Complication rate among people with diabetes at low risk of foot ulceration in Fife, UK: an analysis of routinely collected data.

AIMS: To estimate the rate at which people with diabetes and a low risk of foot ulceration change diabetic foot ulceration risk status over time, and to estimate the rate of ulceration, amputation and death among this population. METHODS: We conducted an observational study of 10 421 people with diabetes attending foot screening in an outpatient setting in NHS Fife, UK, using routinely collected data from a national diabetes register, NHS SCI Diabetes. We estimated the proportion of people who changed risk status and the cumulative incidence of ulceration, amputation and death, respectively, among people with diabetes at low risk of diabetic foot ulceration at 2-year follow-up. RESULTS: At 2-year follow-up, 5.1% (95% CI 4.7, 5.6) of people with diabetes classified as low risk at their first visit had progressed to moderate risk. The cumulative incidence of ulceration, amputation and death was 0.4% (95% CI 0.3, 0.6), 0.1% (95% CI 0.1, 0.2) and 3.4% (95% CI 3.1, 3.8), respectively. CONCLUSIONS: At 2-year follow-up, 5% of people at low risk of diabetic foot ulceration changed clinical risk status and <1% of people experienced foot ulceration or amputation. These findings provide information which will help to inform the current debate regarding optimal foot screening intervals.

The development and validation of a multivariable prognostic model to predict foot ulceration in diabetes using a systematic review and individual patient data meta-analyses.

AIMS: Diabetes guidelines recommend screening for the risk of foot ulceration but vary substantially in the underlying evidence base. Our purpose was to derive and validate a prognostic model of independent risk factors for foot ulceration in diabetes using all available individual patient data from cohort studies conducted worldwide. METHODS: We conducted a systematic review and meta-analysis of individual patient data from 10 cohort studies of risk factors in the prediction of foot ulceration in diabetes. Predictors were selected for plausibility, availability and low heterogeneity. Logistic regression produced adjusted odds ratios (ORs) for foot ulceration by ulceration history, monofilament insensitivity, any absent pedal pulse, age, sex and diabetes duration. RESULTS: The 10 studies contained data from 16 385 participants. A history of foot ulceration produced the largest OR [6.59 (95% CI 2.49 to 17.45)], insensitivity to a 10 g monofilament [3.18 (95% CI 2.65 to 3.82)] and any absent pedal pulse [1.97 (95% CI 1.62 to 2.39)] were consistently, independently predictive. Combining three predictors produced sensitivities between 90.0% (95% CI 69.9% to 97.2%) and 95.3% (95% CI 84.5% to 98.7%); the corresponding specificities were between 12.1% (95% CI 8.2% to 17.3%) and 63.9% (95% CI 61.1% to 66.6%). CONCLUSIONS: This prognostic model of only three risk factors, a history of foot ulceration, an inability to feel a 10 g monofilament and the absence of any pedal pulse, compares favourably with more complex approaches to foot risk assessment recommended in clinical diabetes guidelines.

The value of FDG positron emission tomography/computerised tomography (PET/CT) in pre-operative staging of colorectal cancer: a systematic review and economic evaluation.

