Reference intervals for plasma ß-CTX and P1NP in children: A systematic review and pooled estimates.

OBJECTIVE: Reference intervals for plasma P1NP and ß-CTX in children and adolescents from several studies have recently been published. The aim of this study was to combine the available data into a set of reference intervals for use in clinical laboratories. DESIGN AND METHODS: A systematic literature search for primary studies reporting reference intervals for plasma P1NP and ß-CTX in infants, children and adolescents using the Roche methods was carried out. Reference limits were extracted. For each year of age, mean upper and lower reference limits were calculated, weighted by the number of subjects in each study, and were plotted against age. Proposed reference limits were developed from the weighted mean data with age partitions determined pragmatically. RESULTS: Reference limits for clinical use for females to 25 years and males to 18 years, based on the weighted mean reference data, are presented. Ten studies contributed to the pooled analysis. The proposed reference limits are identical for males and females <9 years age, prior to the pubertal growth spurt. For ß-CTX, the weighted mean reference limits showed relatively constant values during the pre-pubertal years but a marked increase during puberty before a rapid decline towards adult values. Those for P1NP showed high values declining rapidly in the first 2 years of life, followed by a modest increase during early puberty. Limited published information for late adolescent and young adult subjects was noted. CONCLUSIONS: The proposed reference intervals may be useful for clinical laboratories reporting these bone turnover markers measured by the Roche assays.

Learning from the challenges of undertaking an evaluation of a multi-partner housing support initiative delivered within a hospital setting.

Objectives: We present learning from a mixed-methods evaluation of a housing support initiative for hospital inpatients. Study design: A mixed-methods process evaluation. Methods: A social housing provider delivered a housing support service in two hospitals (mental health unit and general hospital). Healthcare providers, the social housing provider and academic researchers designed and undertook a co-produced, mixed-methods process evaluation of the intervention. The evaluation included questionnaires, semi-structured interviews, analysis of routinely collected data and economic analysis. Despite commitment from the partners, the evaluation faced challenges. We reflect on the lessons learnt within our discussion paper. Results: Despite the commitment of the partners, we faced several challenges.We took an iterative approach to the design and processes of the evaluation to respond to arising challenges. Recruitment of service-users was more difficult than anticipated, requiring additional staff resources. Given the small-scale nature of the intervention, and the quality of data recorded in hospital records, the planned economic analysis was not feasible. Positive factors facilitating evaluation included involvement of staff delivering the intervention, as well as managers. Being able to offer payment to partner organisations for staff time also facilitated ongoing engagement. Conclusions: Multi-partner evaluations are useful, however, researchers and partners need to be prepared to take an iterative, resource intensive approach. Both availability and quality of routine data, and the resources required to support data collection, may limit feasibility of specific methods when evaluating small-scale cross-sector initiatives. Thus, this necessitates a flexible approach to design and analysis.

The heart of the matter: cardiac assessment in professional footballers.

AIM: Sudden cardiac death is the leading medical cause of death during exercise.1 Our objective was to retrospectively analyse the routine cardiac assessment of professional footballers to aid physician management and improve player safety. METHODS: Footballers from five professional clubs between March 2012 and October 2014 were included (n=265). All were performed in line with the recommendations of the Football Association Cardiology Committee, incorporating clinical examination, 12-lead ECG, echocardiography and health questionnaire.2 Data was retrospectively collected, inspected and analysed using Excel spreadsheets. Findings were classified as 'normal' or 'not normal', and not normal assessments were further broken down into 'clear-cut pathology' (pathology with widely accepted guidance on management) or 'grey screen'. RESULTS: Footballers were aged 13 to 37 years, with 69% aged over 18 and 31% under. The majority of the review population was White European (66%). Of the review population 11% had 'not normal' assessments, of these assessments 83% were considered grey screens (by Consultant Cardiologist) requiring further investigation or surveillance. Overall clear-cut pathology was identified in 2%. CONCLUSIONS: A high proportion of the players (9%) had grey screens. The majority of these were due to ECG or structural abnormalities, which are clinically challenging to differentiate from physiological adaptation of the athletic heart and potentially fatal conditions. The extent to which these findings put the athlete at risk of a life threatening cardiac event is un-?quantified. Team physician's need to be aware of managing the on-going risk with these patients and ensure suitable ?follow up and assessment on a regular basis to mitigate this.

