The effect of vitamin D supplementation on knee osteoarthritis, the VIDEO study: a randomised controlled trial.

OBJECTIVE: Epidemiological data suggest low serum 25-hydroxyvitamin D3 (25-OH-D3) levels are associated with radiological progression of knee osteoarthritis (OA). This study aimed to assess whether vitamin D supplementation can slow the rate of progression. METHOD: A 3-year, double-blind, randomised, placebo-controlled trial of 474 patients aged over 50 with radiographically evident knee OA comparing 800 IU cholecalciferol daily with placebo. Primary outcome was difference in rate of medial joint space narrowing (JSN). Secondary outcomes included lateral JSN, Kellgren & Lawrence grade, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function, stiffness and the Get up and Go test. RESULTS: Vitamin D supplementation increased 25-OH-D3 from an average of 20.7 (standard deviation (SD) 8.9) µg/L to 30.4 (SD 7.7) µg/L, compared to 20.7 (SD 8.1) µg/L and 20.3 (SD 8.1) µg/L in the placebo group. There was no significant difference in the rate of JSN over 3 years in the medial compartment of the index knee between the treatment group (average -0.01 mm/year) and placebo group (-0.08 mm/year), average difference 0.08 mm/year (95% confidence interval (CI) [-0.14-0.29], P = 0.49). No significant interaction was found between baseline vitamin D levels and treatment effect. There were no significant differences for any of the secondary outcome measures. CONCLUSION: Vitamin D supplementation did not slow the rate of JSN or lead to reduced pain, stiffness or functional loss over a 3-year period. On the basis of these findings we consider that vitamin D supplementation has no role in the management of knee OA.

A randomised controlled trial of flow driver and bubble continuous positive airway pressure in preterm infants in a resource-limited setting.

OBJECTIVES: The variable-flow flow driver (FD; EME) and continuous-flow bubble (Fisher-Paykel) continuous positive airway pressure (CPAP) systems are widely used. As these differ in cost and technical requirements, determining comparative efficacy is important particularly where resources are limited. DESIGN: We performed a randomised, controlled, equivalence trial of CPAP systems. We specified the margin of equivalence as 2 days. We analysed binary variables by logistical regression adjusted for gestation, and log transformed continuous variables by multiple linear regression adjusted for gestation, sex and antenatal steroids. SETTING: A neonatal unit with no blood gas analyser or surfactant availability and limited X-ray and laboratory facilities PATIENTS: Neonates <37 weeks of gestation. INTERVENTIONS: We provided CPAP at delivery followed by randomisation to FD or bubble (B). OUTCOMES: Primary outcome included total days receiving CPAP; secondary outcomes included days receiving CPAP, supplemental oxygen, ventilation, death, pneumothorax and nasal excoriation. RESULTS: We randomised 125 infants (B 66, FD 59). Differences in infant outcomes on B and FD were not statistically significant. The median (range) for CPAP days for survivors was B 0.8 (0.04 to 17.5), FD 0.5 (0.04 to 5.3). B:FD (95% CI) ratios were CPAP days 1.3 (0.9 to 2.1), CPAP plus supplementary oxygen days 1.2 (0.7 to 1.9). B:FD (95% CI) ORs were death 2.3 (0.2 to 28), ventilation 2.1 (0.5 to 9), nasal excoriation 1.2 (0.2 to 8) and pneumothorax 2.4 (0.2 to 26). CONCLUSIONS: In a resource-limited setting we found B CPAP equivalent to FD CPAP in the total number of days receiving CPAP within a margin of 2 days. TRIAL REGISTRATION NUMBER: ISRCTN22578364.

Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE.