OBJECTIVES: In the UK, colorectal cancer (CRC) is the third most common malignancy (behind lung and breast cancer) with 37,514 cases registered in 2006: around two-thirds (23,384) in the colon and one-third (14,130) in the rectum. Treatment of cancers of the colon can vary considerably, but surgical resection is the mainstay of treatment for curative intent. Following surgical resection, there is a comprehensive assessment of the tumour, it's invasion characteristics and spread (tumour staging). A number of imaging modalities are used in the pre-operative staging of CRCs including; computerised tomography (CT), magnetic resonance imaging, ultrasound imaging and positron emission tomography (PET). This report examines the role of CT in combination with PET scanning (PET/CT 'hybrid' scan). The research objectives are: to evaluate the diagnostic accuracy and therapeutic impact of fluorine-18-deoxyglucose (FDG) PET/CT for the pre-operative staging of primary, recurrent and metastatic cancer using systematic review methods; undertake probabilistic decision-analytic modelling (using Monte Carlo simulation); and conduct a value of information analysis to help inform whether or not there is potential worth in undertaking further research. DATA SOURCES: For each aspect of the research - the systematic review, the handsearch study and the economic evaluation - a database was assembled from a comprehensive search for published and unpublished studies, which included database searches, reference lists search and contact with experts. In the systematic review prospective and retrospective patient series (diagnostic cohort) and randomised controlled trials (RCTs) were eligible for inclusion. Both consecutive series and series that are not explicitly reported as consecutive were included. REVIEW METHODS: Two reviewers extracted all data and applied the criteria independently and resolved disagreements by discussion. Data to populate 2 × 2 contingency tables consisting of the number of true positives, true negatives, false positives and false negatives using the studies' own definitions were extracted, as were data relating to changes in management. Fourteen items from the Quality Assessment of Diagnostic Accuracy Studies checklist were used to assess the methodological quality of the included studies. Patient-level data were used to calculate sensitivity and specificity with confidence intervals (CIs). Data were plotted graphically in forest plots. For the economic evaluation, economic models were designed for each of the disease states: primary, recurrent and metastatic. These were developed and populated based on a variety of information sources (in particular from published data sources) and literature, and in consultation with clinical experts. RESULTS: The review found 30 studies that met the eligibility criteria. Only two small studies evaluated the use of FDG PET/CT in primary CRC, and there is insufficient evidence to support its routine use at this time. The use of FDG PET/CT for the detection of recurrent disease identified data from five retrospective studies from which a pooled sensitivity of 91% (95% CI 0.87% to 0.95%) and specificity of 91% (95% CI 0.85% to 0.95%) were observed. Pooled accuracy data from patients undergoing staging for suspected metastatic disease showed FDG PET/CT to have a pooled sensitivity of 91% (95% CI 87% to 94%) and a specificity of 76% (95% CI 58% to 88%), but the poor quality of the studies means the validity of the data may be compromised by several biases. The separate handsearch study did not yield any additional unique studies relevant to FDG PET/CT. Models for recurrent disease demonstrated an incremental cost-effectiveness ratio of £ 21,409 per quality-adjusted life-year (QALY) for rectal cancer, £ 6189 per QALY for colon cancer and £ 21,434 per QALY for metastatic disease. The value of handsearching to identify studies of less clearly defined or reported diagnostic tests is still to be investigated. CONCLUSIONS: The systematic review found insufficient evidence to support the routine use of FDG PET/CT in primary CRC and only a small amount of evidence supporting its use in the pre-operative staging of recurrent and metastatic CRC, and, although FDG PET/CT was shown to change patient management, the data are divergent and the quality of research is generally poor. The handsearch to identify studies of less clearly defined or reported diagnostic tests did not find additional studies. The primary limitations in the economic evaluations were due to uncertainty and lack of available evidence from the systematic reviews for key parameters in each of the five models. In order to address this, a conservative approach was adopted in choosing DTA estimates for the model parameters. Probabilistic analyses were undertaken for each of the models, incorporating wide levels of uncertainty particularly for the DTA estimates. None of the economic models reported cost-savings, but the approach adopted was conservative in order to determine more reliable results given the lack of current information. The economic evaluations conclude that FDG PET/CT as an add-on imaging device is cost-effective in the pre-operative staging of recurrent colon, recurrent rectal and metastatic disease but not in primary colon or rectal cancers. There would be value in undertaking an RCT with a concurrent economic evaluation to evaluate the therapeutic impact and cost-effectiveness of FDG PET/CT compared with conventional imaging (without PET) for the pre-operative staging of recurrent and metastatic CRC.

Brain choline concentration. Early quantitative marker of ischemia and infarct expansion?

OBJECTIVE: Better prediction of tissue prognosis in acute stroke might improve treatment decisions. We hypothesized that there are metabolic ischemic disturbances measurable noninvasively by proton magnetic resonance spectroscopy ((1)H MRS) that occur earlier than any structural changes visible on diffusion-tensor imaging (DTI), which may therefore serve for territorial identification of tissue at risk. METHODS: We performed multivoxel (1)H MRS plus DTI within a maximum of 26 hours, and DTI at 3-7 days, after ischemic stroke. We compared choline, lactate, N-acetylaspartate, and creatine concentrations in normal-appearing voxels that became infarcted (infarct expansion) with normal-appearing voxels around the infarct that remained "healthy" (nonexpansion) on follow-up DTI. Each infarct expansion voxel was additionally classified as either complete infarct expansion (infarcted tissue on follow-up DTI covered > or =50% of the voxel) or partial infarct expansion (<50% of voxel). RESULTS: In 31 patients (NIH Stroke Scale score 0-28), there were 108 infarct nonexpansion voxels and 113 infarct expansion voxels (of which 80 were complete expansion and 33 partial expansion voxels). Brain choline concentration increased for each change in expansion category from nonexpansion, via partial expansion to complete expansion (2,423, 3,843, 4,158 IU; p < 0.05). Changes in lactate, N-acetylaspartate, and creatine concentrations in expansion category were insignificant although for lactate there was a tendency to such association. CONCLUSIONS: Choline concentration measurable with (1)H MRS was elevated in peri-ischemic normal-appearing brain that became infarcted by 3-7 days. The degree of elevation was associated with the amount of infarct expansion. (1)H MRS might identify DTI-normal-appearing tissue at risk of conversion to infarction in early stroke.

When are summary ROC curves appropriate for diagnostic meta-analyses?