Assessing the cost-effectiveness of type 1 diabetes interventions: the Sheffield type 1 diabetes policy model.

AIMS: To build a flexible and comprehensive long-term type 1 diabetes mellitus model incorporating the most up-to-date methodologies to allow a number of cost-effectiveness evaluations. METHODS: This paper describes the conceptual modelling, model implementation and model validation of the Sheffield type 1 diabetes policy model (version 1.0), developed through funding by the U.K. National Institute for Health Research as part of the Dose Adjustment for Normal Eating research programme. The model is an individual patient-level simulation model of type 1 diabetes and it includes long-term microvascular (retinopathy, neuropathy and nephropathy) and macrovascular (myocardial infarction, stroke, revascularization and angina) diabetes-related complications and acute adverse events (severe hypoglycaemia and diabetic ketoacidosis). The occurrence of these diabetes-related complications in the model is linked to simulated individual patient-level risk factors, including HbA1c , age, duration of diabetes, lipids and blood pressure. Transition probabilities were modelled based on a combination of existing risk functions, published trials, epidemiological studies and individual-level data from the Dose Adjustment for Normal Eating research programme. RESULTS: The model takes a lifetime perspective, estimating the impact of interventions on costs, clinical outcomes, survival and quality-adjusted life years. Validation of the model suggested that, for almost all diabetes-related complications predicted, event rates were within 10% of the normalized rates reported in the studies used to build the model. CONCLUSIONS: The model is highly flexible and has broad potential application to evaluate the Dose Adjustment for Normal Eating research programme, other structured diabetes education programmes and other interventions for type 1 diabetes.

Can diabetes prevention programmes be translated effectively into real-world settings and still deliver improved outcomes? A synthesis of evidence.

OBJECTIVE: Randomized trials provide evidence that intensive lifestyle interventions leading to dietary and physical activity change can delay or prevent Type 2 diabetes. Translational studies have assessed the impact of interventions based on, but less intensive than, trial protocols delivered in community settings with high-risk populations. The aim of this review was to synthesize evidence from translational studies of any design to assess the impact of interventions delivered outside large randomized trials. METHODS: Medical and scientific databases were searched using specified inclusion and exclusion criteria. Studies were included that used a tested diabetes preventive study protocol with an adult population at risk from Type 2 diabetes. Included papers were quality assessed and data extracted using recommended methods. RESULTS: From an initial 793 papers, 19 papers reporting 17 studies were included. Translational studies from a range of settings utilized a variety of methods. All were based on the US Diabetes Prevention Programme protocol or the Finnish Diabetes Prevention Study, with modifications that increased feasibility and access. The main outcome that was reported in all studies was weight change. Weight loss, which occurred in all but one study, was greater in intervention arms than in control subjects. No consistent differences were found in blood glucose or waist circumference. CONCLUSIONS: Translational studies based on the intensive diabetes prevention programmes showed that there is potential for less intensive interventions both to be feasible and to have an impact on future progression to diabetes in at-risk individuals.