INTRODUCTION: The current mainstay of the treatment of thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation with vitamin K antagonists (VKAs) such as warfarin. Non-VKA oral anticoagulants (NOACs), which include rivaroxaban, have been shown to be effective and safe compared with warfarin for the treatment of venous thromboembolism (VTE) in major phase III prospective, randomized controlled trials (RCTs), but the results may not be directly generalizable to patients with APS. AIMS: The primary aim is to demonstrate, in patients with APS and previous VTE, with or without systemic lupus erythematosus (SLE), that the intensity of anticoagulation achieved with rivaroxaban is not inferior to that of warfarin. Secondary aims are to compare rates of recurrent thrombosis, bleeding and the quality of life in patients on rivaroxaban with those on warfarin. METHODS: Rivaroxaban in antiphospholipid syndrome (RAPS) is a phase II/III prospective non-inferiority RCT in which eligible patients with APS, with or without SLE, who are on warfarin, target international normalized ratio (INR) 2.5 for previous VTE, will be randomized either to continue warfarin (standard of care) or to switch to rivaroxaban. Intensity of anticoagulation will be assessed using thrombin generation (TG) testing, with the primary outcome the percentage change in endogenous thrombin potential (ETP) from randomization to day 42. Other TG parameters, markers of in vivo coagulation activation, prothrombin fragment 1.2, thrombin antithrombin complex and D-dimer, will also be assessed. DISCUSSION: If RAPS demonstrates i) that the anticoagulant effect of rivaroxaban is not inferior to that of warfarin and ii) the absence of any adverse effects that cause concern with regard to the use of rivaroxaban, this would provide sufficient supporting evidence to make rivaroxaban a standard of care for the treatment of APS patients with previous VTE, requiring a target INR of 2.5.

National audit of the use of surgery and radiological embolization after failed endoscopic haemostasis for non-variceal upper gastrointestinal bleeding.

BACKGROUND: Following non-variceal upper gastrointestinal bleeding (NVUGIB), 10-15 per cent of patients experience further bleeding. Although surgery has been the traditional salvage therapy, there is renewed interest in transcatheter arterial embolization (TAE). This study examined the use, clinical characteristics and outcomes of patients receiving salvage surgery or TAE after failed endoscopic haemostasis for NVUGIB. METHODS: A UK national audit of upper gastrointestinal bleeding was undertaken in May and June 2007. A logistic regression model was used to identify clinical predictors of endoscopic failure. RESULTS: Data were analysed from 4478 patients involving 212 UK centres. Some 533 (11·9 per cent) experienced further bleeding, of whom 163 (30·6 per cent) proceeded to salvage therapy with surgery (97), TAE (60) or both (6). Among surgical patients (mean age 71 years), 66·0 per cent (68 of 103) had a Rockall score of at least 3 and emergency surgery was carried out between midnight and 08.00 hours in 21 per cent, with a consultant surgeon present in 89 per cent of operations. Some 9 per cent of patients had further bleeding after TAE, resulting in later surgery. The mortality rate was 29 per cent after surgery, 10 per cent after TAE and 23·2 per cent among those with further bleeding after the index endoscopy that was managed by endoscopy alone. The strongest predictors of endoscopic failure were coagulopathy (odds ratio 3·27, 95 per cent confidence interval 2·37 to 4·53) and a haemoglobin level of 10 g/dl or less (odds ratio 2·22, 1·71 to 2·87, for haemoglobin 8-10 g/dl). CONCLUSION: Salvage surgery and embolization are required in fewer than 4 per cent of patients with NVUGIB. The high postoperative mortality rate, reflecting age, co-morbidity and severity of bleeding, warrants a prospective study to establish the effectiveness and safety of TAE as an alternative to surgery in the management of bleeding after failure of endoscopic therapy.

Outcomes following acute nonvariceal upper gastrointestinal bleeding in relation to time to endoscopy: results from a nationwide study.