Diagnostic tests are increasingly evaluated with systematic reviews and this has lead to the recent developments of statistical methods to analyse such data. The most commonly used method is the summary receiver operating characteristic (SROC) curve, which can be fitted with a non-linear bivariate random-effects model. This paper focuses on the practical problems of interpreting and presenting data from such analyses. First, many meta-analyses may be underpowered to obtain reliable estimates of the SROC parameters. Second, the SROC model may be inappropriate. In these situations, a summary with two univariate meta-analyses of the true and false positive rates (TPRs and FPRs) may be more appropriate. We characterize the type of problems that can occur in fitting these models and present an algorithm to guide the analyst of such studies, with illustrations from analyses of published data. A set of R functions, freely available to perform these analyses, can be downloaded from (www.diagmeta.info).

Development and initial testing of normal reference MR images for the brain at ages 65-70 and 75-80 years.

Interpretation of brain images from older patients requires knowledge of changes that occur with healthy ageing. We constructed and tested a reference template for older subjects. We used MR images from normal subjects aged 65-70 and 75-80 to generate average age-specific images. We ranked the T2-weighted images by worsening brain tissue loss to create a diagram of key centiles. Two neuroradiologists tested the template during routine reporting; eight radiologists read 99 MR examinations without and then with the template. Fifty-four subjects (65-70 years) and 25 subjects (75-80 years) formed the reference images. For the two neuroradiologists, the reference template reduced the abnormal scan reporting from 28/42 without to 3/42 with the template. Of 99 MR examinations assessed by eight radiologists, 39/58 scans (67%) reported as moderate or severe atrophy without the template were reported as normal with the template (p = 0.00011). Reference templates of the brain at older ages can "calibrate" radiology reporting. They could also be useful for research into ageing and related conditions. Larger numbers of examinations from more diverse populations and at different ages are required to increase the versatility of these templates.

Changes in NAA and lactate following ischemic stroke: a serial MR spectroscopic imaging study.

OBJECTIVE: Although much tissue damage may occur within the first few hours of ischemic stroke, the duration of tissue injury is not well defined. We assessed the temporal pattern of neuronal loss and ischemia after ischemic stroke using magnetic resonance spectroscopic imaging (MRSI) and diffusion-weighted imaging (DWI). METHODS: We measured N-acetylaspartate (NAA) and lactate in 51 patients with acute ischemic stroke at five time points, from admission to 3 months, in voxels classified as normal, possibly or definitely abnormal (ischemic) according to the appearance of the stroke lesion on the admission DWI. We compared changes in NAA and lactate in different voxel classes using linear mixed models. RESULTS: NAA was significantly reduced from admission in definitely and possibly abnormal (p < 0.01) compared to contralateral normal voxels, reaching a nadir by 2 weeks and remaining reduced at 3 months. Lactate was significantly increased in definitely and possibly abnormal voxels (p < 0.01) during the first 5 days, falling to normal at 2 weeks, rising again later in these voxels. CONCLUSION: The progressive fall in N-acetylaspartate suggests that some additional neuronal death may continue beyond the first few hours for up to 2 weeks or longer. The mechanism is unclear but, if correct, then it is possible that interventions to limit this ongoing subacute tissue damage might add to the benefit of hyperacute treatment, making further improvements in outcome possible.

Accurate, practical and cost-effective assessment of carotid stenosis in the UK.