Non-pharmacological interventions to reduce the risk of diabetes in people with impaired glucose regulation: a systematic review and economic evaluation.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) is increasing in the UK and worldwide. Before the onset of T2DM, there are two conditions characterised by blood glucose levels that are above normal but below the threshold for diabetes. If screening for T2DM in introduced, many people with impaired glucose tolerance (IGT) will be found and it is necessary to consider how they should be treated. The number would depend on what screening test was used and what cut-offs were chosen. OBJECTIVE: To review the clinical effectiveness and cost-effectiveness of non-pharmacological interventions, including diet and physical activity, for the prevention of T2DM in people with intermediate hyperglycaemia. DATA SOURCES: Electronic databases, MEDLINE (1996-2011), EMBASE (1980-2011) and all sections of The Cochrane Library, were searched for systematic reviews, randomised controlled trials (RCTs) and other relevant literature on the effectiveness of diet and/or physical activity in preventing, or delaying, progression to T2DM.The databases were also searched for studies on the cost-effectiveness of interventions. REVIEW METHODS: The review of clinical effectiveness was based mainly on RCTs, which were critically appraised. Subjects were people with intermediate hyperglycaemia, mainly with IGT. Interventions could be diet alone, physical activity alone, or the combination. For cost-effectiveness analysis, we updated the Sheffield economic model of T2DM. Modelling based on RCTs may not reflect what happens in routine care so we created a 'real-life' modelling scenario wherein people would try lifestyle change but switch to metformin after 1 year if they failed. RESULTS: Nine RCTs compared lifestyle interventions (predominantly dietary and physical activity advice, with regular reinforcement and frequent follow-up) with standard care. The primary outcome was progression to diabetes. In most trials, progression was reduced, by over half in some trials. The best effects were seen in participants who adhered best to the lifestyle changes; a scenario of a trial of lifestyle change but a switch to metformin after 1 year in those who did not adhere sufficiently appeared to be the most cost-effective option. LIMITATIONS: Participants in the RCTs were volunteers and their results may have been better than in general populations. Even among the volunteers, many did not adhere. Some studies were not long enough to show whether the interventions reduced cardiovascular mortality as well as diabetes. The main problem is that we know what people should do to reduce progression, but not how to persuade most to do it. CONCLUSION: In people with IGT, dietary change to ensure weight loss, coupled with physical activity, is clinically effective and cost-effective in reducing progression to diabetes. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Delivering the diabetes education and self management for ongoing and newly diagnosed (DESMOND) programme for people with newly diagnosed type 2 diabetes: cost effectiveness analysis.

OBJECTIVES: To assess the long term clinical and cost effectiveness of the diabetes education and self management for ongoing and newly diagnosed (DESMOND) intervention compared with usual care in people with newly diagnosed type 2 diabetes. DESIGN: We undertook a cost-utility analysis that used data from a 12 month, multicentre, cluster randomised controlled trial and, using the Sheffield type 2 diabetes model, modelled long term outcomes in terms of use of therapies, incidence of complications, mortality, and associated effect on costs and health related quality of life. A further cost-utility analysis was also conducted using current "real world" costs of delivering the intervention estimated for a hypothetical primary care trust. SETTING: Primary care trusts in the United Kingdom. PARTICIPANTS: Patients with newly diagnosed type 2 diabetes. INTERVENTION: A six hour structured group education programme delivered in the community by two professional healthcare educators. MAIN OUTCOME MEASURES: Incremental costs and quality adjusted life years (QALYs) gained. RESULTS: On the basis of the data in the trial, the estimated mean incremental lifetime cost per person receiving the DESMOND intervention is pound209 (95% confidence interval - pound704 to pound1137; euro251, -euro844 to euro1363; $326, -$1098 to $1773), the incremental gain in QALYs per person is 0.0392 (-0.0813 to 0.1786), and the mean incremental cost per QALY is pound5387. Using "real world" intervention costs, the lifetime incremental cost of the DESMOND intervention is pound82 (- pound831 to pound1010) and the mean incremental cost per QALY gained is pound2092. A probabilistic sensitivity analysis indicated that the likelihood that the DESMOND programme is cost effective at a threshold of pound20 000 per QALY is 66% using trial based intervention costs and 70% using "real world" costs. Results from a one way sensitivity analysis suggest that the DESMOND intervention is cost effective even under more modest assumptions that include the effects of the intervention being lost after one year. CONCLUSION: Our results suggest that the DESMOND intervention is likely to be cost effective compared with usual care, especially with respect to the real world cost of the intervention to primary care trusts, with reductions in weight and smoking being the main benefits delivered.

Screening for type 2 diabetes: literature review and economic modelling.