BACKGROUND AND STUDY AIMS: Despite the established efficacy of therapeutic endoscopy, the optimum timeframe for performing endoscopy in patients with nonvariceal upper gastrointestinal bleeding (NVUGIB) remains unclear. The aim of the current audit study was to examine the relationship between time to endoscopy and clinical outcomes in patients presenting with NVUGIB. PATIENTS AND METHODS: This study was a prospective national audit performed in 212 UK hospitals. Regression models examined the relationship between time to endoscopy and mortality, rebleeding, need for surgery, and length of hospital stay. RESULTS: In 4478 patients, earlier endoscopy ( < 12 hours) was not associated with a lower mortality or need for surgery compared with later ( > 24 hours) endoscopy (odds ratio [OR] for mortality 0.98, 95 % confidence interval [CI] 0.88 - 1.09 for endoscopy > 24 hours vs. < 12 hours; P = 0.70). In patients receiving therapeutic endoscopy, there was a nonsignificant trend towards an increase in rebleeding associated with later endoscopy (OR 1.13, 95 %CI 0.97 - 1.32 for endoscopy > 24 hours vs. < 12 hours), with the converse seen in patients not requiring therapeutic endoscopy (OR 0.83, 95 %CI 0.73 - 0.95 for endoscopy > 24 hours vs. < 12 hours; interaction P = 0.003). Later endoscopy ( > 24 hours) was associated with an increase in risk-adjusted length of hospital stay (1.7 days longer, 95 %CI 1.39 - 1.99 vs. < 12 hours; P < 0.001). CONCLUSIONS: Earlier endoscopy was not associated with a reduction in mortality or need for surgery. However, it was associated with an increased efficiency of care and potentially improved control of hemorrhage in higher risk patients, supporting the routine use of early endoscopy unless specific contraindications exist. These results may help inform the debate about emergency endoscopy service provision.

Patients' views on an education booklet following spinal surgery.

PURPOSE: This study evaluated an evidence-based education booklet developed for patients undergoing spinal surgery which was used as a treatment intervention in a multi-centre, factorial, randomised controlled trial (FASTER: Function after spinal treatment, exercise and rehabilitation) investigating the post-operative management of spinal surgery patients. This study sought to determine the acceptability and content of the booklet to patients. METHODS: Patients receiving the educational booklet before discharge from hospital as part of the FASTER study were asked to complete an evaluation, which rated the booklet "Your Back Operation" with regard to content, information, usability, etc. using forced and open questions. This assessment was conducted at the same time as the initial 6-week post-operative review performed as part of the larger study. RESULTS: Therefore, 97% of the 117 trial participants who returned their 6-week evaluation and randomised to receive a booklet returned their questionnaire. The booklet was highly rated receiving an overall rating of 7 or more out of 10 from 101/111 (91%), and high ratings for content, readability and information. The booklet's key messages were clear to the majority of patients; however, many patients highlighted deficiencies with respect to content particularly in relation to wound care and exercise. CONCLUSIONS: Patients valued the booklet and rated its content highly. Many suggested that the booklet be developed further and there was a clear desire for specific exercises to be included even though there is no evidence to support specific exercise prescription.

A randomised controlled trial of subcutaneous sodium salicylate therapy for osteoarthritis of the thumb.

BACKGROUND: Current treatment for osteoarthritis (OA) is limited. Many patients with OA of the hand have areas of tender subcutaneous thickening in the forearm and upper scapular region. A pilot study showed an improvement in pain from OA at the first carpometacarpal joint after injection of such areas with 0.5% sodium salicylate or saline, an inexpensive treatment that can be administered by general practitioners and nurses. The study indicated that a randomised, sham-controlled trial was justified. METHODS: 40 patients with OA of the first carpometacarpal joint were randomised to receive either injections of sodium salicylate into tender, thickened areas of subcutaneous tissue on the forearm (baseline) and upper scapular region (week 1) or sham injections consisting of pressure without skin penetration. Blinded assessments were made at weeks 3, 7 and 13 after baseline. RESULTS: Pain and tenderness during follow-up were both significantly lower in the active treatment group compared with the sham group: 19% and 14% greater reduction in mean visual analogue scale (VAS) score, respectively (p=0.007 and 0.02, baseline mean 5.65 and 5.35 cm, average difference in change from baseline VAS 1.9 and 1.4 cm, 95% CI 0.6 to 3.2 and 0.2 to 2.5). Active and sham injections were painful, the former significantly more so; however, there was no significant correlation between the pain of active injections and response. CONCLUSION: The data show that subcutaneous sodium salicylate injections are an effective symptomatic treatment for OA of the thumb. The results provide a basis for further physiological and therapeutic research in this area.

Plaque area at carotid and common femoral bifurcations and prevalence of clinical cardiovascular disease.

