An international, open-label, randomised trial comparing a two-step approach versus the standard three-step approach of the WHO analgesic ladder in patients with cancer.

BACKGROUND: Worldwide, cancer pain management follows the World Health Organization (WHO) three-step analgesic ladder. Using weak opioids (e.g. codeine) at step 2 is debatable with low-dose strong opioids being potentially better, particularly in low- and middle-income countries where weak opioids are expensive. We wanted to assess the efficiency, safety and cost of omitting step 2 of the WHO ladder. PATIENTS AND METHODS: We carried out an international, open-label, randomised (1 : 1) parallel group trial. Eligible patients had cancer, pain ≥4/10 on a 0-10 numerical rating scale, required at least step 1 (paracetamol) of the WHO ladder and were randomised to the control arm (weak opioid, step 2 of the WHO ladder) or the experimental arm (strong opioid, step 3). Primary outcome was time to stable pain control (3 consecutive days with pain ≤3). Secondary outcomes included distress, opioid-related side-effects and costs. The primary outcome analysis was by intention to treat and the follow-up was for 20 days. RESULTS: One hundred and fifty-three patients were randomised (76 control, 77 experimental). There was no statistically significant difference in time to stable pain control between the arms, P = 0.667 (log-rank test). The adjusted hazard ratio for the control arm was 1.03 (95% confidence interval 0.72-1.49). In the control arm, 38 patients (53%) needed to change to a strong opioid due to ineffective analgesia. The median time to change was day 6 (interquartile range 4-11). Compared to the control arm, patients in the experimental arm had less nausea (P = 0.009) and costs were less. CONCLUSION: This trial provides some evidence that the two-step approach is an alternative option for cancer pain management.

Elevated Baseline C-Reactive Protein as a Predictor of Outcome After Aneurysmal Subarachnoid Hemorrhage: Data From the Simvastatin in Aneurysmal Subarachnoid Hemorrhage (STASH) Trial.

BACKGROUND: There remains a proportion of patients with unfavorable outcomes after aneurysmal subarachnoid hemorrhage, of particular relevance in those who present with a good clinical grade. A forewarning of those at risk provides an opportunity towards more intensive monitoring, investigation, and prophylactic treatment prior to the clinical manifestation of advancing cerebral injury. OBJECTIVE: To assess whether biochemical markers sampled in the first days after the initial hemorrhage can predict poor outcome. METHODS: All patients recruited to the multicenter Simvastatin in Aneurysmal Hemorrhage Trial (STASH) were included. Baseline biochemical profiles were taken between time of ictus and day 4 post ictus. The t-test compared outcomes, and a backwards stepwise binary logistic regression was used to determine the factors providing independent prediction of an unfavorable outcome. RESULTS: Baseline biochemical data were obtained in approximately 91% of cases from 803 patients. On admission, 73% of patients were good grade (World Federation of Neurological Surgeons grades 1 or 2); however, 84% had a Fisher grade 3 or 4 on computed tomographic scan. For patients presenting with good grade on admission, higher levels of C-reactive protein, glucose, and white blood cells and lower levels of hematocrit, albumin, and hemoglobin were associated with poor outcome at discharge. C-reactive protein was found to be an independent predictor of outcome for patients presenting in good grade. CONCLUSION: Early recording of C-reactive protein may prove useful in detecting those good grade patients who are at greater risk of clinical deterioration and poor outcome.

Group therapy for people with bulimia nervosa: systematic review and meta-analysis.

