Cervical spine immobilisation following blunt trauma in pre-hospital and emergency care: A systematic review.

OBJECTIVES: To assess whether different cervical spine immobilisation strategies (full immobilisation, movement minimisation or no immobilisation), impact neurological and/or other outcomes for patients with suspected cervical spinal injury in the pre-hospital and emergency department setting. DESIGN: Systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Cochrane Library and two research registers were searched until September 2023. ELIGIBILITY CRITERIA: All comparative studies (prospective or retrospective) that examined the potential benefits and/or harms of immobilisation practices during pre-hospital and emergency care of patients with a potential cervical spine injury (pre-imaging) following blunt trauma. DATA EXTRACTION AND SYNTHESIS: Two authors independently selected and extracted data. Risk of bias was appraised using the Cochrane ROBINS-I tool for non-randomised studies. Data were synthesised without meta-analysis. RESULTS: Six observational studies met the inclusion criteria. The methodological quality was variable, with most studies having serious or critical risk of bias. The effect of cervical spine immobilisation practices such as full immobilisation or movement minimisation during pre-hospital and emergency care did not show clear evidence of benefit for the prevention of neurological deterioration, spinal injuries and death compared with no immobilisation. However, increased pain, discomfort and anatomical complications were associated with collar application during immobilisation. CONCLUSIONS: Despite the limited evidence, weak designs and limited generalisability, the available data suggest that pre-hospital cervical spine immobilisation (full immobilisation or movement minimisation) was of uncertain value due to the lack of demonstrable benefit and may lead to potential complications and adverse outcomes. High-quality randomised comparative studies are required to address this important question. TRIAL REGISTRATION: PROSPERO REGISTRATION Fiona Lecky, Abdullah Pandor, Munira Essat, Anthea Sutton, Carl Marincowitz, Gordon Fuller, Stuart Reid, Jason Smith. A systematic review of cervical spine immobilisation following blunt trauma in pre-hospital and emergency care. PROSPERO 2022 CRD42022349600 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022349600.

Prognostic factors for liver, blood and kidney adverse events from glucocorticoid sparing immune-suppressing drugs in immune-mediated inflammatory diseases: a prognostic systematic review.

BACKGROUND: Immune-suppressing drugs can cause liver, kidney or blood toxicity. Prognostic factors for these adverse-events are poorly understood. PURPOSE: To ascertain prognostic factors associated with liver, blood or kidney adverse-events in people receiving immune-suppressing drugs. DATA SOURCES: MEDLINE, Web of Science, EMBASE and the Cochrane library (01 January 1995 to 05 January 2023), and supplementary sources. DATA EXTRACTION AND SYNTHESIS: Data were extracted by one reviewer using a modified CHARMS-PF checklist and validated by another. Two independent reviewers assessed risk of bias using Quality in Prognostic factor Studies tool and assessed the quality of evidence using a Grading of Recommendations Assessment, Development and Evaluation-informed framework. RESULTS: Fifty-six studies from 58 papers were included. High-quality evidence of the following associations was identified: elevated liver enzymes (6 studies) and folate non-supplementation (3 studies) are prognostic factors for hepatotoxicity in those treated with methotrexate; that mercaptopurine (vs azathioprine) (3 studies) was a prognostic factor for hepatotoxicity in those treated with thiopurines; that mercaptopurine (vs azathioprine) (3 studies) and poor-metaboliser status (4 studies) were prognostic factors for cytopenia in those treated with thiopurines; and that baseline elevated liver enzymes (3 studies) are a prognostic factor for hepatotoxicity in those treated with anti-tumour necrosis factors. Moderate and low quality evidence for several other demographic, lifestyle, comorbidities, baseline bloods/serologic or treatment-related prognostic factors were also identified. LIMITATIONS: Studies published before 1995, those with less than 200 participants and not published in English were excluded. Heterogeneity between studies included different cut-offs for prognostic factors, use of different outcome definitions and different adjustment factors. CONCLUSIONS: Prognostic factors for target-organ damage were identified which may be further investigated for their potential role in targeted (risk-stratified) monitoring. PROSPERO REGISTRATION NUMBER: CRD42020208049.

The Incidence and Costs of Adverse Events Associated with Antidepressants: Results from a Systematic Review, Network Meta-Analysis and Multi-Country Economic Model.

