Pruning and prioritising: a case study of a pragmatic method for managing a rapid systematic review with limited resources

Full systematic reviews are time and resource heavy. We describe a method successfully used to produce a rapid review of yoga for health and wellbeing, with limited resources, using mapping methods. Inclusion and exclusion criteria were developed a priori and refined post hoc, with the review team blind to the study results to minimise the introduction of bias. This method allowed the review to be tailored to make use of the best available evidence and the health topics of most relevance to the commissioners, and to enable the evidence base to be disseminated to practitioners in a timely fashion

Systematic review of time lag between antibiotic use and rise of resistant pathogens among hospitalized adults in Europe

Background: Antimicrobial resistance (AMR) causes substantial health and economic burden to individuals, healthcare systems and societies globally. Understanding the temporal relationship between antibiotic consumption and antibiotic resistance in hospitalized patients can better inform antibiotic stewardship activities and the time frame for their evaluation. Objectives: This systematic review examined the temporal relationship between antibiotic use and development of antibiotic resistance for 42 pre-defined antibiotic and pathogen combinations in hospitalized adults in Europe. Methods: Searches in MEDLINE, Embase, Cochrane Library and NIHR Centre for Reviews and Dissemination were undertaken from 2000 to August 2021. Pathogens of interest were Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus faecium, CoNS, Pseudomonas aeruginosa and Acinetobacter baumannii complex. Results: Twenty-eight ecological studies and one individual-level study were included. Ecological studies were predominantly retrospective in design (19 studies) and of reasonable (20 studies) to high (8 studies) methodological quality. Of the eight pathogens of interest, no relevant data were identified for S. pneumoniae and CoNS. Across all pathogens, the time-lag data from the 28 ecological studies showed a similar pattern, with the majority of studies reporting lags ranging from 0 to 6 months. Conclusions: Development of antibiotic resistance for the investigated antibiotic/pathogen combinations tends to occur over 0 to 6 months following exposure within European hospitals. This information could inform planning of antibiotic stewardship activities in hospital settings

The relationship between chronic kidney disease–associated pruritus and health-related quality of life: a systematic review

Background Chronic kidney disease–associated pruritus (CKD-aP) is a common and burdensome condition for end-stage kidney disease (ESKD) patients, especially those receiving haemodialysis. High-quality evidence of the relationship between CKD-aP and health-related quality of life (HRQoL) can therefore inform clinicians and policymakers about treatment choice and reimbursement decisions. Methods A systematic literature review and narrative synthesis stratified by study design and HRQoL instrument was conducted to evaluate in adult ESKD patients receiving in-centre haemodialysis the relationship between CKD-aP and HRQoL assessed using multi dimensional generic or condition-specific preference- or non-preference-based measures. MEDLINE, Embase, Web of Science, BIOSIS Citation Index, Cochrane Library and PsycINFO from inception to March 2020 were searched, with two reviewers extracting data independently. Results Searches identified 2684 unique records, of which 20 papers relating to 18 unique studies [5 randomised controlled trials (RCTs) and 13 observational studies] were included. HRQoL was assessed using four generic and eight disease-specific measures. The impact of CKD-aP was assessed by comparison of means, linear regression and correlation. Observational studies employing comprehensively adjusted multivariable linear regression largely found associations between CKD-aP severities and HRQoL. Analyses suggest this relationship is partially mediated by the sleep disturbance caused by CKD-aP. RCTs showing improvements in CKD-aP severity were associated with clinically meaningful improvements in HRQoL. Compared with generic measures, disease-specific HRQoL instruments reported greater changes with reduced CKD-aP. Heterogeneity in study design and reporting precluded meta-analysis. Conclusions CKD-aP severity was found to be associated with a worsening of HRQoL in the majority of observational and RCT studies. Parallel improvements in CKD-aP and HRQoL with interventions may support their use (PROSPERO registration 175035)

The risk of hip and non-vertebral fractures in type 1 and type 2 diabetes: A systematic review and meta-analysis update