BACKGROUND: Approximately 25% of people with bulimia nervosa (BN) who undertake therapy are treated in groups. National guidelines do not discriminate between group and individual therapy, yet each has potential advantages and disadvantages and it is unclear how their effects compare. We therefore evaluated how group therapy for BN compares with individual therapy, no treatment, or other therapies, in terms of remission from binges and binge frequency. METHOD: We performed a systematic review and meta-analysis of randomized controlled trials of group therapies for BN, following standard guidelines. RESULTS: A total of 10 studies were included. Studies were generally small with unclear risk of bias. There was low-quality evidence of a clinically relevant advantage for group cognitive behavioural therapy (CBT) over no treatment at therapy end. Remission was more likely with group CBT versus no treatment [relative risk (RR) 0.77, 95% confidence interval (CI) 0.62-0.96]. Mean weekly binges were lower with group CBT versus no treatment (2.9 v. 6.9, standardized mean difference = -0.56, 95% CI -0.96 to -0.15). One study provided low-quality evidence that group CBT was inferior compared with individual CBT to a clinically relevant degree for remission at therapy end (RR 1.24, 95% CI 1.03-1.50); there was insufficient evidence regarding frequency of binges. CONCLUSIONS: Conclusions could only be reached for CBT. Low-quality evidence suggests that group CBT is effective compared with no treatment, but there was insufficient or very limited evidence about how group and individual CBT compared. The risk of bias and imprecise estimates of effect invite further research to refine and increase confidence in these findings.

Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events.

BACKGROUND: The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS. DESIGN: An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events. METHODS: Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events. RESULTS: In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women. CONCLUSIONS: An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

Systematic review of head cooling in adults after traumatic brain injury and stroke.

BACKGROUND: Brain injuries resulting from trauma and stroke are common and costly. Cooling therapy may reduce damage and potentially improve outcome. Head cooling targets the site of injury and may have fewer side effects than systemic cooling, but there has been no systematic review and the evidence base is unclear. OBJECTIVE: To assess the effect of non-invasive head cooling after traumatic brain injury (TBI) and stroke on intracranial and/or core body temperature, functional outcome and mortality, determine adverse effects and evaluate cost-effectiveness. REVIEW METHODS: Search strategy Major international databases [including MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Web of Science, the British Library's Electronic Table of Contents (Zetoc)], The Cochrane Library, trial registers, country-specific databases (including China, Japan), Google Scholar, hypothermia conference reports and reference lists of papers were searched with no publication or language restrictions. The searches were conducted from March 2010 to April 2011, with no back date restriction. Selection criteria For formal analysis of effect of head cooling on functional outcome and mortality: randomised controlled trials (RCTs) of non-invasive head cooling in TBI or stroke in adults (aged ≥ 18 years). RCT prespecified in protocol to include adequate randomisation and blinded outcome assessment. For assessment of effect on temperature and adverse effects of cooling methods/devices: studies of any type in TBI, stroke, cardiac arrest and neonatal hypoxic-ischaemic encephalopathy (adverse effects only). Data collection and analysis A study assessment and data collection form was developed and piloted. Data on functional outcome, mortality, temperature change and adverse effects of devices were sought and extracted. Two authors independently assessed RCTs for quality using the Cochrane Renal Group checklist. RESULTS: Out of 46 head-cooling studies in TBI and stroke, there were no RCTs of suitable quality for formal outcome analysis. Twelve studies had useable data on intracranial and core body temperature. These included 99 patients who were cooled after TBI or stroke and 198 patients cooled after cardiac arrest. The data were too heterogeneous for a single summary measure of effect (many studies had no measure of spread) and are therefore presented descriptively. The most effective techniques for which there were adequate data (nasal coolant and liquid cooling helmets) could reduce intracranial temperature by ≥ 1 °C in 1 hour. The main device-related adverse effects were localised skin problems, which were generally mild and self-limiting. There were no suitable data for economic modelling, but an exploratory model of possible treatment effects and cost-effectiveness of head cooling in TBI was created using local patient data. LIMITATIONS: We conducted extensive and sensitive searches but found no good-quality RCTs of the effect of head cooling on functional outcome that met the review inclusion criteria. Most trials were small and/or of low methodological quality. However, if the trial reports did not reflect the true quality of the research, there may be some excluded trials that should have been included. Temperature data were often poorly reported which made it difficult to assess the effect of head cooling on temperature. CONCLUSIONS: Whether head cooling improves functional outcome or has benefits and fewer side effects compared with systemic cooling or no cooling could not be established. Some methods of head cooling can reduce intracranial temperature, which is an important first step in determining effectiveness, but there is insufficient evidence to recommend its use outside of research trials. The principal recommendations for research are that active cooling devices show the most promise for further investigation and more robust proof of concept of intracranial and core body temperature reduction with head cooling is required, clearly showing whether temperature has changed and by how much. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Application of Variable Life Adjusted Display (VLAD) to risk-adjusted mortality of esophagogastric cancer surgery.