Purpose: There is variation in the safety profile of antidepressants. Rates of adverse events along with the costs of treating them can be an important factor influencing the choice of depression treatment. This study sought to estimate the comparative safety of commonly prescribed antidepressants, and how the costs of treating these varied across European countries. Methods: A systematic literature review was conducted (in Medline, Embase, PsycINFO and CENTRAL) to identify placebo-controlled trials reporting rates of at least one type of sexual dysfunction, weight change, insomnia, anxiety, and anhedonia. Eight antidepressants were considered: duloxetine, escitalopram, fluoxetine, paroxetine, sertraline, trazodone, venlafaxine, and vortioxetine. This evidence was synthesised via Bayesian random effects network meta-analyses to provide comparative estimates of safety. A systematic search identified country-specific costs of managing depression and adverse events of antidepressants. Evidence on costs and safety was combined in an economic model to provide country-specific costs for Bulgaria, the Czech Republic, Greece, Hungary, Italy, Romania, Slovakia, Portugal, and Poland. Results: Trazodone had the lowest rates of both insomnia (odds ratio 0.66, 95% credible interval 0.31 to 1.38) and anxiety (0.13, <0.01 to 1.80). All antidepressants were associated with increased rates of sexual dysfunction relative to placebo. Weight change was largest for fluoxetine (kg change -1.01, -1.40 to -0.60) and sertraline (-1.00, -1.36 to -0.65), although heterogeneity was extreme for this outcome. No evidence was identified for anhedonia. Total costs were lowest for trazodone in all nine of the countries evaluated. This was primarily due to reduced rates of treatment discontinuation. Conclusion: Trazodone generally had the best safety profile of the antidepressants evaluated. This led to healthcare costs being lowest for trazodone in all nine European countries, emphasising the importance of considering rates of adverse events when choosing a pharmacological treatment to treat symptoms of depression.

Understanding the current nutritional management for people with amyotrophic lateral sclerosis - A mapping review.

BACKGROUND & AIMS: Poor nutritional outcomes are observed in people with Amyotrophic Lateral Sclerosis (pwALS) including weight loss and poor dietary intake. Surveys of healthcare professionals have highlighted the lack of evidence and knowledge regarding nutritional management of ALS throughout the disease course. Furthermore, national evidence-based guidance is lacking. This mapping review aims to understand the structure and input of nutritional management services for pwALS. METHODS: Systematic searches were conducted across eight electronic databases to identify qualitative and quantitative research on structure and input of nutritional care in ALS. Supplementary searches included grey literature, citation and reference list searching of included studies and key reviews, web searching and contacting experts and organisations that provide ALS services to identify guidelines. Study selection and data extraction were undertaken independently by at least two reviewers. Data was synthesised using a narrative approach. RESULTS: One hundred and nine documents were identified. These consisted of journal articles, guidelines and related documents that contributed evidence towards mapping of nutritional management of pwALS. No evidence on commissioning of nutritional care was identified. Guidelines provided high-level overviews and gave general guidance or recommendations for care; however, these typically focused on gastrostomy with limited guidance on broader aspects, including oral nutrition support. Evidence from primary studies found nutritional care delivery in ALS consisted of multiple types of nutritional management, at different time points during the disease course and involving a range of professionals. There was little evidence relating to proactive nutritional care. Details of healthcare setting, number of professionals involved in care, team composition and how services were delivered in community settings were sparse. Although the role of the speech and language therapist in swallowing assessment and provision of advice on the management of swallowing difficulties was consistent; there was limited evidence on care provided by dietitians. In addition, a small number of studies reported on the use of screening tools. Overall, evidence was consistent that weight management, including monitoring of weight change by professionals and patients, was central and recommended that this should be part of nutritional assessment and follow-up. CONCLUSIONS: The evidence identified in this mapping review has highlighted the requirement for further primary research providing specific details on how nutritional management of pwALS is structured and delivered.

Individual risk factors predictive of major trauma in pre-hospital injured older patients: a systematic review.

Background: Older adults with major trauma are frequently under-triaged, increasing the risk of preventable morbidity and mortality. The aim of this systematic review was to identify which individual risk factors and predictors are likely to increase the risk of major trauma in elderly patients presenting to emergency medical services (EMS) following injury, to inform future elderly triage tool development. Methods: Several electronic databases (including Medline, EMBASE, CINAHL and the Cochrane Library) were searched from inception to February 2021. Prospective or retrospective diagnostic studies were eligible if they examined a prognostic factor (often termed predictor or risk factor) for, or diagnostic test to identify, major trauma. Selection of studies, data extraction and risk of bias assessments using the Quality in Prognostic Studies (QUIPS) tool were undertaken independently by at least two reviewers. Narrative synthesis was used to summarise the findings. Results: Nine studies, all performed in US trauma networks, met review inclusion criteria. Vital signs (Glasgow Coma Scale (GCS) score, systolic blood pressure, respiratory rate and shock index with specific elderly cut-off points), EMS provider judgement, comorbidities and certain crash scene variables (other occupants injured, occupant not independently mobile and head-on collision) were identified as significant pre-hospital variables associated with major trauma in the elderly in multi-variable analyses. Heart rate and anticoagulant were not significant predictors. Included studies were at moderate or high risk of bias, with applicability concerns secondary to selected study populations. Conclusions: Existing pre-hospital major trauma triage tools could be optimised for elderly patients by including elderly-specific physiology thresholds. Future work should focus on more relevant reference standards and further evaluation of novel elderly relevant triage tool variables and thresholds.

