Isabella Butcher

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.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.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lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies.Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect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.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.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.Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Background Traumatic brain injury (TBI) is a leading cause of death and disability. A reliable prediction of outcome on admission is of great clinical relevance. We aimed to develop prognostic models with readily available traditional and novel predictors. Methods and Findings Prospectively collected individual patient data were analyzed from 11 studies. We considered predictors available at admission in logistic regression models to predict mortality and unfavorable outcome according to the Glasgow Outcome Scale at 6 mo after injury. Prognostic models were developed in 8,509 patients with severe or moderate TBI, with cross-validation by omission of each of the 11 studies in turn. External validation was on 6,681 patients from the recent Medical Research Council Corticosteroid Randomisation after Significant Head Injury (MRC CRASH) trial. We found that the strongest predictors of outcome were age, motor score, pupillary reactivity, and CT characteristics, including the presence of traumatic subarachnoid hemorrhage. A prognostic model that combined age, motor score, and pupillary reactivity had an area under the receiver operating characteristic curve (AUC) between 0.66 and 0.84 at cross-validation. This performance could be improved (AUC increased by approximately 0.05) by considering CT characteristics, secondary insults (hypotension and hypoxia), and laboratory parameters (glucose and hemoglobin). External validation confirmed that the discriminative ability of the model was adequate (AUC 0.80). Outcomes were systematically worse than predicted, but less so in 1,588 patients who were from high-income countries in the CRASH trial. Conclusions Prognostic models using baseline characteristics provide adequate discrimination between patients with good and poor 6 mo outcomes after TBI, especially if CT and laboratory findings are considered in addition to traditional predictors. The model predictions may support clinical practice and research, including the design and analysis of randomized controlled trials.

We studied the prognostic value of a wide range of conventional and novel prognostic factors on admission after traumatic brain injury (TBI) using both univariate and multivariable analysis. The outcome measure was Glasgow Outcome Scale at 6 months after injury. Individual patient data were available on a cohort of 8686 patients drawn from eight randomized controlled trials and three observational studies. The most powerful independent prognostic variables were age, Glasgow Coma Scale (GCS) motor score, pupil response, and computerized tomography (CT) characteristics, including the Marshall CT classification and traumatic subarachnoid hemorrhage. Prothrombin time was also identified as a powerful independent prognostic factor, but it was only available for a limited number of patients coming from three of the relevant studies. Other important prognostic factors included hypotension, hypoxia, the eye and verbal components of the GCS, glucose, platelets, and hemoglobin. These results on prognostic factors will underpin future work on the IMPACT project, which is focused on the development of novel approaches to the design and analysis of clinical trials in TBI. In addition, the results provide pointers to future research, including further analysis of the prognostic value of prothrombin time, and the evaluation of the clinical impact of intervening aggressively to correct abnormalities in hemoglobin, glucose, and coagulation.

We determined the relationship between secondary insults (hypoxia, hypotension, and hypothermia) occurring prior to or on admission to hospital and 6-month outcome after traumatic brain injury (TBI). A meta-analysis of individual patient data, from seven Phase III randomized clinical trials (RCT) in moderate or severe TBI and three TBI population-based series, was performed to model outcome as measured by the Glasgow Outcome Scale (GOS). Proportional odds modeling was used to relate the probability of a poor outcome to hypoxia (N = 5661), hypotension ( N = 6629), and hypothermia ( N = 4195) separately. We additionally analyzed the combined effects of hypoxia and hypotension and performed exploratory analysis of associations with computerized tomography (CT) classification and month of injury. Having a pre-enrollment insult of hypoxia, hypotension or hypothermia is strongly associated with a poorer outcome (odds ratios of 2.1 95% CI [1.7-2.6], 2.7 95% CI [2.1-3.4], and 2.2 95% CI [1.6-3.2], respectively). Patients with both hypoxia and hypotension had poorer outcomes than those with either insult alone. Radiological signs of raised intracranial pressure (CT class III or IV) were more frequent in patients who had sustained hypoxia or hypotension. A significant association was observed between month of injury and hypothermia. The occurrence of secondary insults prior to or on admission to hospital in TBI patients is strongly related to poorer outcome and should therefore be a priority for emergency department personnel.