OBJECTIVES: To determine whether less invasive imaging tests [ultrasound (US), magnetic resonance angiography (MRA), computed tomographic angiography (CTA) and contrast-enhanced MRA (CEMRA)], alone or combined, could replace intra-arterial angiography (IAA), what effect this would have on strokes and deaths, endarterectomies performed and costs, and whether less invasive tests were cost-effective. DATA SOURCES: Electronic databases covering the years 1980-2003 inclusive, updated to April 2004. Key journals from 1990 to the end of 2002. REVIEW METHODS: The authors constituted a panel of experts in stroke, imaging, vascular surgery, statistics and health economic modelling. The accuracy of less invasive carotid imaging was systematically reviewed using Standards for Reporting of Diagnostic Accuracy (STARD) methodology, supplemented by individual patient data from UK primary research and audit studies. A systematic review of the costs of less invasive tests, outpatient clinics, endarterectomy and stroke was performed, along with a microcosting exercise. A model of the process of care following a transient ischaemic attack (TIA)/minor stroke was developed, populated with data from stroke epidemiology studies in the UK, effects of medical and surgical interventions, outcomes, quality of life and costs. A survey of UK stroke prevention clinics provided typical timings. Twenty-two different carotid imaging strategies were evaluated for short- and long-term outcomes, quality-adjusted life-years (QALYs) and net benefit. RESULTS: In 41 included studies (2404 patients, median age 60-65 years), most data were available on 70-99% stenosis. CEMRA was the most accurate [sensitivity 0.94, 95% confidence interval (CI) 0.88 to 0.97; specificity 0.93, 95% CI 0.89 to 0.96], compared with US, MRA and CTA, which were all similar (e.g. for US: sensitivity 0.89, 95% CI 0.85 to 0.92; specificity 0.84, 95% CI 0.77 to 0.89). Data for 50-69% stenoses and on combinations of tests were too sparse to be reliable. There was heterogeneity between studies for all imaging modalities except for CTA. The individual patient data (2416 patients) showed that the literature overestimated test accuracy in routine practice and that, in general, tests perform with higher sensitivity and specificity in asymptomatic than in symptomatic arteries. In the cost-effectiveness model, on current UK timings, strategies allowed more patients to reach endarterectomy very quickly, and where those with 50-69% stenosis would be offered surgery in addition to those with 70-99%, prevented most strokes and produced greatest net benefit. This included most strategies with US as first or repeat test, and not those with IAA. However, the model was sensitive to less invasive test accuracy, cost and timing of endarterectomy. In patients investigated late after TIA, test accuracy is crucial and CEMRA should be used before surgery. CONCLUSIONS: In the UK, less invasive tests can be used in place of IAA if radiologists trained in carotid imaging are available. Imaging should be carefully audited. Stroke prevention clinics should reduce waiting times at all stages to improve speed of access to endarterectomy. In patients presenting late after TIA, test accuracy is very important and US results should be confirmed by CEMRA, as patients with 50-69% stenosis are less likely to benefit. More data are required to define the accuracy of the less invasive tests, with improvements made in the data collection methods used and how data are presented. Consideration should also be given to the use of new technologies and randomised trials.

Non-invasive imaging compared with intra-arterial angiography in the diagnosis of symptomatic carotid stenosis: a meta-analysis.

BACKGROUND: Accurate carotid imaging is important for effective secondary stroke prevention. Non-invasive imaging, now widely available, is replacing intra-arterial angiography for carotid stenosis, but the accuracy remains uncertain despite an extensive literature. We systematically reviewed the accuracy of non-invasive imaging compared with intra-arterial angiography for diagnosing carotid stenosis in patients with carotid territory ischaemic symptoms. METHODS: We searched for articles published between 1980 and April 2004; included studies comparing non-invasive imaging with intra-arterial angiography that met Standards for Reporting of Diagnostic Accuracy (STARD) criteria; extracted data to calculate sensitivity and specificity of non-invasive imaging, to test for heterogeneity and to perform sensitivity analyses; and categorised percent stenosis by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method. RESULTS: In 41 included studies (2541 patients, 4876 arteries), contrast-enhanced MR angiography was more sensitive (0.94, 95% CI 0.88-0.97) and specific (0.93, 95% CI 0.89-0.96) for 70-99% stenosis than Doppler ultrasound, MR angiography, and CT angiography (sensitivities 0.89, 0.88, 0.76; specificities 0.84, 0.84, 0.94, respectively). Data for 50-69% stenoses and combinations of non-invasive tests were sparse and unreliable. There was heterogeneity between studies and evidence of publication bias. INTERPRETATION: Non-invasive tests, used cautiously, could replace intra-arterial carotid angiography for 70-99% stenosis. However, more data are required to determine their accuracy, especially at 50-69% stenoses where the balance of risk and benefit for carotid endarterectomy is particularly narrow, and to explore and overcome heterogeneity. Methodology for evaluating imaging tests should be improved; blinded, prospective studies in clinically relevant patients are essential basic characteristics.

Cytotoxic cell populations in normal and alloimmunized pregnant mice.

Cytotoxic cell activity directed against paternal alloantigens was investigated in primiparous C57BL/10 and CBA/Ca mice using a microcytotoxicity assay. Most allogeneically or syngeneically mated females lacked effector cells in their spleens or paraaortic lymph nodes both during pregnancy and immediately postpartum. However, spleen, cells from 33% of C57BL/10 females mated to CBA/Ca males exhibited low levels of paternal target cell killing (P less than 0.05-0.01). Alloimmunization of virgin mice prior to mating resulted in only allogeneically mated females producing cytotoxic cells and alloantibody. These responses were not detectable during pregnancy but appeared immediately postpartum. The ability of pregnancy to induce memory cell formation was tested by allowing females one successful pregnancy before challenging them postpartum with allogeneic spleen cells. Kinetic studies of cytotoxic cell production showed that C57BL/10 females that had borne (C57BL/10 X CBA/Ca)F1 litters responded earlier than their syngeneically mated sisters giving a peak response at 4 days compared to 7 days after immunization. This indicates that a single allogeneic pregnancy can prime the mother against paternal alloantigens suggesting that the conceptus is weakly immunogenic.