Diagnostic accuracy of conventional oral examination for detecting oral cavity cancer and potentially malignant disorders in patients with clinically evident oral lesions: Systematic review and meta-analysis.

This systematic review evaluates the diagnostic accuracy of conventional oral examination (COE) versus incisional or excisional biopsy for the diagnosis of malignant and/or dysplastic lesions in patients with clinically evident lesions. Searches were conducted across five electronic databases from inception to January 2020. Meta-analyses were undertaken, where appropriate. Among 18 included studies, 14 studies were included in the meta-analysis, giving summary estimates for COE of 71% sensitivity and 85% specificity for the diagnosis of dysplastic and/or malignant lesions. The pooled diagnostic accuracy of identifying malignant-only lesions was reported in seven studies, giving a pooled estimate of 88% sensitivity and 81% specificity. Diagnostic accuracy of different types of dental/medical professionals in identifying dysplastic or malignant lesions gave varying estimates of sensitivity and specificity across three studies. Further research is needed to improve the diagnostic accuracy of COE for early detection of dysplastic and malignant oral lesions.

Diagnostic accuracy of prehospital triage tools for identifying major trauma in elderly injured patients: A systematic review.

BACKGROUND: Older adults with major trauma are frequently undertriaged, increasing the risk of preventable morbidity and mortality. The aim of this systematic review was to evaluate the diagnostic performance of prehospital triage tools to identify suspected elderly trauma patients in need of specialized trauma care. METHODS: Several electronic databases (including MEDLINE, EMBASE, and the Cochrane Library) were searched from inception to February 2019. Prospective or retrospective diagnostic studies were eligible if they examined prehospital triage tools as index tests (either scored theoretically using observed patient variables or evaluated according to actual paramedic transport decisions) compared with a reference standard for major trauma in elderly adults who require transport by paramedics following injury. Selection of studies, data extraction, and risk of bias assessments using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool were undertaken independently by at least two reviewers. Narrative synthesis was used to summarize the findings. RESULTS: Fifteen studies met the inclusion criteria, with 11 studies examining theoretical accuracy, three evaluating real-life transport decisions, and one assessing both (of 21 individual index tests). Estimates for sensitivity and specificity were highly variable with sensitivity estimates ranging from 19.8% to 95.5% and 57.7% to 83.3% for theoretical accuracy and real life triage performance, respectively. Specificity results were similarly diverse ranging from 17.0% to 93.1% for theoretical accuracy and 46.3% to 78.9% for actual paramedic decisions. Most studies had unclear or high risk of bias and applicability concerns. There were no obvious differences between different triage tools, and findings did not appear to vary systematically with major trauma prevalence, age, alternative reference standards, study designs, or setting. CONCLUSION: Existing prehospital triage tools may not accurately identify elderly patients with serious injury. Future work should focus on more relevant reference standards, establishing the best trade-off between undertriage and overtriage, optimizing the role prehospital clinician judgment, and further developing geriatric specific triage variables and thresholds. LEVEL OF EVIDENCE: Systematic review, level III.

Interventions to promote oral nutritional behaviours in people living with neurodegenerative disorders of the motor system: A systematic review.

BACKGROUND & AIMS: Weight loss is common in people with neurodegenerative diseases of the motor system (NDMS), such as Parkinson's disease and Amyotrophic Lateral Sclerosis, and is associated with reduced quality of life, functional ability and survival. This systematic review aims to identify interventions and intervention components (i.e. behaviour change techniques [BCTs] and modes of delivery [MoDs]) that are associated with increased effectiveness in promoting oral nutritional behaviours that help people with NDMS to achieve a high calorie diet. METHODS: Eight electronic databases including MEDLINE and CINAHL were searched from inception to May 2018. All interventions from included studies were coded for relevant BCTs and MoDs. Methodological quality of studies was assessed using the Cochrane risk of bias tool. RESULTS: Fourteen studies were included. Of these, eight studies reported interventions to assist with swallowing difficulties and six studies reported interventions targeting dietary content. Beneficial effects in managing swallowing difficulties were observed with video assisted swallowing therapy, lung volume recruitment and swallowing management clinics with outpatient support. In contrast, studies reporting effectiveness of chin down posture, use of thickened liquids and respiratory muscle training were inconclusive. Positive effects in interventions targeting dietary content included the use of food pyramid tools, individualised nutritional advice with nutritional interventions, electronic health applications, face-to-face dietary counselling and high fat, high carbohydrate and milk whey protein supplements. Individualised nutritional advice with weekly phone contact did not appear to be effective. Most frequently coded BCTs were 'instructions on how to perform the behaviour', 'self-monitoring' and 'behavioural practice/rehearsal'. Most commonly identified MoDs were 'human, face-to-face' and 'somatic therapy'. However, the robustness of these findings are low due to the small number of studies, small sample sizes and large between-study variability. CONCLUSIONS: Despite the limited evidence, these findings may help inform the development of more effective interventions to promote oral nutritional behaviours in people with NDMS. However, further research is needed to demonstrate which interventions, or intervention components, yield most benefit.

