cetuximab (Erbitux®, Merck Serono UK Ltd, Feltham, UK) and panitumumab (Vecitibix®, Amgen UK Ltd, Cambridge, UK). OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of panitumumab in combination with chemotherapy and cetuximab in combination with chemotherapy for rat sarcoma (RAS) wild-type (WT) patients for the first-line treatment of metastatic colorectal cancer. DATA SOURCES: The assessment included a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions, and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted up to 27 April 2015 in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library. REVIEW METHODS: Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab or panitumumab in participants with previously untreated metastatic colorectal cancer with RAS WT status. All steps in the review were performed by one reviewer and checked independently by a second. Narrative synthesis and network meta-analyses (NMAs) were conducted for outcomes of interest. An economic model was developed focusing on first-line treatment and using a 30-year time horizon to capture costs and benefits. Costs and benefits were discounted at 3.5% per annum. Scenario analyses and probabilistic and univariate deterministic sensitivity analyses were performed. RESULTS: The searches identified 2811 titles and abstracts, of which five clinical trials were included. Additional data from these trials were provided by the manufacturers. No data were available for panitumumab plus irinotecan-based chemotherapy (folinic acid + 5-fluorouracil + irinotecan) (FOLFIRI) in previously untreated patients. Studies reported results for RAS WT subgroups. First-line treatment with anti-EGFR therapies in combination with chemotherapy appeared to have statistically significant benefits for patients who are RAS WT. For the independent economic evaluation, the base-case incremental cost-effectiveness ratio (ICER) for RAS WT patients for cetuximab plus oxaliplatin-based chemotherapy (folinic acid + 5-fluorouracil + oxaliplatin) (FOLFOX) compared with FOLFOX was £104,205 per quality-adjusted life-year (QALY) gained; for panitumumab plus FOLFOX compared with FOLFOX was £204,103 per QALY gained; and for cetuximab plus FOLFIRI compared with FOLFIRI was £122,554 per QALY gained. The ICERs were sensitive to treatment duration, progression-free survival, overall survival (resected patients only) and resection rates. LIMITATIONS: The trials included RAS WT populations only as subgroups. No evidence was available for panitumumab plus FOLFIRI. Two networks were used for the NMA and model, based on the different chemotherapies (FOLFOX and FOLFIRI), as insufficient evidence was available to the assessment group to connect these networks. CONCLUSIONS: Although cetuximab and panitumumab in combination with chemotherapy appear to be clinically beneficial for RAS WT patients compared with chemotherapy alone, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK. It would be useful to conduct a RCT in patients with RAS WT. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015016111. FUNDING: The National Institute for Health Research Health Technology Assessment programme.