PURPOSE: In the new era of revalidation, there is an increasing need to measure surgical outcome objectively. We apply a graphical method, the Variable Life Adjusted Display (VLAD), to esophagogastric resection for malignancy. This technique charts the cumulative difference between expected and actual risk-adjusted mortality over time, allowing observation of performance trends irrespective of case-mix. METHODS: P-POSSUM was applied retrospectively to 182 consecutive patients who underwent resection for esophageal or gastric malignancy in a district general hospital. The primary outcome measured was 30-day mortality. RESULTS: A total of 168 patients were eligible for inclusion, with a median age of 68 years. The overall 30-day mortality rate was 4.2% compared with 7.1% as predicted by P-POSSUM. The resulting VLAD plot demonstrates an upward trend of better than predicted surgical performance. CONCLUSIONS: VLAD has been hereby applied to esophagogastric surgery and has graphically demonstrated risk-adjusted trends in a single general surgeon's performance. For qualitative comparative purposes, including recertification, VLAD is judged to be a simple, directly interpretable, and useful technique for monitoring surgical performance.

Reprinted article "The fate of the claudicant--a prospective study of 1969 claudicants".

A prospective study of 1969 patients with intermittent claudication receiving placebo medication for a minimum of 1 year is reported. Patients were carefully monitored and only four patients were lost to follow-up. Annual mortality was 4.3%. Thirty-six patients developed a definite myocardial infarction, 27 a major stroke, 32 required a major amputation and 111 required surgical or radiological intervention for deteriorating ischaemia of the leg. The entry characteristics of the patients were analysed as a predictor of serious cardiovascular events. The most sensitive predictors of total mortality were age, history of coronary heart disease and an ankle/arm pressure ratio below 0.5. Of the laboratory measurements performed only the initial white cell count was a significant predictor of myocardial infarction, stroke and vascular deaths.

Randomised comparison of uterine artery embolisation (UAE) with surgical treatment in patients with symptomatic uterine fibroids (REST trial): 5-year results.

OBJECTIVE: To compare the long-term results of uterine artery embolisation (UAE) with surgery for women with symptomatic uterine fibroids. DESIGN: Pragmatic, open, multicentre, randomised trial. SETTING: Twenty-seven participating UK secondary care centres. SAMPLE: Women aged ≥18 years with symptomatic fibroids who were considered to justify surgical treatment. METHODS: In total, 157 women were randomised (in a 2:1 ratio): 106 to UAE and 51 to surgery (hysterectomy 42; myomectomy nine). MAIN OUTCOME MEASURES: Quality of life at 5 years, as assessed by the Short Form General Health Survey (SF-36). Secondary measures included complications, adverse events and the need for further intervention. RESULTS: There were no significant differences between groups in any of the eight components of the SF-36 scores at 5 years (minimum P = 0.45). Symptom score reduction and patient satisfaction with either treatment was very high, with no group difference. Rates of adverse events were similar in both groups (19% embolization and 25% surgery; P = 0.40). The 5-year intervention rate for treatment failure or complications was 32% (UAE arm) and 4% (surgery arm), respectively. The initial cost benefit of UAE over surgery at 12 months was substantially reduced because of subsequent interventions, with treatments being cost neutral at 5 years. CONCLUSIONS: We have found that UAE is a satisfactory alternative to surgery for fibroids. The less invasive nature of UAE needs to be balanced against the need for re-intervention in almost a third of patients. The choice should lie with the informed patient.

The effects of uterine artery embolisation and surgical treatment on ovarian function in women with uterine fibroids.