AIM: Different ultrasonic arterial wall measurements have been used as predictors of future myocardial infarction or stroke. The aim of the present study was to determine the relationship of total plaque area (TPA) (the sum of the atherosclerotic plaque area measurements from both carotid and both common femoral arteries) with prevalence of cardiovascular disease in a population-based cross-sectional study and compare it with intima-media thickness (IMT). METHODS: Seven hundred sixty-two individuals (47% male) over the age of 40 were screened for cardiovascular risk factors. RESULTS: Evidence of clinical cardiovascular disease was present in 113 (14.8%). Both carotid and both common femoral bifurcations were scanned with ultrasound. After adjustment for conventional risk factors the association of IMT with prevalence of clinical cardiovascular disease was low (P=0.84, OR of upper IMT quintile 1.36; 95% CI 0.56 to 3.26) and of TPA high (P<0.001, OR of upper TPA quintile 8.38; 95% CI 2.57 to 27.32). TPA greater than 42 mm2 (cut-point derived from ROC curve analysis) identified 266 (34.9%) of the population that contained 87/113 (76.9%) of the clinical events (sensitivity: 77%; specificity: 73%; positive predictive value: 33%; negative predictive value: 94%; positive likelihood ratio of 2.79). In contrast, IMT greater than 0.07 mm had a sensitivity, specificity, positive and negative predictive value and positive likelihood ratio of 68%, 60%, 23%, 91% and 1.69 respectively. CONCLUSION: Total plaque area appears to be more strongly associated with the prevalence of cardiovascular disease than IMT. This finding warrants further prospective studies.

Function after spinal treatment, exercise and rehabilitation (FASTER): improving the functional outcome of spinal surgery.

BACKGROUND: The life-time incidence of low back pain is high and diagnoses of spinal stenosis and disc prolapse are increasing. Consequently, there is a steady rise in surgical interventions for these conditions. Current evidence suggests that while the success of surgery is incomplete, it is superior to conservative interventions. A recent survey indicates that there are large differences in the type and intensity of rehabilitation, if any, provided after spinal surgery as well as in the restrictions and advice given to patients in the post-operative period. This trial will test the hypothesis that functional outcome following two common spinal operations can be improved by a programme of post-operative rehabilitation that combines professional support and advice with graded active exercise and/or an educational booklet based on evidence-based messages and advice. METHODS/DESIGN: The study design is a multi-centre, factorial, randomised controlled trial with patients stratified by surgeon and operative procedure. The trial will compare the effectiveness and cost-effectiveness of a rehabilitation programme and an education booklet for the postoperative management of patients undergoing discectomy or lateral nerve root decompression, each compared with "usual care"using a 2 x 2 factorial design. The trial will create 4 sub-groups; rehabilitation-only, booklet-only, rehabilitation-plus-booklet, and usual care only. The trial aims to recruit 344 patients, which equates to 86 patients in each of the four sub-groups. All patients will be assessed for functional ability (through the Oswestry Disability Index - a disease specific functional questionnaire), pain (using visual analogue scales), and satisfaction pre-operatively and then at 6 weeks, 3, 6 and 9 months and 1 year post-operatively. This will be complemented by a formal analysis of cost-effectiveness. DISCUSSION: This trial will determine whether the outcome of spinal surgery can be enhanced by either a post-operative rehabilitation programme or an evidence-based advice booklet or a combination of the two and as such will contribute to our knowledge on how to manage spinal surgery patients in the post-operative period.

A case definition for national and international neonatal bloodstream infection surveillance.