Pirfenidone for Treating Idiopathic Pulmonary Fibrosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) published guidance on the use of pirfenidone (Esbriet®, Roche) for the treatment of mild to moderate idiopathic pulmonary fibrosis (IPF) in 2013. NICE decided to review existing guidance following publication of an additional clinical trial, and invited the manufacturer of pirfenidone to submit evidence of its clinical and cost effectiveness for the treatment of mild to moderate IPF when compared with best supportive care (BSC) or nintedanib; nintedanib was a comparator only for moderate IPF. An independent Evidence Review Group (ERG) critiqued the company submission and this paper summarises their report and subsequent NICE guidance. The key clinical effectiveness evidence was based on three randomised controlled trials (RCTs) and an open-label extension study. Supportive data were provided from two additional RCTs conducted in Japan, while one additional open-label study was included for safety outcomes. Meta-analysis of the three key RCTs found pirfenidone to be effective at reducing disease progression compared with placebo, but statistically significant differences were not identified in all of the RCTs. A statistically significant reduction in all-cause mortality was only demonstrated when pooling data across studies. The treatment effects of pirfenidone and nintedanib were broadly similar, based on an indirect comparison using network meta-analysis, although they have slightly different adverse event profiles. There remains considerable uncertainty in the cost-effectiveness estimates for pirfenidone versus BSC, particularly due to uncertainty regarding the duration of treatment effect and the method used to implement the stopping rule within the economic model.

Assessing prognosis and prediction of treatment response in early rheumatoid arthritis: systematic reviews.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, debilitating disease associated with reduced quality of life and substantial costs. It is unclear which tests and assessment tools allow the best assessment of prognosis in people with early RA and whether or not variables predict the response of patients to different drug treatments. OBJECTIVE: To systematically review evidence on the use of selected tests and assessment tools in patients with early RA (1) in the evaluation of a prognosis (review 1) and (2) as predictive markers of treatment response (review 2). DATA SOURCES: Electronic databases (e.g. MEDLINE, EMBASE, The Cochrane Library, Web of Science Conference Proceedings; searched to September 2016), registers, key websites, hand-searching of reference lists of included studies and key systematic reviews and contact with experts. STUDY SELECTION: Review 1 - primary studies on the development, external validation and impact of clinical prediction models for selected outcomes in adult early RA patients. Review 2 - primary studies on the interaction between selected baseline covariates and treatment (conventional and biological disease-modifying antirheumatic drugs) on salient outcomes in adult early RA patients. RESULTS: Review 1 - 22 model development studies and one combined model development/external validation study reporting 39 clinical prediction models were included. Five external validation studies evaluating eight clinical prediction models for radiographic joint damage were also included. c-statistics from internal validation ranged from 0.63 to 0.87 for radiographic progression (different definitions, six studies) and 0.78 to 0.82 for the Health Assessment Questionnaire (HAQ). Predictive performance in external validations varied considerably. Three models [(1) Active controlled Study of Patients receiving Infliximab for the treatment of Rheumatoid arthritis of Early onset (ASPIRE) C-reactive protein (ASPIRE CRP), (2) ASPIRE erythrocyte sedimentation rate (ASPIRE ESR) and (3) Behandelings Strategie (BeSt)] were externally validated using the same outcome definition in more than one population. Results of the random-effects meta-analysis suggested substantial uncertainty in the expected predictive performance of models in a new sample of patients. Review 2 - 12 studies were identified. Covariates examined included anti-citrullinated protein/peptide anti-body (ACPA) status, smoking status, erosions, rheumatoid factor status, C-reactive protein level, erythrocyte sedimentation rate, swollen joint count (SJC), body mass index and vascularity of synovium on power Doppler ultrasound (PDUS). Outcomes examined included erosions/radiographic progression, disease activity, physical function and Disease Activity Score-28 remission. There was statistical evidence to suggest that ACPA status, SJC and PDUS status at baseline may be treatment effect modifiers, but not necessarily that they are prognostic of response for all treatments. Most of the results were subject to considerable uncertainty and were not statistically significant. LIMITATIONS: The meta-analysis in review 1 was limited by the availability of only a small number of external validation studies. Studies rarely investigated the interaction between predictors and treatment. SUGGESTED RESEARCH PRIORITIES: Collaborative research (including the use of individual participant data) is needed to further develop and externally validate the clinical prediction models. The clinical prediction models should be validated with respect to individual treatments. Future assessments of treatment by covariate interactions should follow good statistical practice. CONCLUSIONS: Review 1 - uncertainty remains over the optimal prediction model(s) for use in clinical practice. Review 2 - in general, there was insufficient evidence that the effect of treatment depended on baseline characteristics. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016042402. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Patient-Reported Outcome Measures in Carotid Artery Revascularization: Systematic Review and Psychometric Analysis.