OBJECTIVE: The aim of this study was to evaluate and compare both ovarian function and menstrual characteristics following uterine artery embolisation (UAE) and surgery. DESIGN: Subgroup of women from a randomised controlled trial. SETTING: Gynaecology and radiology units in Scotland, UK. POPULATION: Ninety-six women from the randomised controlled trial comparing embolisation with surgery as a treatment for fibroids (REST), which recruited 157 patients (106 UAE; 51 surgery). METHODS: Seventy-three women undergoing UAE and 23 women undergoing surgery (with ovarian conservation) had serum follicle-stimulating hormone (FSH) measurements taken on day 3 of the menstrual cycle prior to treatment, and at 6 and 12 months post-treatment. Data on menstrual cycle characteristics was also collected. MAIN OUTCOME MEASURES: Ovarian failure, as defined by an FSH level of >40 iu/l, and change in duration of menses and length of menstrual cycle. RESULTS: There was no significant difference in the rate of ovarian failure at 12 months between UAE (11%) and surgical patients (18%) (P = 0.44). This finding was not influenced by age. The mean duration of menstrual flow decreased significantly, from baseline to 12 months, by 1.7 days (SD 3.8), (95% CI 0.8-2.6). There was no statistically significant change in mean cycle length at 12 months (0.7 days [SD 4.9]; 95% CI [-0.5, 1.9]). CONCLUSIONS: There is no evidence for UAE accelerating a deterioration in ovarian function at 1 year, when compared with surgery. UAE is associated with a decrease in the duration of menstrual flow at 1 year.

Associations between polymorphisms in five inflammation-related genes and cognitive ability in older persons.

Several studies have found associations between inflammatory biomarker levels and cognitive ability. This study tested the relationship between polymorphisms in genes that are associated with or encode the biomarkers and cognitive ability and estimated lifetime cognitive change. Data came from the aspirin for asymptomatic atherosclerosis trial (n = 2091, mean age = 67.2 years ). Twelve single nucleotide polymorphisms (SNPs) were genotyped from five genes (IL-1alpha, IL-1beta, IL-6, HNF-1A and F13A1). Cognition was assessed via administration of a five-test battery of psychometric tests, which were used to derive a general intelligence factor, g. A vocabulary-based cognitive test was also administered and adjusted for in the analysis to enable an estimation of lifetime cognitive change. Age- and sex-adjusted analyses yielded one weakly significant association between the IL-1alpha rs2856838 SNP and a measure of mental flexibility/processing speed (P = 0.044). Adjustment for the vocabulary-based scores resulted in a single, significant association between the IL-1alpha rs3783546 SNP and a measure of processing speed (P = 0.048). There is little evidence to suggest an association between SNPs in the inflammation-related genes IL-1alpha, IL-1beta, IL-6, TCF-1 and F13A1 and cognition in an elderly population of community-dwelling Scottish citizens.

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Forced convective head cooling device reduces human cross-sectional brain temperature measured by magnetic resonance: a non-randomized healthy volunteer pilot study.

BACKGROUND: This pilot study in five healthy adult humans forms the pre-clinical assessment of the effect of a forced convective head cooling device on intracranial temperature, measured non-invasively by magnetic resonance spectroscopy (MRS). METHODS: After a 10 min baseline with no cooling, subjects received 30 min of head cooling followed by 30 min of head and neck cooling via a hood and neck collar delivering 14.5 degrees C air at 42.5 litre s(-1). Over baseline and at the end of both cooling periods, MRS was performed, using chemical shift imaging, to measure brain temperature simultaneously across a single slice of brain at the level of the basal ganglia. Oesophageal temperature was measured continuously using a fluoroptic thermometer. RESULTS: MRS brain temperature was calculated for baseline and the last 10 min of each cooling period. The net brain temperature reduction with head cooling was 0.45 degrees C (SD 0.23 degrees C, P=0.01, 95% CI 0.17-0.74 degrees C) and with head and neck cooling was 0.37 degrees C (SD 0.30 degrees C, P=0.049, 95% CI 0.00-0.74 degrees C). The equivalent net reductions in oesophageal temperature were 0.16 degrees C (SD 0.04 degrees C) and 0.36 degrees C (SD 0.12 degrees C). Baseline-corrected brain temperature gradients from outer through intermediate to core voxels were not significant for either head cooling (P=0.43) or head and neck cooling (P=0.07), indicating that there was not a significant reduction in cooling with progressive depth into the brain. CONCLUSIONS: Convective head cooling reduced MRS brain temperature and core brain was cooled.

