Risks of Hip and Nonvertebral Fractures in Patients With CKD G3a-G5D: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: Disordered mineral metabolism complicates chronic kidney disease (CKD), but the effect of reduced kidney function on fracture risk has not been fully established. We conducted a systematic review and meta-analysis of the risks for hip and nonvertebral fractures in people with CKD. We also investigated the effects of age, sex, and CKD stage. STUDY DESIGN: Systematic review and meta-analysis. STUDY POPULATION: Adults with CKD glomerular filtration rate (GFR) categories 3a-5D (G3a-G5D) compared with adults without CKD G3a-G5D. SELECTION CRITERIA FOR STUDIES: Observational studies. DATA EXTRACTION: Data extraction was conducted by 1 reviewer and checked by a second reviewer. ANALYTICAL APPROACH: MEDLINE, EMBASE, and Cochrane databases were searched in March 2018 and an update was conducted in November 2019. We used random-effects models to calculate pooled risk estimates and 95% CIs. RESULTS: 17 studies met the inclusion criteria. We included 13 studies in the hip fracture systematic review and 10 studies in the meta-analysis. Studies reported data from 250,440,035 participants; 5,798,566 with CKD G3a-G5D and 363,410 with hip fractures. 4 studies were included in the nonvertebral fracture analysis, reporting data from 1,396,976 participants; 464,978 with CKD G3a-G5D and 115,284 fractures. Studies reported data from participants aged 18 to older than 90 years. We found a significant increase in fracture risk both for hip (relative risk [RR], 2.36; 95% CI, 1.64-3.39) and nonvertebral fractures (RR, 1.47; 95% CI, 1.15-1.88). For hip fractures, younger patients (<65 years) had higher relative risk (RR, 7.66; 95% CI, 2.76-21.26) than older patients (>65 years; RR, 2.11; 95% CI, 1.41-3.16). Greater GFR loss was associated with higher relative risk for fractures. LIMITATIONS: We could not assess the effects of bone mineral density, biochemical abnormalities, renal osteodystrophy, frailty, falls, or medications on risk for fractures. CONCLUSIONS: Risks for hip and nonvertebral fractures are increased in CKD G3a-G5D. The relative risk of hip fracture is greater in the younger than the older population and increases progressively with loss of GFR. We suggest that fracture prevention should be a consideration in CKD at any age.

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.

Effectiveness and cost-effectiveness of an awareness campaign for colorectal cancer: a mathematical modeling study.

BACKGROUND: A campaign to increase the awareness of the signs and symptoms of colorectal cancer (CRC) and encourage self-presentation to a GP was piloted in two regions of England in 2011. Short-term data from the pilot evaluation on campaign cost and changes in GP attendances/referrals, CRC incidence, and CRC screening uptake were available. The objective was to estimate the effectiveness and cost-effectiveness of a CRC awareness campaign by using a mathematical model which extrapolates short-term outcomes to predict long-term impacts on cancer mortality, quality-adjusted life-years (QALYs), and costs. METHODS: A mathematical model representing England (aged 30+) for a lifetime horizon was developed. Long-term changes to cancer incidence, cancer stage distribution, cancer mortality, and QALYs were estimated. Costs were estimated incorporating costs associated with delivering the campaign, additional GP attendances, and changes in CRC treatment. RESULTS: Data from the pilot campaign suggested that the awareness campaign caused a 1-month 10 % increase in presentation rates. Based on this, the model predicted the campaign to cost £5.5 million, prevent 66 CRC deaths and gain 404 QALYs. The incremental cost-effectiveness ratio compared to "no campaign" was £13,496 per QALY. Results were sensitive to the magnitude and duration of the increase in presentation rates and to disease stage. CONCLUSIONS: The effectiveness and cost-effectiveness of a cancer awareness campaign can be estimated based on short-term data. Such predictions will aid policy makers in prioritizing between cancer control strategies. Future cost-effectiveness studies would benefit from campaign evaluations reporting as follows: data completeness, duration of impact, impact on emergency presentations, and comparison with non-intervention regions.

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.

Acute ischaemic stroke patients - direct admission to a specialist centre or initial treatment in a local hospital? A systematic review.