Background Diabetes is associated with increased fracture risk but we do not know what affects this risk. We investigated the risk of hip and non-vertebral fractures in diabetes and whether this risk was affected by age, gender, body mass index, diabetes type and duration, insulin use and diabetic complications. Methods We selected a previously published review to be updated. MEDLINE, Embase and Cochrane databases were searched up to March 2020. We included observational studies with age and gender-adjusted risk of fractures in adults with diabetes compared to adults without diabetes. We extracted data from published reports that we summarised using random effects model. Findings From the 3140 records identified, 49 were included, 42 in the hip fracture analysis, reporting data from 17,571,738 participants with 319,652 fractures and 17 in the non-vertebral fracture review, reporting data from 2,978,487 participants with 181,228 fractures. We found an increase in the risk of fracture in diabetes both for hip (RR 4.93, 3.06–7.95, in type 1 diabetes and RR1.33, 1.19–1.49, in type 2 diabetes) and for non-vertebral fractures (RR 1.92, 0.92–3.99, in type 1 and RR 1.19, 1,11–1.28 in type 2). At the hip, the risk was higher in the younger population in both type 1 and type 2 diabetes. In those with type 2 diabetes, longer diabetes duration and insulin use was associated with an increased risk. We did not investigate the effect of bone density, falls, anti-diabetic drugs and hypoglycemia. Conclusion Diabetes is associated with an increase in both hip and non-vertebral fracture risk

The risk of hip and non-vertebral fractures in patients with Parkinson's disease and parkinsonism : a systematic review and meta-analysis

Parkinson's disease (PD) is a neurodegenerative disorder that is common in older individuals. PD patients have an increased risk of fractures compared to the general population, perhaps due to multiple falls. However, the fracture risk has not been fully assessed. To assess the impact of PD on the risk of hip and non-vertebral fractures, we conducted a systematic review and meta-analysis. Comprehensive searches of three key bibliographic databases were conducted to identify reviews and primary studies relating to the risk of fractures in patients with PD. Search terms included all relevant terms for Parkinson's disease and for fractures. We selected observational studies with data on the risk of fractures in adults with PD compared to controls without the diagnosis. Study quality was assessed using the Newcastle Ottawa Scale. The random-effects model was used to pool the results. Eighteen studies were included in the review. Seventeen independent studies (14 cohort and 3 case-control studies) were included in the hip fracture analysis. Nine studies (all cohorts, no case-control studies) were included in the non-vertebral fracture analysis. Study quality was judged to be moderate to good. Overall, PD patients had an increased risk for both hip fractures (2.40, 95% CI 2.04 to 2.82) and non-vertebral fractures (1.80, 95% CI 1.60 to 2.01) compared to controls. The relative risk for hip fractures was higher in men (2.93, 95% CI 2.05 to 4.18) than in women (1.81, 95% CI 1.61 to 2.04). There were no effects of the study design, geographical region, or criteria for diagnosing Parkinson's disease on these estimates of fracture risk. There is an increase in the risk of hip and non-vertebral fractures in patients with Parkinson's disease and we recommend a re-evaluation of the clinical guidelines on bone health in patients with PD to address this

Magnetic resonance for assessment of axillary lymph node status in early breast cancer: A systematic review and meta-analysis