Enhanced upper respiratory tract airflow and head fanning reduce brain temperature in brain-injured, mechanically ventilated patients: a randomized, crossover, factorial trial.

BACKGROUND: Heat loss from the upper airways and through the skull are physiological mechanisms of brain cooling which have not been fully explored clinically. METHODS: This randomized, crossover, factorial trial in 12 brain-injured, orally intubated patients investigated the effect of enhanced nasal airflow (high flow unhumidified air with 20 p.p.m. nitric oxide gas) and bilateral head fanning on frontal lobe brain temperature and selective brain cooling. After a 30 min baseline, each patient received the four possible combinations of the interventions--airflow, fanning, both together, no intervention--in randomized order. Each combination was delivered for 30 min and followed by a 30 min washout, the last 5 min of which provided the baseline for the next intervention. RESULTS: The difference in mean brain temperature over the last 5 min of the preceding washout minus the mean over the last 5 min of intervention, was 0.15 degrees C with nasal airflow (P=0.001, 95% CI 0.06-0.23 degrees C) and 0.26 degrees C with head fanning (P<0.001, 95% CI 0.17-0.34 degrees C). The estimate of the combined effect of airflow and fanning on brain temperature was 0.41 degrees C. Selective brain cooling did not occur. CONCLUSION: Physiologically, this study demonstrates that heat loss through the upper airways and through the skull can reduce parenchymal brain temperature in brain-injured humans and the onset of temperature reduction is rapid. Clinically, in ischaemic stroke, a temperature decrease of 0.27 degrees C may reduce the relative risk of poor outcome by 10-20%. Head fanning may have the potential to achieve a temperature decrease of this order.

Selectivity of NSAIDs for COX-2 and cardiovascular outcome.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) with increased selectivity for the cyclooxygenase-2 (COX-2) isoform reduce gastrotoxicity but may increase adverse cardiovascular events. METHODS: We searched the literature for studies that reported the odds ratio (OR) for such events following exposure to NSAIDs. RESULTS: For studies comparing NSAID use with no use, increased COX-2 selectivity was significantly related to cardiovascular risk (log OR) amongst observational studies (R = -0.34, P < 0.001) and randomized controlled trials (RCTs) (R = -0.56, P < 0.001). For studies comparing NSAIDs, difference in selectivity was related to risk for observational studies (R = -0.28, P = 0.005) but not for RCTs (R = -0.23, P = 0.15). CONCLUSIONS: Although increased COX-2 selectivity may reduce gastrotoxicity, this may be at the cost of increasing cardiovascular risk.

Disability in young people and adults after head injury: 5-7 year follow up of a prospective cohort study.

BACKGROUND: Improvement 1-2 years after head injury is well established but the pattern thereafter is unclear. Past studies have not examined representative head injury populations and typically report findings in terms of functioning across social, psychological, neurobehavioural, or cognitive domains rather than global outcome. OBJECTIVE: To determine the late outcome of a representative cohort of participants admitted to hospital after a head injury 5-7 years previously and to identify early and late factors correlating with persisting disability and change between one and 5-7 years. METHODS: A representative cohort of head injured people whose outcome one year after injury was reported previously, were followed up 5-7 years after injury. Participants were assessed using structured and validated measures of global outcome (Glasgow Outcome Scale Extended), cognitive impairment, psychological wellbeing, health status, and social factors. RESULTS: Of 475 survivors studied at one year, 115 (24%) had died by seven years. In survivors at 5-7 years, disability remained frequent (53%); and the rate, similar to that found at one year (57%). Sixty three participants (29%) had improved but 55 (25%) deteriorated. The persistence of disability and its development after previous recovery each showed stronger associations with indices of depression, anxiety, and low self-esteem than with initial severity of injury or persisting cognitive impairment. CONCLUSIONS: Admission to hospital after head injury is followed 5-7 years later by disability in a high proportion of survivors. Persistence of disability and development of new disability are strongly associated with psychosocial factors that may be open to remediation, even late after injury.