BACKGROUND: Patient-reported outcome measures (PROMs) provide a way to measure the impact of a disease and its associated treatments on the quality of life (QoL) from the patients' perspective. The aim of this review was to identify PROMs that have been developed and/or validated in patients with carotid artery stenosis (CAS) undergoing revascularization and to assess their psychometric properties and examine suitability for research and clinical use. METHODS: Eight electronic databases including MEDLINE and CINAHL were searched using a 2-stage search approach to identify studies reporting the development and/or validation of relevant PROMs in patients with CAS undergoing revascularization. Supplementary citation searching and hand-searching reference lists of included studies were also undertaken. The COnsensus-based Standards for the selection of health Measurement INstruments and Oxford criteria were used to assess the methodological quality of the included studies, and the psychometric properties of the PROMs were evaluated using established assessment criteria. RESULTS: Five studies reporting on 6 PROMs were included: 36-Item Short Form Health Survey (SF-36), Euro-QoL-5-Dimension Scale (EQ-5D), Hospital Anxiety and Depression Scale, Dizziness Handicap Inventory, QoL for carotid artery disease scale, and a disease-specific PROM for CAS. The rigor of the psychometric assessment of the PROMs was variable with most only attempting to assess a single psychometric criterion. No study reported evidence on construct validity and test-retest reliability. Evidence for acceptability for the use of SF-36, EQ-5D, and the disease-specific PROM was rated good in most studies. Only one study reported a Cronbach alpha score >0.70 as evidence of internal consistency. Overall, the psychometric evaluation of all included PROMs was rated as poor within the CAS population undergoing revascularization. CONCLUSIONS: This review highlighted a lack of evidence in validated PROMs used for patients undergoing carotid artery revascularization. As a result, the development and validation of a new PROM for this patient population is warranted to provide data which can supplement traditional clinical outcomes (stroke<30 days post-procedural, myocardial infarction, and death) and capture changes in health status and QoL to help inform treatment decisions.

GENE EXPRESSION PROFILING AND EXPANDED IMMUNOHISTOCHEMISTRY TESTS TO GUIDE SELECTION OF CHEMOTHERAPY REGIMENS IN BREAST CANCER MANAGEMENT: A SYSTEMATIC REVIEW.

OBJECTIVES: The aim of this report was to assess the clinical effectiveness of two Gene expression profiling (GEP) and two expanded immunohistochemistry (IHC) tests compared with current prognostic tools in guiding the use of adjuvant chemotherapy in patients with early breast cancer. METHODS: A systematic review of the evidence on clinical effectiveness of OncotypeDX, IHC4, MammaPrint, and Mammostrat, compared with current clinical practice using clinicopathological parameters, in women with early breast cancer was conducted. Ten databases were searched to include citations to May 2016. RESULTS: Searches identified 7,064 citations, of which forty-one citations satisfied the criteria for the review. A narrative synthesis was performed. Evidence for OncotypeDX demonstrated the impact of the test on decision making and there was some support for OncotypeDX predicting chemotherapy benefit. There were relatively lower levels of evidence for the other three tests included in the analysis. MammaPrint, Mammostrat, and IHC4 tests were limited to a small number of studies. Limitations in relation to study design were identified for all tests. CONCLUSIONS: The evidence base for OncotypeDX is considered to be the most robust. Methodological weaknesses relating to heterogeneity of patient cohorts and issues arising from the retrospective nature of the evidence were identified. Further evidence is required for all of the tests using prospective randomized controlled trial data.

The Relationship between Hospital or Surgeon Volume and Outcomes in Lower Limb Vascular Surgery in the United Kingdom and Europe.