Introduction Current methods of identifying axillary node metastases in breast cancer patients are highly accurate, but are associated with several adverse events. This review evaluates the diagnostic accuracy of magnetic resonance imaging (MRI) techniques for identification of axillary metastases in early stage newly diagnosed breast cancer patients. Methods Comprehensive searches were conducted in April 2009. Study quality was assessed. Sensitivity and specificity were meta-analysed using a bivariate random effects approach, utilising pathological diagnosis via node biopsy as the comparative gold standard. Results Based on the highest sensitivity and specificity reported in each of the nine studies evaluating MRI (n = 307 patients), mean sensitivity was 90% (95% CI: 78–96%; range 65–100%) and mean specificity 90% (95% CI: 75–96%; range 54–100%). Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), mean sensitivity was 98% (95% CI: 61–100%) and mean specificity 96% (95% CI: 72–100%). Across three studies of gadolinium-enhanced MRI (n = 187), mean sensitivity was 88% (95% CI: 78–94%) and mean specificity 73% (95% CI: 63–81%). In the single study of in-vivo proton MR spectroscopy (n = 27), sensitivity was 65% (95% CI: 38–86%) and specificity 100% (95% CI: 69–100%). Conclusions USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity and may make a useful addition to the current diagnostic pathway. Additional larger studies with standardised methods and standardised criteria for classifying a node as positive are needed. Current estimates of sensitivity and specificity do not support replacement of SLNB with any current MRI technology in this patient group

The evidence base for circulating tumour DNA blood-based biomarkers for the early detection of cancer: a systematic mapping review

Background: The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types. Methods: The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded. Results: The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods). Conclusion: We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection

Mepolizumab for Treating Severe Eosinophilic Asthma: 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 company (GlaxoSmithKline) that manufactures mepolizumab (Nucala(®)) to submit evidence on the clinical and cost effectiveness of mepolizumab for the treatment of severe eosinophilic asthma. The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). The ERG produced a review of the evidence for the clinical and cost effectiveness of mepolizumab as add-on to standard of care (SoC) compared with SoC and omalizumab, based upon the company's submission to NICE. The clinical-effectiveness evidence in the company's submission was based predominantly on three randomised controlled trials (DREAM, MENSA and SIRIUS) comparing add-on mepolizumab with placebo plus SoC. The relevant population was defined in terms of degree of asthma severity (four or more exacerbations in the previous year and/or dependency on maintenance oral corticosteroids [mOCS]) and degree of eosinophilia (a blood eosinophil count of ≥ 300 cells/µl in the previous year) based on post hoc subgroup analyses of the pivotal trials. Other subpopulations were considered throughout the appraisal, defined by different eosinophil measurements, number of exacerbations and dependency (or lack thereof) on mOCS. Statistically significant reductions in clinically significant exacerbations were observed in patients receiving mepolizumab compared with SoC meta-analysed across MENSA and DREAM in the modified intention-to-treat (ITT) population (rate ratio [RR] 0.51; 95% confidence interval [CI] 0.42-0.62) as well as in the relevant population (RR 0.47; 95% CI 0.36-0.62). In terms of quality of life, differences on the St. George's Respiratory Questionnaire in MENSA for add-on subcutaneous mepolizumab 100 mg vs. placebo were 7 and 7.5 units in the modified ITT and relevant populations, respectively. A number of issues in the clinical evidence base warrant caution in its interpretation. The ERG noted that the definition of SoC used in the trials differed from that in clinical practice, where patients with severe uncontrolled asthma start treatment with a mOCS. The company's economic post-consultation analysis incorporating a confidential patient access scheme (PAS) estimated that the incremental cost-effectiveness ratio (ICER) for add-on mepolizumab compared with SoC was £27,418 per quality-adjusted life-year (QALY) gained in the relevant population if patients stopped mepolizumab after 1 year unless (1) the number of exacerbations decreased at least 50% or (2) a reduction in corticosteroids dose was achieved whilst maintaining asthma control. The ERG applied an age adjustment to all utilities and corrected the post-continuation assessment utilities, which resulted in an ICER for add-on mepolizumab compared with SoC of £29,163 per QALY gained. The ERG noted that this ICER was not robust for patients who continued treatment due to a corticosteroid dose reduction where exacerbations had decreased by less than 50%, because corticosteroid dose reduction was not allowed in the main trial in which the evidence was gathered (MENSA). The NICE appraisal committee (AC) concluded that add-on mepolizumab could be recommended as an option for treating severe refractory eosinophilic asthma in adults for the relevant population when the stopping rule suggested by the company was applied. The AC also concluded that the comparison between mepolizumab and omalizumab was not clinically relevant or methodologically robust