Risk of mortality and cardiovascular disease associated with the ankle-brachial index: Systematic review.

OBJECTIVE: To determine the strength and consistency with which a low ankle brachial pressure index (ABI), measured in the general population, is associated with an increased risk of subsequent death and/or cardiovascular events. DESIGN: Systematic review. DATA SOURCES: Medline, Embase, reference lists and grey literature were searched; studies known to experts were also retrieved. MAIN OUTCOME MEASURES: All cause mortality, fatal and non-fatal coronary heart disease and stroke. REVIEW METHODS: Longitudinal studies in which participants were representative of the general population (all ages, either sex) and which used any standard method for measurement and calculation of the ABI. Studies in which participants were selected according to presence of pre-existing disease or were post intervention (e.g. angioplasty or peripheral arterial grafting) were excluded. RESULTS: 11 studies comprising 44,590 subjects from six different countries were included. Despite clinical heterogeneity between studies, the findings were remarkably consistent in demonstrating an increased risk of clinical cardiovascular disease associated with a low ABI. A low ABI (<0.9) was associated with an increased risk of subsequent all cause mortality (pooled RR 1.60, 95% CI 1.32-1.95), cardiovascular mortality (pooled RR 1.96, 95% CI 1.46-2.64), coronary heart disease (pooled RR 1.45, 95% CI 1.08-1.93) and stroke (pooled RR 1.35, 95% CI 1.10-1.65) after adjustment for age, sex, conventional cardiovascular risk factors and prevalent cardiovascular disease. CONCLUSIONS: The ABI may help to identify asymptomatic individuals in the general population who are at increased risk of subsequent cardiovascular events. Evaluation is now required of the potential of incorporating ABI measurement into cardiovascular prevention programmes.

The association between APOE epsilon4, age and outcome after head injury: a prospective cohort study.

Previous preliminary studies have suggested that possession of the APOE epsilon4 allele is associated with a poor outcome after head injury. This study was designed to confirm and extend those observations in a larger study with examination of additional variables. We prospectively identified admissions to a Neurosurgical Unit for head injury, collected demographic and clinical data, determined APOE genotypes and obtained follow-up information at 6 months. A total of 1094 subjects were enrolled (age range: 0-93 years, mean 37 years). Outcome was assessed using the Glasgow Outcome Scale. There was no overall association between APOE genotype and outcome, with 36% of APOE epsilon4 carriers having an unfavourable outcome compared with 33% of non-carriers of APOE epsilon4. However, there was evidence of an interaction between age and APOE genotype on outcome (P = 0.007) such that possession of APOE epsilon4 reduced the prospect of a favourable outcome in children and young adults. The influence of APOE genotype in younger patients after head injury can be expressed as, at age <15 years, carriage of APOE epsilon4 being equivalent to ageing by 25 years. This finding is consistent with experimental data suggesting that the effect of APOE genotype on outcome after head injury may be expressed through the processes of repair and recovery.

Randomized controlled trial of effects of the airflow through the upper respiratory tract of intubated brain-injured patients on brain temperature and selective brain cooling.