OBJECTIVES: To assess the clinical effectiveness, in acute ischaemic stroke patients, of bypassing non-specialist centres in preference for a specialist stroke centre to receive the time-critical intervention of thrombolysis. METHODS: Systematic review and meta-analysis using: MEDLINE; MEDLINE In-Process; EMBASE; CINAHL; Cochrane Library including Cochrane Database of Systematic Reviews, Cochrane CENTRAL Controlled Trials Register, DARE, NHS EED and HTA databases. Studies were included if they compared acute ischaemic stroke patients directly triaged to a specialist centre versus those initially triaged to a non-specialist centre with some or all later transferred to a specialist centre. Studies were excluded if they compared patients ever treated in a specialist centre versus those never treated in such a centre, since the aim was to assess the optimum initial triage route rather than the optimum location for overall management. The assumption being, based on previous research, that management in a specialist centre leads to better patient outcomes. RESULTS: Fourteen studies investigating 2790 patients were identified. Studies comparing commencement of thrombolysis in non-specialist centres versus the specialist centres (n=1394) showed no significant difference in unadjusted mortality (OR = 0.89; 95% CI = 0.61-1.30) or morbidity (favourable modified Rankin Score, n = 899) (OR = 1.16; 95% CI = 0.85-1.59) among thrombolysed patients. In studies where thrombolysis could only be administered in a specialist centre, data for patients arriving within the therapeutic window (n = 140) revealed significantly higher mortality for those initially admitted to a non-specialist centre compared to directly admitted to a specialist centre (OR = 6.62; 95% CI = 2.60-16.82); morbidity data also favoured direct admission to a specialist centre, although not consistently. CONCLUSIONS: For ischaemic stroke patients, the location of initial thrombolysis treatment does not affect outcomes. However, if thrombolysis is only available at a specialist centre, outcomes are considerably better for those patients admitted directly. However, these conclusions are based on poor quality data with small sample populations, significant heterogeneity and subject to confounding.

Building the Evidence Base of Blood-Based Biomarkers for Early Detection of Cancer: A Rapid Systematic Mapping Review.

BACKGROUND: The Early Cancer Detection Consortium is developing a blood-test to screen the general population for early identification of cancer, and has therefore conducted a systematic mapping review to identify blood-based biomarkers that could be used for early identification of cancer. METHODS: A mapping review with a systematic approach was performed to identify biomarkers and establish their state of development. Comprehensive searches of electronic databases Medline, Embase, CINAHL, the Cochrane library and Biosis were conducted in May 2014 to obtain relevant literature on blood-based biomarkers for cancer detection in humans. Screening of retrieved titles and abstracts was performed using an iterative sifting process known as "data mining". All blood based biomarkers, their relevant properties and characteristics, and their corresponding references were entered into an inclusive database for further scrutiny by the Consortium, and subsequent selection of biomarkers for rapid review. This systematic review is registered with PROSPERO (no. CRD42014010827). FINDINGS: The searches retrieved 19,724 records after duplicate removal. The data mining approach retrieved 3990 records (i.e. 20% of the original 19,724), which were considered for inclusion. A list of 814 potential blood-based biomarkers was generated from included studies. Clinical experts scrutinised the list to identify miss-classified and duplicate markers, also volunteering the names of biomarkers that may have been missed: no new markers were identified as a result. This resulted in a final list of 788 biomarkers. INTERPRETATION: This study is the first to systematically and comprehensively map blood biomarkers for early detection of cancer. Use of this rapid systematic mapping approach found a broad range of relevant biomarkers allowing an evidence-based approach to identification of promising biomarkers for development of a blood-based cancer screening test in the general population.

Impact of prehospital transfer strategies in major trauma and head injury: systematic review, meta-analysis, and recommendations for study design.