OBJECTIVE: Neonatal bloodstream infection (BSI) is a major contributor to mortality, health service costs, and the population burden of lifelong neurodisability. BSI surveillance, an essential component of infection control, requires an unambiguous standardised case definition as variability would invalidate any comparative analyses. In neonates a high proportion of blood cultures yield a mixed growth or skin commensals, principally coagulase-negative staphylococci (CoNS). As this might represent either genuine BSI or contamination, clinical correlates are necessary, but this adds to the difficulty of agreeing an objective, standardised case definition. DESIGN: Utilising data from 26 UK neonatal units, the population prevalence of 12 predefined clinical signs of infection captured daily for 28 days was evaluated. The sensitivity, specificity, odds ratio and positive predictive value of each sign and sequential numbers of grouped signs were determined to develop a predictive model for a positive blood culture. Sandwich estimates of the standard errors of the logistic regression coefficients were used to take account of the correlations between these repeated measures. The model was tested in an independent data set. RESULTS: > or =3 clinical signs had the best predictive accuracy for a positive blood culture (76.2% specificity; 61.5%, 46.9% and 78.2% sensitivity for all positive cultures, cultures yielding CoNS, or a recognised pathogen, respectively). CONCLUSION: This study suggests that a simple case definition for national and international neonatal BSI surveillance is provided by a blood culture yielding a recognised pathogen in pure culture, or a mixed growth or skin commensal plus > or =3 predefined clinical signs.

Risk factors and recommendations for rate stratification for surveillance of neonatal healthcare-associated bloodstream infection.

Neonates are among the most vulnerable patient groups for healthcare-associated infection with multiple endogenous and exogenous risks. Interpretation of neonatal bloodstream infection (BSI) rates requires stratification for case-mix. We assessed 1367 consecutive admissions to a single neonatal unit over a 34-month period. Four intrinsic and seven extrinsic risks were evaluated using Poisson regression analyses both individually and in combination. Nine of the 11 evaluated risk factors were significantly associated with BSI on univariate analyses. The only significant independent risks were parenteral nutrition, whether administered centrally or peripherally [incidence rate ratio (IRR): 14.2; 95% confidence interval (CI): 8.8-22.9; P<0.001], and gestational age <26 weeks (IRR: 2.5; 95% CI: 1.7-3.8; P<0.001). The rate of BSI per 1000 patient-days was 40 times higher in infants with both of these than in infants with neither. If validated in other settings, stratification of neonatal BSI rate by two unambiguous risk factors, parenteral nutrition and birth gestational age <26 weeks, offers a simple method to make meaningful intra- and inter-hospital comparisons.

Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon: a multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril.

OBJECTIVE: To evaluate the efficacy and tolerability of prolonged administration of quinapril, a long-acting angiotensin-converting enzyme inhibitor, in the management of the peripheral vascular manifestations of limited cutaneous systemic sclerosis (lcSSc) and in the prevention of the progression of visceral organ involvement in the disease. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study evaluating quinapril 80 mg/day, or the maximum tolerated dosage, in 210 patients with lcSSc or with Raynaud's phenomenon (RP) and the presence of SSc-specific antinuclear antibodies. Treatment was for 2-3 years. The primary outcome measure was the number of new ischemic ulcers appearing on the hands; secondary measures were the frequency and severity of RP attacks, skin score, treatments for ischemia, health status (measured by the Short Form 36 instrument), measures of kidney and lung function, and echocardiographic estimates of pulmonary artery pressure. An intent-to-treat analysis was used. RESULTS: Quinapril did not affect the occurrence of digital ulcers or the frequency or severity of RP episodes. It did not alter the treatments that were prescribed for either infected ulcers or severe RP symptoms. There was no apparent effect on the estimated tricuspid gradient. Health status was not affected by quinapril, and one-half of the patients who believed they had benefited from the trial treatment were in the placebo arm. Quinapril was not tolerated by one-fifth of the patients, with dry cough being the most frequent side effect. CONCLUSION: Administration of quinapril for up to 3 years had no demonstrable effects on the occurrence of upper limb digital ulcers or on other vascular manifestations of lcSSc in this patient population.

Accelerated postnatal head growth follows preterm birth.