OBJECTIVES: To reconsider the aims of screening for undiagnosed diabetes, and whether screening should be for other abnormalities of glucose metabolism such as impaired glucose tolerance (IGT), or the 'metabolic syndrome'. Also to update the previous review for the National Screening Committee (NSC) on screening for diabetes, including reviewing choice of screening test; to consider what measures would be taken if IGT and impaired fasting glucose (IFG) were identified by screening, and in particular to examine evidence on treatment to prevent progression to diabetes in these groups; to examine the cost-effectiveness of screening; and to consider groups at higher risk at which screening might be targeted. DATA SOURCES: Electronic databases were searched up to the end of June 2005. REVIEW METHODS: Literature searches and review concentrated on evidence published since the last review of screening, both reviews and primary studies. The review of economic studies included only those models that covered screening. The new modelling extended an existing diabetes treatment model by developing a screening module. The NSC has a set of criteria, which it applies to new screening proposals. These criteria cover the condition, the screening test or tests, treatment and the screening programme. Screening for diabetes was considered using these criteria. RESULTS: Detection of lesser degrees of glucose intolerance such as IGT is worthwhile, partly because the risk of cardiovascular disease (CVD) can be reduced by treatment aimed at reducing cholesterol level and blood pressure, and partly because some diabetes can be prevented. Several trials have shown that both lifestyle measures and pharmacological treatment can reduce the proportion of people with IGT who would otherwise develop diabetes. Screening could be two-stage, starting with the selection of people at higher risk. The second-stage choice of test for blood glucose remains a problem, as in the last review for NSC. The best test is the oral glucose tolerance test (OGTT), but it is the most expensive, is inconvenient and has weak reproducibility. Fasting plasma glucose would miss people with IGT. Glycated haemoglobin does not require fasting, and may be the best compromise. It may be that more people would be tested and diagnosed if the more convenient test was used, rather than the OGTT. Five economic studies assessed the costs and short-term outcomes of using different screening tests. None examined the long-term impact of different proportions of false negatives. All considered the costs that would be incurred and the numbers identified by different tests, or different cut-offs. Results differed depending on different assumptions. They did not give a clear guide as to which test would be the best in any UK screening programme, but all recognised that the choice of cut-off would be a compromise between sensitivity and specificity; there is no perfect test. The modelling exercise concluded that screening for diabetes appears to be cost-effective for the 40-70-year age band, more so for the older age bands, but even in the 40-49-year age group, the incremental cost-effectiveness ratio for screening versus no screening is only 10,216 pounds per quality-adjusted life-year. Screening is more cost-effective for people in the hypertensive and obese subgroups and the costs of screening are offset in many groups by lower future treatment costs. The cost-effectiveness of screening is determined as much by, if not more than, assumptions about the degree of control of blood glucose and future treatment protocols than by assumptions relating to the screening programme. The very low cost now of statins is also an important factor. Although the prevalence of diabetes increases with age, the relative risk of CVD falls, reducing the benefits of screening. Screening for diabetes meets most of the NSC criteria, but probably fails on three: criterion 12, on optimisation of existing management of the condition; criterion 13, which requires that there should be evidence from high-quality randomised controlled trials (RCTs) showing that a screening programme would reduce mortality or morbidity; and criterion 18, that there should be adequate staffing and facilities for all aspects of the programme. It is uncertain whether criterion 19, that all other options, including prevention, should have been considered, is met. The issue here is whether all methods of improving lifestyles in order to reduce obesity and increase exercise have been sufficiently tried. The rise in overweight and obesity suggests that health promotion interventions have not so far been effective. CONCLUSIONS: The case for screening for undiagnosed diabetes is probably somewhat stronger than it was at the last review, because of the greater options for reduction of CVD, principally through the use of statins, and because of the rising prevalence of obesity and hence type 2 diabetes. However, there is also a good case for screening for IGT, with the aim of preventing some future diabetes and reducing CVD. Further research is needed into the duration of undiagnosed diabetes, and whether the rise in blood glucose levels is linear throughout or whether there may be a slower initial phase followed by an acceleration around the time of clinical diagnosis. This has implications for the interval after which screening would be repeated. Further research is also needed into the natural history of IGT, and in particular what determines progression to diabetes. An RCT of the type required by NSC criterion 13 is under way but will not report for about 7 years.

Relationship between testosterone, sex hormone binding globulin and plasma amyloid beta peptide 40 in older men with subjective memory loss or dementia.

In a group of 28 older men with either subjective memory loss or dementia, serum total testosterone and sex hormone binding globulin (SHBG) correlated inversely with plasma levels of amyloid beta peptide 40 (Abeta40, r=-0.5, P=0.01 and r=-0.4, P=0.04, respectively). Calculated free testosterone was also inversely correlated (r=-0.4, P=0.03), and all three relationships remained statistically significant after allowing for age. A similar but non-significant trend was seen with dehydroepiandrosterone sulphate (DHEAS), and neither luteinising hormone (LH) nor estradiol correlated with Abeta40. These data demonstrate that lower androgen levels are associated with increased plasma Abeta40 in older men with memory loss or dementia, suggesting that subclinical androgen deficiency enhances the expression of Alzheimer's disease-related peptides in vivo. An inverse correlation exists between SHBG and Abeta40, warranting further investigation.