BACKGROUND: Peripheral vascular disease is a major cause of death and disability. The extent to which volume influences outcome of lower limb (LL) vascular surgery remains unclear. This review evaluated the relationship between hospital/surgeon volume and outcome in LL surgery. METHODS: Electronic databases-MEDLINE, Embase, the Cochrane Library Databases, Science Citation Index, and CINAHL-proceedings from conferences, citations, and references of included studies were searched. Studies from Europe, of adults undergoing LL vascular surgery reporting outcomes by hospital or surgeon volume were included. The quality of studies was assessed using a modified Cochrane Risk Of Bias Assessment Tool: for Non-Randomized Studies of Interventions (Robins1) tool. The association between hospital/surgeon volume and outcome was summarized using tables. RESULTS: Nine studies from different European countries, comprising 67,445 patients who had undergone diverse LL surgeries were included. The increase in hospital/surgeon volume was associated with a decrease in post-operative amputations (hospital at 30 days [odds ratio {OR}: 0.20, 95% confidence interval {CI} 0.29-0.45, P = 0.01; OR: 0.67, 95% CI 0.44-0.9, P = 0.05; OR: 0.96, 95% CI 0.92-1.00, P = 0.06], at 1 year [OR: 0.96, 95% CI 0.93-0.98, P = 0.002; OR: 0.66, 95% CI 0.52-0.84, P < 0.001; OR: 2.05, 95% CI 1.24-3.42, P = 0.01], surgeon at 30 days [OR: 0.53, 95% CI 0.36-0.87, P = 0.01; OR: 0.40, 95% CI 0.18-0.91, P = 0.03; OR: 0.41, 95% CI 0.24-0.69, P = 0.0006]). The evidence on an association between hospital/surgeon volume and mortality was contradictory, but mortality and amputations may covary by hospital volume. There were an insufficient number of studies reporting on the other variables to draw firm conclusions, but their results suggest that high-volume hospitals may undertake more repeated surgeries/revascularizations and limb salvage. The impact of hospital/surgical volume on adverse events and length of hospitalization could not be determined. CONCLUSIONS: High-volume hospitals/surgeons may undertake fewer amputations and mortality and amputations may covary. The finding that hospital and surgeon volume affected the number of secondary amputations has implications on reorganization of vascular surgery services. However, due to the small number and poor quality of some of the included studies, decisions on reorganization of LL vascular surgery services should be supplemented by results from clinical audits. There is need for standardization of definition of volume stratification of outcomes by patient's clinical conditions.

Patient-reported outcome measures in patients with peripheral arterial disease: a systematic review of psychometric properties.

BACKGROUND: Peripheral arterial disease (PAD) is generally associated with considerable morbidity and reduced quality of life. Patient-reported outcome measures (PROMs) provide important information about the burden of disease and impact of treatment in affected patients. OBJECTIVES: The objective of the review was to identify and appraise studies reporting the psychometric evaluation of PROMs administered to a specified population of patients with PAD with a view to recommending suitable PROMs. METHODS: A systematic review of peer-reviewed English language articles was undertaken to identify primary studies reporting psychometric properties of PROMs in English-speaking patients with various stages of PAD. Comprehensive searches were completed up until January 2015. Study selection, data extraction and quality assessment were undertaken independently by at least two researchers. Findings were presented as tabular and narrative summaries based on accepted guidance. RESULTS: Psychometric evaluation of 6 generic and 7 condition-specific PROMs reported in 14 studies contributed data to the review. The frequently reported measure was the SF-36 (n = 11 studies); others included the Walking Impairment Questionnaire (n = 8 studies), EQ-5D (n = 5 studies) and the Vascular Quality of Life Questionnaire (n = 3 studies). Studies included a diverse PAD population and varied in methodology, including approach to validation of PROMs. CONCLUSIONS: Various PROMs have been validated in patients with PAD but no study provided evidence of a full psychometric evaluation in the patient population. Careful selection is required to identify reliable and valid PROMs to use in clinical and research settings.

Fractional exhaled nitric oxide for the management of asthma in adults: a systematic review.

The aim of this review was to evaluate the clinical effectiveness of fractional exhaled nitric oxide (FeNO) measured in a clinical setting for the management of asthma in adults.13 electronic databases were searched and studies were selected against predefined inclusion criteria. Quality assessment was conducted using QUADAS-2. Class effect meta-analyses were performed.Six studies were included. Despite high levels of heterogeneity in multiple study characteristics, exploratory class effect meta-analyses were conducted. Four studies reported a wider definition of exacerbation rates (major or severe exacerbation) with a pooled rate ratio of 0.80 (95% CI 0.63-1.02). Two studies reported rates of severe exacerbations (requiring oral corticosteroid use) with a pooled rate ratio of 0.89 (95% CI 0.43-1.72). Inhaled corticosteroid use was reported by four studies, with a pooled standardised mean difference of -0.24 (95% CI -0.56-0.07). No statistically significant differences for health-related quality of life or asthma control were found.FeNO guided management showed no statistically significant benefit in terms of severe exacerbations or inhaled corticosteroid use, but showed a statistically significant reduction in exacerbations of any severity. However, further research is warranted to clearly define which management protocols (including cut-off points) offer best efficacy and which patient groups would benefit the most.

A systematic review of fractional exhaled nitric oxide in the routine management of childhood asthma.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is a non-invasive biomarker of eosinophilic inflammation which may be used to guide the management of asthma in childhood. OBJECTIVES: To synthesise the available evidence on the efficacy of FeNO-guided management of childhood asthma. METHODS: Databases including MEDLINE and the Cochrane Library were searched, and randomised controlled trials (RCTs) comparing FeNO-guided management with any other monitoring strategy were included. Study quality was assessed using the Cochrane risk of bias tool for RCTs, and a number of outcomes were examined, including: exacerbations, medication use, quality of life, adverse events, and other markers of asthma control. Meta-analyses were planned if multiple studies with suitable heterogeneity were available. However, due to wide variations in study characteristics, meta-analysis was not possible. RESULTS: Seven RCTs were identified. There was some evidence that FeNO-guided monitoring results in improved asthma control during the first year of management, although few results attained statistical significance. The impact on severe exacerbations was unclear. Similarly, the impact on use of anti-asthmatic drugs was unclear, and appears to depend on the step up/down protocols, and the clinical characteristics of patients. CONCLUSIONS: The potential benefit of FeNO monitoring is equivocal. Trends toward reduced exacerbation and increased medication use were seen, but typically failed to reach statistical significance. There are a number of issues that complicate data interpretation, including differences in the likely severity of included cohorts and variations in treatment algorithms. Further work is needed to systematically explore the impact of these parameters.