BACKGROUND: Poor growth after preterm birth, particularly poor head growth, is associated with impaired neurodevelopmental outcome. OBJECTIVE: To evaluate weight gain and head growth between birth and term in a contemporary cohort of preterm infants, taking into account breast milk intake and illness severity. METHODS: Subjects were inborn infants or=37 weeks postmenstrual age. Weight and head circumference (HC) were expressed as standard deviation score (SDS), growth between birth and discharge as SDS gain (SDSG), and illness severity and breast milk exposure as the number of days of level 1 (full) intensive care (%L1IC) and the number of days on which breast milk was received (%BM) as a percentage of days from birth to discharge. RESULTS: Infants showed poor postnatal weight gain but accelerated head growth. There was a highly significant fall in mean (SD) weight SDS between birth and discharge (-0.31 (0.96) and -1.32 (1.02) respectively, p<0.001) and a highly significant increase in HC SDS (-0.52 (0.95) and -0.03 (1.25) respectively, p = 0.003). %L1IC had a highly significant negative impact on weight SDSG (p = 0.006), and %BM had a significant positive impact on HC SDSG (p = 0.043). CONCLUSIONS: Accelerated postnatal head growth suggests catch up after antenatal restraint. This raises the possibility that poor neurocognitive outcomes after extremely preterm birth may in part be consequent on poor intrauterine brain growth. As postnatal head growth may be facilitated by breast milk, there is an urgent need to evaluate the optimal use of breast milk in preterm neonates. Illness severity is a significant determinant of poor postnatal weight gain.

The impact of ethnicity on glucose regulation and the metabolic syndrome following gestational diabetes.

AIMS/HYPOTHESIS: We assessed the impact of ethnic origin on metabolism in women following gestational diabetes mellitus (GDM). MATERIALS AND METHODS: Glucose regulation and other features of the metabolic syndrome were studied at 20.0 (18.2-22.1) months (geometric mean [95% CI]) post-partum in women with previous GDM (185 European, 103 Asian-Indian, 80 African-Caribbean). They were compared with the same features in 482 normal control subjects who had normal glucose regulation during and following pregnancy. RESULTS: Impaired glucose regulation or diabetes by WHO criteria were present in 37% of women with previous GDM (diabetes in 17%), especially in those of African-Caribbean and Asian-Indian origin (50 and 44%, respectively vs 28% in European, p=0.009). BMI, waist circumference, diastolic blood pressure, fasting triglyceride and insulin levels, and insulin resistance by homeostatic model assessment (HOMA), were increased following GDM (p<0.001 for all, vs control subjects). Where glucose regulation was normal following GDM, basal insulin secretion (by HOMA) was high (p<0.001 vs control subjects). Irrespective of glucose regulation in pregnancy, Asian-Indian origin was associated with high triglyceride and low HDL cholesterol levels, and African-Caribbean with increased waist circumference, blood pressure, and insulin levels, together with insulin resistance and low triglyceride concentrations. Nonetheless, the GDM-associated features were consistent within each ethnic group. The metabolic syndrome by International Diabetes Federation criteria was present in 37% of women with previous GDM, especially in non-Europeans (Asian-Indian 49%, African-Caribbean 43%, European 28%, p=0.001), and in 10% of controls. CONCLUSIONS/INTERPRETATION: Following GDM, abnormal glucose regulation and the metabolic syndrome are common, especially in non-European women, indicating a need for diabetes and cardiovascular disease prevention strategies.

Severity of asymptomatic carotid stenosis and risk of ipsilateral hemispheric ischaemic events: results from the ACSRS study.

OBJECTIVES: This study determines the risk of ipsilateral ischaemic neurological events in relation to the degree of asymptomatic carotid stenosis and other risk factors. METHODS: Patients (n=1115) with asymptomatic internal carotid artery (ICA) stenosis greater than 50% in relation to the bulb diameter were followed up for a period of 6-84 (mean 37.1) months. Stenosis was graded using duplex, and clinical and biochemical risk factors were recorded. RESULTS: The relationship between ICA stenosis and event rate is linear when stenosis is expressed by the ECST method, but S-shaped if expressed by the NASCET method. In addition to the ECST grade of stenosis (RR 1.6; 95% CI 1.21-2.15), history of contralateral TIAs (RR 3.0; 95% CI 1.90-4.73) and creatinine in excess of 85 micromol/L (RR 2.1; 95% CI 1.23-3.65) were independent risk predictors. The combination of these three risk factors can identify a high-risk group (7.3% annual event rate and 4.3% annual stroke rate) and a low risk group (2.3% annual event rate and 0.7% annual stroke rate). CONCLUSIONS: Linearity between ECST per cent stenosis and risk makes this method for grading stenosis more amenable to risk prediction without any transformation not only in clinical practice but also when multivariable analysis is to be used. Identification of additional risk factors provides a new approach to risk stratification and should help refine the indications for carotid endarterectomy.