Association between blood levels of lead, blood pressure and risk of diabetes and heart disease in workers.

BACKGROUND: Previous studies have supported the association between high levels of blood lead levels (BLL) and elevated blood pressure. In addition, significant correlations between BLL and a variety of risk factors for blood pressure and diabetes mellitus have been well-established. OBJECTIVE: To examine the relationship between BLL, blood pressure and diabetes as well as other selected social and biochemical factors, among workers in the United Arab Emirates (UAE). METHODS: This comparative study included 110 industrial workers (exposed to lead in the workplace) and 110 non-industrial workers (not exposed); all were recruited in the city of Al-Ain, Abu-Dhabi Emirate, UAE and the groups were evenly matched for age, gender and nationality. RESULTS: The industrial workers had a significantly higher mean of BLL (median 81 and geometric mean (GM) 62 microg/dl) than did non-industrial workers (median 11 and GM 13 microg/dl). In the present study, the lead-exposed group also had significantly higher blood lead levels, body-mass index (BMI), systolic and diastolic blood pressures, fasting blood glucose and plasma levels of total cholesterol, lactate dehydrogenase and uric acid than did the non-exposed group. Furthermore a significant correlation between BLL and systolic blood pressure was observed. CONCLUSION: The study supports the hypothesis of a positive association between lead exposure, high blood pressure and risk of diabetes and heart disease.

Hypotriglyceridemic and hypocholesterolemic effects of anti-diabetic Momordica charantia (karela) fruit extract in streptozotocin-induced diabetic rats.

Momordica charantia (karela) is commonly used as an antidiabetic and antihyperglycemic agent in Asian, Oriental and Latin American countries. This study was undertaken to investigate the effects of long term feeding (10 weeks) of M. charantia fruit extract on blood plasma and tissue lipid profiles in normal and streptozotocin (STZ)-induced Type 1 diabetic rats. The results show that there was a significant (P < 0.05) increase in plasma non-esterified cholesterol, triglycerides and phospholipids in STZ-induced diabetic rats, accompanied by a decrease in high density lipoprotein (HDL)-cholesterol. A moderate increase in plasma (LPO) product, malonedialdehyde (MDA), and about two-fold increase in kidney LPO was also observed in STZ-induced diabetic rats. The treatment of diabetic rats with M. charantia fruit extract over a 10-week period returned these levels close to normal. In addition, karela juice also exhibited an inhibitory effect on membrane LPO under in vitro conditions. These results suggest that M. charantia fruit extract exhibits hypolipidemic as well as hypoglycemic effects in the STZ-induced diabetic rat.

Lecithin: cholesterol acyltransfer, dyslipoproteinaemia and membrane lipids in uraemia.

BACKGROUND: Dyslipoproteinaemia is the most important complication linked to the increased morbidity and mortality of uraemic patients from cardiovascular disease. Many factors contribute to the dyslipoproteinaemia, including increased production of very low density lipoproteins (VLDL), decreased lipolysis and impaired low density lipoprotein (LDL) receptor activity. In this study, the role of decreased lecithin:cholesterol acyltransferase (LCAT) activity in relation to plasma and membrane lipid changes is examined. METHODS: Fasted blood samples were taken from 65 uraemic patients, including roughly equal numbers of haemodialysis, peritoneal dialysis and undialysed subjects, and from 29 apparently healthy individuals. Plasma total and free cholesterol, cholesteryl esters (CE), total and individual phospholipids, high density lipoprotein (HDL)-, LDL- and VLDL-cholesterol were all measured, as were erythrocyte and lymphocyte free cholesterol and phospholipids. RESULTS: More than half of all patients, including those both on haemodialysis and peritoneal dialysis, as well as untreated individuals, had relative plasma concentrations of CE below the normal mean - 2SD. These patients had significantly decreased LDL- (2.62 +/- 1.04 compared to 3.61 +/- 0.97 mmol/L; p < 0.001) and HDL-cholesterol (0.71 +/- 0.30 compared to 0.94 +/- 0.27 mmol/L; p < 0.01) and increased VLDL-cholesterol (0.60 +/- 0.50 compared to 0.47 +/- 0.26 mmol/L; p < 0.05) as well as significant increases in membrane cholesterol and cholesterol/phospholipid molar ratio in erythrocytes (3.30 +/- 0.49 and 0.87 +/- 0.08 compared to 2.95 +/- 0.18 mmol/g wet weight and 0.76 +/- 0.04 mol/mol respectively, both p < 0.001) and cholesterol/phospholipid molar ratio of lymphocytes (0.58 +/- 0.14 compared to 0.45 +/- 0.04 mol/mol; p < 0.001). They were markedly deficient in LCAT activity (56.1 +/- 20.4 compared to 105.5 +/- 17.5 nmol/ml/h; p < 0.001). The LCAT activity in plasma of patients with high CE was higher than for those with low CE, but it was also significantly less than normal and this group showed smaller changes in other lipid parameters. CONCLUSIONS: LCAT deficiency is common in uraemia and is associated with changes not just in plasma lipids, but also in membrane lipids which may be relevant to the progression of the disease.