Vedolizumab for the Treatment of Adults with Moderate-to-Severe Active Ulcerative Colitis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe active ulcerative colitis (UC). The Evidence Review Group (ERG) produced a critical review of the evidence for the clinical effectiveness and cost effectiveness of the technology, based upon the company's submission to NICE. The evidence was derived mainly from GEMINI 1, a Phase 3, multicentre, randomised, double-blinded, placebo-controlled study of the induction and maintenance of clinical response and remission by vedolizumab (MLN0002) in patients with moderate-to-severe active UC with an inadequate response to, loss of response to or intolerance of conventional therapy or anti-tumour necrosis factor (TNF)-α. The clinical evidence showed that vedolizumab performed significantly better than placebo in both the induction and maintenance phases. In the post hoc subgroup analyses in patients with or without prior anti-TNF-α therapy, vedolizumab performed better then placebo (p value not reported). In addition, a greater improvement in health-related quality of life was observed in patients treated with vedolizumab, and the frequency and types of adverse events were similar in the vedolizumab and placebo groups, but the evidence was limited to short-term follow-up. There were a number of limitations and uncertainties in the clinical evidence base, which warrants caution in its interpretation--in particular, the post hoc subgroup analyses and high dropout rates in the maintenance phase of GEMINI 1. The company also presented a network meta-analysis of vedolizumab versus other biologic therapies indicated for moderate-to-severe UC. However, the ERG considered that the results presented may have underestimated the uncertainty in treatment effects, since fixed-effects models were used, despite clear evidence of heterogeneity among the trials included in the network. Results from the company's economic evaluation (which included price reductions to reflect the proposed patient access scheme for vedolizumab) suggested that vedolizumab is the most effective option compared with surgery and conventional therapy in the following three populations: (1) a mixed intention-to-treat population, including patients who have previously received anti-TNF-α therapy and those who are anti-TNF-α naïve; (2) patients who are anti-TNF-α naïve only; and (3) patients who have previously failed anti-TNF-α therapy only. The ERG concluded that the results of the company's economic evaluation could not be considered robust, because of errors in model implementation, omission of relevant comparators, deviations from the NICE reference case and questionable model assumptions. The ERG amended the company's model and demonstrated that vedolizumab is expected to be dominated by surgery in all three populations.

Measurement of exhaled nitric oxide concentration in asthma: a systematic review and economic evaluation of NIOX MINO, NIOX VERO and NObreath.