Factors associated with mortality in patients with asymptomatic carotid stenosis: results from the ACSRS Study.

AIM: This study determines the factors associated with mortality in patients with asymptomatic carotid stenosis. METHODS: Patients (n=1,101) with asymptomatic internal carotid artery stenosis greater than 50% in relation to the bulb diameter were followed up for a period of 6 to 84 (median 38) months. Stenosis was graded using duplex scanning and expressed as a percentage of the carotid bulb diameter. Clinical and biochemical risk factors were recorded. The end-points were ipsilateral ischemic stroke, cardiovascular death and all cause mortality. RESULTS: In a Cox multivariate analysis 6 factors emerged as independent predictors of risk. Age, male gender, cardiac failure, left ventricular hypertrophy on electrocardiogram (ECG) and myocardial ischemia on ECG were associated with increased risk. Antiplatelet therapy was associated with decreased risk. Based on these risk factors a high-risk group consisting of one third of the population with a 40% cumulative cardiovascular death rate and a 66% all cause death rate at 7 years could be identified. The remaining 2/3 consisted of a low-risk group with a 10% cumulative cardiovascular death rate and a 21% all cause death rate at 7 years (P<0.0001 compared to the high risk group). There was not any significant difference in the cumulative ipsilateral stroke rate, which was 12% in the low and 13% in the high cardiovascular risk group (Log Rank P>0.05). CONCLUSIONS: The methodology and findings from the ACSRS natural history study need to be applied to randomized controlled trials on the value of carotid endarterectomy or stenting in patients with asymptomatic carotid stenosis. They may help refine the indications for intervention in patients with carotid endarterectomy.

A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal.

INTRODUCTION: Combinations of disease-modifying anti-rheumatic drugs (DMARDs) are increasingly used to treat rheumatoid arthritis (RA). Early trials showed their toxicity while recent trials suggest superior efficacy. Trials of DMARD combinations have enrolled different types of patient (early or established RA), used different designs (step-up, parallel or step-down) and utilized a range of outcome measures. We undertook a systematic review of combination DMARD therapy for RA and carried out a meta-analysis to evaluate the evidence for efficacy and toxicity. METHOD: Medline, PubMed and EmBase were searched using MESH headlines 'arthritis, rheumatoid', 'drug therapy, combination' and 'randomized controlled trial' (RCT) for papers published from 1975 to April 2004. References from published articles were also searched. Three independent assessors evaluated abstracts and selected trials for detailed examination. Trials were excluded if their quality was poor, were not published in English or studied DMARDs not licensed to treat RA. Two independent assessors extracted data. Efficacy was assessed by the numbers of patients withdrawn due to lack of efficacy. Toxicity was assessed by the numbers of patients withdrawn due to adverse events. Risk ratios (RR) with 95% confidence intervals (CI) were calculated and meta-analysis was carried out based on a random effects model. Sensitivity analyses evaluated different treatment combinations, trial designs, study populations and outcome measures. RESULTS: Fifty-three potentially relevant RCTs were identified. Twelve were excluded due to: using unlicensed DMARDs (n = 3); reporting in journal supplements of RCTs already included (n = 2); follow-up of an earlier RCT, report of biological outcomes or pharmacokinetics (n = 5); and non-English language publications (n = 2). Forty-one RCTs were evaluated in detail and another five excluded (three open-labelled studies and two with high patient attrition); 36 studies were included in the meta-analysis. These comprised 13 step-up, 16 parallel and 7 step-down trials. Nine assessed early RA and 27 established RA. Seven added steroids to DMARD monotherapy and one study added steroids to DMARD combinations. Six assessed methotrexate (MTX) plus tumour necrosis factor (TNF) inhibitors. Overall, combination DMARD therapy was more effective than monotherapy (RR 0.35; 95% CI 0.28, 0.45) although the risk of toxicity was also slightly higher (RR 1.37; 95% CI 1.16, 1.62). Combinations of MTX with TNF inhibitors and MTX with sulphasalazine or anti-malarials showed good efficacy/toxicity ratios. CONCLUSIONS: DMARD combinations vary in their efficacy/toxicity ratio. MTX plus sulphasalazine and/or anti-malarials and MTX plus TNF inhibitors have particularly favourable benefit/risk ratios.