BACKGROUND: Pyrexia is common after brain injury; it is generally believed to affect outcome adversely and the usual clinical methods of reducing temperature are not effective. The normal physiological mechanisms of brain cooling are heat loss from the upper airways and through the skull, and these can produce selective brain cooling. METHODS: Air at room temperature and humidity was continuously administered to 15 brain-injured, intubated and mechanically ventilated patients via a sponge-tipped oxygen catheter in each nostril at a combined rate of 115 ml kg(-1) min(-1). Brain temperature was measured using a pressure-temperature Camino catheter which is designed to site the thermistor 1 cm into the parenchyma in the frontal lobe. Oesophageal temperature was measured using an oesophageal stethoscope with a thermistor. After establishing baseline for 30 min, patients were randomized to receive airflow or no airflow for 6 h and then crossed over for a further 6 h. RESULTS: Airflow replicating normal resting minute volume did not produce clinically relevant or statistically significant reductions in brain temperature [0.13 (SD 0.55) degrees C; 95% CI, 0.43-0.17 degrees C]. However, we serendipitously found some evidence of selective brain cooling via the skull, but this needs further substantiation. CONCLUSIONS: A flow of humidified air at room temperature through the upper respiratory tracts of intubated brain-injured patients did not produce clinically relevant or statistically significant reductions in brain temperature measured in the frontal lobe.

Clinical trials in traumatic brain injury: current problems and future solutions.

Over the past decade many neuroprotective agents have been developed with the hope of being able to improve outcome in patients with traumatic brain injury. Unfortunately, none of the phase III trials performed have convincingly demonstrated efficacy in the overall population. A common misconception is that consequently these agents are ineffective. Such has not been proven and some trials show evidence of efficacy in subgroups of the population studied. The negative results, as reported in the overall population, may in part be caused by specific aspects of the TBI population, as well as by aspects of clinical trial design and analysis. Clinical trials in TBI pose several complicated design issues. Methodological challenges relate particularly to heterogeneity of the population and to outcome assessment. Heterogeneity pertains both to the range of pathologies included in TBI, and to prognostic factors, each causing specific problems. Mechanistic and/or prognostic targeting, as well as possibilities for covariate adjustment, are suggested as possible solutions to deal with the problems of heterogeneity. The aim in most trials was to demonstrate a 10% absolute improvement in favorable outcome in patients with head injury. This may be considered overoptimistic and unrealistic in relation to the heterogeneous patient population. Specific problems are further incurred by the use of the dichotomized Glasgow Outcome Scale as primary outcome measure. Optimal statistical power may expected to be present when the point of dichotomization results in a 50:50 distribution of outcome categories. It is proposed to differentiate the point of dichotomization according to prognostic risk profile, in order to maintain statistical power. Solutions described may be expected to enhance chances of demonstrating benefit of potentially effective neuroprotective agents in future studies. The complexity of problems occurring in clinical trial design and analysis in TBI is such that a strong and sustained multidisciplinary input and effort is required from all experts involved in the field of neurotrauma.

Effects of carvedilol on left ventricular remodelling in chronic stable heart failure: a cardiovascular magnetic resonance study.

BACKGROUND: The ability of beta blockers to improve left ventricular function has been demonstrated, but data on the effects on cardiac remodelling are limited. OBJECTIVE: To investigate, using cardiovascular magnetic resonance (CMR), the effects of carvedilol on left ventricular remodelling in patients with chronic stable heart failure and left ventricular systolic dysfunction caused by coronary artery disease. DESIGN: Randomised, double blind, placebo controlled study. SETTING: Chronic stable heart failure. PATIENTS AND INTERVENTION: 34 patients with chronic stable heart failure and left ventricular systolic function taking part in the CHRISTMAS trial (double blind carvedilol v placebo) underwent CMR before randomisation and after six months of treatment. MAIN OUTCOME MEASURE: Left ventricular remodelling at six months. RESULTS: The carvedilol and placebo groups were well balanced at baseline, with no significant intergroup differences. Over the study period, there was a significant reduction in end systolic volume index (ESV(I)) and end diastolic volume index (EDV(I)) between the carvedilol and the placebo group (carvedilol -9 v placebo +3 ml/m2, p = 0.0004; carvedilol -8 v placebo 0 ml/m2, p = 0.05). The ejection fraction increased significantly between the groups (carvedilol +3% v placebo -2%, p = 0.003). CONCLUSIONS: Treatment of chronic stable heart failure with carvedilol results in significant improvement in left ventricular volumes and function. These effects might contribute to the benefits of carvedilol on mortality and morbidity in patients with chronic heart failure.