BACKGROUND: It is unclear whether trauma patients should be transferred initially to a trauma center or local hospital. METHODS: A systematic review and meta-analysis assessed the evidence for direct transport to specialist centers (SCs) versus initial stabilization at non-SCs (NSCs) for major trauma or moderate-to-severe head injury. Nine databases were searched from 1988 to 2012. Limitations in the study design informed recommendations for future studies. RESULTS: Of 19 major trauma studies, five (n = 19,910) included patients not transferred to SCs and adjusted for case mix. Meta-analysis showed no difference in mortality for initial triage to NSCs versus SCs (odds ratio [OR] 1.03; 95% confidence interval [CI], 0.85-1.23). Within studies excluding patients not transferred to SCs, unadjusted analyses of mortality nonsignificantly favored transfer via NSCs (16 studies; n = 37,079; OR, 0.83; 95% CI, 0.68-1.01), whereas adjusted analysis nonsignificantly favored direct triage to SCs (9 studies; n = 34,266; OR, 1.18; 95% CI, 0.96-1.44). Of 11 head injury studies, all excluded patients not transferred to SCs and half were in remote locations. There was no significant mortality difference between initial triage to NSCs versus SCs within adjusted analyses (3 studies; n = 1,507; OR, 0.74; 95% CI, 0.31-1.79) or unadjusted analyses (10 studies; n = 3,671; OR, 0.87; 95% CI, 0.62-1.23). CONCLUSION: This systematic review demonstrated no difference in outcomes for direct transport to a trauma center versus initial triage to a local hospital. Many studies had significant limitations in the design, and heterogeneity was high. Recommendations for future studies include the following: (i) inclusion of patients not transferred to SCs and those dying during transport; (ii) clear description of centers plus transport distances/times; (iii) adjustments for case mix; and (iv) assessment of morbidity and mortality. LEVEL OF EVIDENCE: Systematic review, level IV.

Diagnostic accuracy of clinical characteristics for identifying CT abnormality after minor brain injury: a systematic review and meta-analysis.

Clinical features can be used to identify which patients with minor brain injury need CT scanning. A systematic review and meta-analysis was undertaken to estimate the value of these characteristics for diagnosing intracranial injury (including the need for neurosurgery) in adults, children, and infants. Potentially relevant studies were identified through electronic searches of several key databases, including MEDLINE, from inception to March 2010. Cohort studies of patients with minor brain injury (Glasgow Coma Score [GCS], 13-15) were selected if they reported data on the diagnostic accuracy of individual clinical characteristics for intracranial or neurosurgical injury. Where applicable, meta-analysis was used to estimate pooled sensitivity, specificity and likelihood ratios. Data were extracted from 71 studies (with cohort sizes ranging from 39 to 31,694 patients). Depressed or basal skull fracture were the most useful clinical characteristics for the prediction of intracranial injury in both adults and children (positive likelihood ratio [PLR], >10). Other useful characteristics included focal neurological deficit, post-traumatic seizure (PLR >5), persistent vomiting, and coagulopathy (PLR 2 to 5). Characteristics that had limited diagnostic value included loss of consciousness and headache in adults and scalp hematoma and scalp laceration in children. Limited studies were undertaken in children and only a few studies reported data for neurosurgical injuries. In conclusion, this review identifies clinical characteristics that indicate increased risk of intracranial injury and the need for CT scanning. Other characteristics, such as headache in adults and scalp laceration of hematoma in children, do not reliably indicate increased risk.

Clinical decision rules for children with minor head injury: a systematic review.

INTRODUCTION: Clinical decision rules aid clinicians with the management of head injured patients. This study aimed to identify clinical decision rules for children with minor head injury and compare their diagnostic accuracy for detection of intracranial injury (ICI) and injury requiring neurosurgical intervention (NSI). METHODS: Relevant studies were identified by an electronic search of key databases. Papers in English were included with a cohort of at least 20 children suffering minor head injury (GCS 13-15). Studies of a decision rule derived to identify patients at risk of ICI or NSI had to include a proportion of the cohort undergoing imaging. Study quality was assessed using the QUADAS checklist. RESULTS: 16 publications, representing 14 cohorts, with 79 740 patients were included. Only four rules were tested in more than one cohort. Of the validated rules the paediatric emergency care applied research network (PECARN) rule was most consistent (sensitivity 98%; specificity 58%). For neurosurgical injury all had high sensitivity (98-100%) but the children's head injury algorithm for the prediction of important clinical events (CHALICE) rule had the highest specificity (86%) in its derivation cohort. CONCLUSION: Of the current decision rules for minor head injury the PECARN rule appears the best for children and infants, with the largest cohort, highest sensitivity and acceptable specificity for clinically significant ICI. Application of this rule in the UK would probably result in an unacceptably high rate of CT scans per injury, and continued use of the CHALICE-based NICE guidelines represents an appropriate alternative.