Hepatic triglyceride content and its relation to body adiposity: a magnetic resonance imaging and proton magnetic resonance spectroscopy study.

BACKGROUND: Hepatic steatosis is associated with obesity and type II diabetes. Proton magnetic resonance spectroscopy (1H MRS) is a non-invasive method for measurement of tissue fat content, including intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL). PATIENTS AND METHODS: We used 1H MRS and whole body magnetic resonance imaging (MRI) to assess the relationship between IHCL accumulation, total body adipose tissue (AT) content/distribution, and IMCL content in 11 subjects with biopsy proven hepatic steatosis and 23 normal volunteers. RESULTS: IHCL signals were detectable in all subjects but were significantly greater in hepatic steatosis (geometric mean (GM) 11.5 (interquartile range (IQR) 7.0-39.0)) than in normal volunteers (GM 2.7 (IQR 0.7-9.3); p=0.02). In the study group as a whole, IHCL levels were significantly greater in overweight compared with lean subjects (body mass index (BMI) >25 kg/m2 (n=23): GM 7.7 (IQR 4.0-28.6) v BMI <25 kg/m2 (n=11): GM 1.3 (IQR 0.3-3.6; p=0.004)). There was a significant association between IHCL content and indices of overall obesity (expressed as a percentage of body weight) for total body fat (p=0.001), total subcutaneous AT (p=0.007), and central obesity (subcutaneous abdominal AT (p=0.001) and intra-abdominal AT (p=0.001)), after allowing for sex and age. No correlation between IHCL content and IMCL was observed. A significant correlation was observed between serum alanine aminotransferase and liver fat content (r=0.57, p=0.006). CONCLUSIONS: Our results suggest that hepatic steatosis appears to be closely related to body adiposity, especially central obesity. MRS may be a useful method for monitoring IHCL in future interventional studies.

The effect of remifentanil on the middle latency auditory evoked response and haemodynamic measurements with and without the stimulus of orotracheal intubation.

BACKGROUND AND OBJECTIVE: Changes in the middle latency auditory evoked response following the administration of opioids have been shown. However, it remains unclear as to whether these changes are due to a direct depressant effect of opioids on the middle latency auditory evoked response itself, or an indirect effect on account of their action in attenuating central nervous system arousal associated with noxious stimuli. By comparing changes in the middle latency auditory evoked response in intubated and non-intubated patients, receiving saline or remifentanil in different doses, this study attempts to answer this question. METHODS: Fifty-four patients were anaesthetized with isoflurane and nitrous oxide (0.9 MAC) and randomized to 1-6 groups. Groups 1-3 received a bolus injection of either saline 0.9%, low-dose remifentanil (1 microg kg(-1)) or high-dose remifentanil (3 microg kg(-1)) prior to intubation of the trachea. Groups 4-6 were not intubated following the bolus injection. RESULTS: Pa and Nb amplitudes of the middle latency auditory evoked response increased by 82% and 79% with intubation in the saline group (P < 0.005) and these changes were not seen in the patients given remifentanil. There was a significant linear trend for the reduction in Pa and Nb amplitude with increasing remifentanil dose (P < 0.05). In the absence of endotracheal intubation remifentanil had no effect on either the amplitudes or latencies of the waves Pa and Nb and there was no effect of dose. For the haemodynamic measurements remifentanil attenuated the pressor response to intubation (P < 0.001) and had a significant dose-related effect (P < 0.001) in the absence of intubation. CONCLUSIONS: We demonstrated an effect of remifentanil on both the middle latency auditory evoked response and haemodynamic changes to endotracheal intubation. For the non-intubated patients there was only an effect of remifentanil on the haemodynamic measurements. This suggests that remifentanil has an effect on the middle latency auditory evoked response in attenuating the arousal associated with intubation of the trachea but has no effect in the absence of a stimulus.