BACKGROUND: High fractions of exhaled nitric oxide (FeNO) in the breath of patients with symptoms of asthma are correlated with high levels of eosinophils and indicate that a patient is likely to respond to inhaled corticosteroids. This may have a role in the diagnosis and management of asthma. OBJECTIVE: To assess the diagnostic accuracy, clinical effectiveness and cost-effectiveness of the hand-held electrochemical devices NIOX MINO(®) (Aerocrine, Solna, Sweden), NIOX VERO(®) (Aerocrine) and NObreath(®) (Bedfont Scientific, Maidstone, UK) for the diagnosis and management of asthma. DATA SOURCES: Systematic searches were carried out between March 2013 and April 2013 from database inception. Databases searched included MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, Science Citation Index Expanded and Conference Proceedings Citation Index - Science. Trial registers such as ClinicalTrials.gov and the metaRegister of Controlled Trials were also searched in March 2013. All searches were updated in September 2013. REVIEW METHODS: A rapid review was conducted to assess the equivalence of hand-held and chemiluminescent FeNO monitors. Systematic reviews of diagnostic accuracy and management efficacy were conducted. A systematic review of economic analyses was also conducted and two de novo health economic models were developed. All three reviews were undertaken according to robust high-quality methodology. RESULTS: The rapid review (27 studies) found varying levels of agreement between monitors (Bland-Altman 95% limits of agreement up to ±10 parts per billion), with better agreement at lower FeNO values. Correlation was good (generally r > 0.9). The diagnostic accuracy review identified 22 studies in adults (all ages) and four in children. No studies used NObreath or NIOX VERO and seven used NIOX MINO. Estimates of diagnostic accuracy varied widely. FeNO used in combination with another test altered diagnostic accuracy only slightly. High levels of heterogeneity precluded meta-analysis. Limited observations included that FeNO may be more reliable and useful as a rule-in than as a rule-out test; lower cut-off values in children and in smokers may be appropriate; and FeNO may be less reliable in the elderly. The management review identified five randomised controlled trials in adults, one in pregnant asthmatics and seven in children. Despite clinical heterogeneity, exacerbation rates were lower in all studies but not generally statistically significantly so. Effects on inhaled corticosteroid (ICS) use were inconsistent, possibly because of differences in management protocols, differential effectiveness in adults and children and differences in population severity. One UK diagnostic model and one management model were identified. Aerocrine also submitted diagnostic and management models. All had significant limitations including short time horizons and the selective use of efficacy evidence. The de novo diagnostic model suggested that the expected difference in quality-adjusted life-year (QALY) gains between diagnostic options is likely to be very small. Airway hyper-responsiveness by methacholine challenge test is expected to produce the greatest QALY gain but with an expected incremental cost-effectiveness ratio (ICER) compared with FeNO (NObreath) in combination with bronchodilator reversibility of £1.125M per QALY gained. All remaining options are expected to be dominated. The de novo management model indicates that the ICER of guidelines plus FeNO monitoring using NObreath compared with guidelines alone in children is expected to be approximately £45,200 per QALY gained. Within the adult subgroup, FeNO monitoring using NObreath compared with guidelines alone is expected to have an ICER of approximately £2100 per QALY gained. The results are particularly sensitive to assumptions regarding changes in ICS use over time, the number of nurse visits for FeNO monitoring and duration of effect. CONCLUSIONS: Limitations of the evidence base impose considerable uncertainty on all analyses. Equivalence of devices was assumed but not assured. Evidence for diagnosis is difficult to interpret in the context of inserting FeNO monitoring into a diagnostic pathway. Evidence for management is also inconclusive, but largely consistent with FeNO monitoring resulting in fewer exacerbations, with a small or zero reduction in ICS use in adults and a possible increased ICS use in children or patients with more severe asthma. It is unclear which specific management protocol is likely to be most effective. The economic analysis indicates that FeNO monitoring could have value in diagnostic and management settings. The diagnostic model indicates that FeNO monitoring plus bronchodilator reversibility dominates many other diagnostic tests. FeNO-guided management has the potential to be cost-effective, although this is largely dependent on the duration of effect. The conclusions drawn from both models require strong technical value judgements with respect to several aspects of the decision problem in which little or no empirical evidence exists. There are many potential directions for further work, including investigations into which management protocol is best and long-term follow-up in both diagnosis and management studies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013004149. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

ITERATIVE SIFTING IN THE SELECTION OF RESEARCH EVIDENCE: IMPLICATIONS FOR REVIEWS AND OTHER DECISION PROBLEMS.

OBJECTIVES: A rapid scoping review was performed to support the development of a new clinical technology platform. An iterative sifting approach was adopted to address the challenges posed by the nature of the review question and the extremely large volume of search results to be sifted within the timescales of the review. METHODS: This study describes the iterative sifting approach applied in the scoping review and a preliminary validation of the methods applied. RESULTS: The searches performed for the rapid scoping review retrieved 27,198 records. This was the full set of records subjected to the staged, iterative sifting approach and the subsequent validation process. The iterative sifting approach involved the screening for relevance of 17,354 (i.e., 63.8 percent) of the 27,198 records. A list of fifty-three potential biomarker names was generated as a result of this iterative sifting method, of which nineteen were selected by clinical specialists for further scrutiny. The preliminary validation involved the exhaustive sifting of the remaining 9,844 previously unsifted records. The validation process identified sixteen additional potential biomarker names not identified by the iterative sifting process. The clinical specialists subsequently concluded that none were of further clinical interest. CONCLUSIONS: This study describes an approach to the screening of search records that can be successfully applied in appropriate review and decision problems to allow the prioritization of the most relevant search records and achieve time savings. Following further refinement and standardization, this iterative sifting method may have potential for further applications in reviews and other decision problems.

Identification and review of cost-effectiveness model parameters: a qualitative study.

OBJECTIVES: Health economic models are developed as part of the health technology assessment process to determine whether health interventions represent good value for money. These models are often used to directly inform healthcare decision making and policy. The information needs for the model require the use of other types of information beyond clinical effectiveness evidence to populate the model's parameters. The purpose of this research study was to explore issues concerned with the identification and use of information for the development of such models. METHODS: Three focus groups were held in February 2011 at the University of Sheffield with thirteen UK HTA experts. Attendees included health economic modelers, information specialists and systematic reviewers. Qualitative framework analysis was used to analyze the focus group data. RESULTS: Six key themes, with related sub-themes, were identified dealing with decisions and judgments; searching methods; selection and rapid review of evidence; team communication; modeler experience and clinical input and reporting methods. There was considerable overlap between themes. CONCLUSIONS: Key issues raised by the respondents included the need for effective communication and teamwork throughout the model development process, the importance of using clinical experts as well as the need for transparent reporting of methods and decisions.