Levels of cholesteryl esters and other lipids in the plasma of patients with end-stage renal failure.

BACKGROUND: The importance of plasma lipid abnormalities in chronic renal failure (CRF) is well recognized, but surprisingly little attention has been given to the study of some plasma lipid fractions, including cholesteryl esters (CE) and phospholipids, which might be expected to be important factors in the pathogenesis of the disease. MATERIALS AND METHODS: Fasting blood samples were taken from 25 control subjects and 53 CRF patients (29 predialysis and 24 on hemodialysis). Samples were analyzed for urea nitrogen, creatinine, triacylglycerols, total and individual phospholipids, total and free cholesterol, as well as cholesterol bound to very low-, low- and highdensity lipoproteins (VLDL, LDL and HDL). Plasma CE was calculated and expressed as a percentage of total cholesterol. RESULTS: Over half of the patients had CE levels more than two standard deviations below the control value. In this subgroup of low CE patients, total, LDL- and HDL-cholesterol levels were also significantly lower than for controls, while levels of phosphatidylcholine and lysophosphatidylcholine were decreased and increased, respectively. In patients with high CE, no significant lipid abnormalities were observed. CONCLUSION: In this study, CE was an excellent marker for lipid disturbances--if CE was high, then the other lipid fractions were normal, but if CE was low, most other lipid fractions were abnormal. The changes noted appear to be consequences of or related to deficiency of the plasma enzyme lecithin-cholesterol acyltransferase.

Colchicine-induced bone marrow suppression: treatment with granulocyte colony-stimulating factor.

Bone marrow aplasia is a frequent complication of colchicine poisoning. This typically occurs on day 3 to 5 postexposure, and the blood cell counts remain depressed for a week or more. Unfortunately, because patients suffering from colchicine toxicity develop multiple organ complications and sepsis, the morbidity and mortality associated with bone marrow depression is high. In this article, we present three cases of colchicine toxicity in which granulocyte colony-stimulating factor (G-CSF) was used to treat bone marrow depression. In all three cases, there was a dramatic increase in the white cell count and, to a lesser extent, the platelet count. In view of the critical nature of the bone marrow depression and multi-organ toxicity induced by colchicine, we believe that consideration of the use of G-CSF to shorten the duration of neutropenia is warranted.

Consistency of retrospective triage decisions as a standardised instrument for audit.

OBJECTIVES: To determine the level of agreement between senior medical staff when asked to perform retrospective case note review of nursing triage decisions, both before and after development of a consensus approach. METHODS: Four medical reviewers independently allocated triage categories to 50 emergency department patients after review of their case notes. They were blind to the identity of the triage nurse and their triage categorisation. The process was repeated twice, firstly after agreement on a consensus approach and then using formal guidelines. RESULTS: Agreement between reviewers was initially fair to moderate (kappa = 0.27 to 0.53). This failed to improve after development of a consensus approach (kappa = 0.29 to 0.57). There was a trend towards better agreement when guidelines were used but agreement was still only moderate (kappa = 0.31 to 0.63). CONCLUSIONS: Audit of nurse triage categorisation by senior medical staff performing case note review has only fair to moderate consistency between reviewers. Use of this technique will result in frustration among those whose performance is being audited if they recognise inconsistency in the standard they are compared against.