We studied the prognostic strength of the individual components of the Glasgow Coma Scale (GCS) and pupil reactivity to Glasgow Outcome Score (GOS) at 6 months post-injury. A total of 8721 moderate or severe traumatic brain injury (TBI) patient data from the IMPACT database on traumatic brain injury comprised the study cohort. The associations between motor score and pupil reactivity and 6-month GOS were analyzed by binary logistic regression and proportional odds methodology. The strength of prognostic effects were expressed as the unadjusted odds ratios presented for all individual studies as well as in meta-analysis. We found a consistent strong association between motor score and 6-month GOS across all studies (OR 1.74–7.48). The Eye and Verbal components were also strongly associated with GOS. In the pooled population, one or both un-reactive pupils and lower motor scores were significantly associated with unfavorable outcome (range 2.71–7.31). We also found a significant change in motor score from pre-hospital direct to study hospital enrollment ( p < 0.0001) and from the first in-hospital to study enrollment scores (p < 0.0001). Pupil reactivity was more robust between these time points. It is recommended that the study hospital enrollment GCS and pupil reactivity be used for prognostic analysis.

Rigorous, informative meta-analyses rely on availability of appropriate summary statistics or individual participant data. For continuous outcomes, especially those with naturally skewed distributions, summary information on the mean or variability often goes unreported. While full reporting of original trial data is the ideal, we sought to identify methods for handling unreported mean or variability summary statistics in meta-analysis. We undertook two systematic literature reviews to identify methodological approaches used to deal with missing mean or variability summary statistics. Five electronic databases were searched, in addition to the Cochrane Colloquium abstract books and the Cochrane Statistics Methods Group mailing list archive. We also conducted cited reference searching and emailed topic experts to identify recent methodological developments. Details recorded included the description of the method, the information required to implement the method, any underlying assumptions and whether the method could be readily applied in standard statistical software. We provided a summary description of the methods identified, illustrating selected methods in example meta-analysis scenarios. For missing standard deviations (SDs), following screening of 503 articles, fifteen methods were identified in addition to those reported in a previous review. These included Bayesian hierarchical modelling at the meta-analysis level; summary statistic level imputation based on observed SD values from other trials in the meta-analysis; a practical approximation based on the range; and algebraic estimation of the SD based on other summary statistics. Following screening of 1124 articles for methods estimating the mean, one approximate Bayesian computation approach and three papers based on alternative summary statistics were identified. Illustrative meta-analyses showed that when replacing a missing SD the approximation using the range minimised loss of precision and generally performed better than omitting trials. When estimating missing means, a formula using the median, lower quartile and upper quartile performed best in preserving the precision of the meta-analysis findings, although in some scenarios, omitting trials gave superior results. Methods based on summary statistics (minimum, maximum, lower quartile, upper quartile, median) reported in the literature facilitate more comprehensive inclusion of randomised controlled trials with missing mean or variability summary statistics within meta-analyses.

The International Mission on Prognosis and Analysis of Clinical Trials and Corticoid Randomisation After Significant Head injury prognostic models predict outcome after traumatic brain injury but have not been compared in large datasets. The objective of this is study is to validate externally and compare the International Mission on Prognosis and Analysis of Clinical Trials and Corticoid Randomisation after Significant Head injury prognostic models for prediction of outcome after moderate or severe traumatic brain injury.External validation study.We considered five new datasets with a total of 9,036 patients, comprising three randomized trials and two observational series, containing prospectively collected individual traumatic brain injury patient data.Outcomes were mortality and unfavorable outcome, based on the Glasgow Outcome Score at 6 months after injury. To assess performance, we studied the discrimination of the models (by area under the receiver operating characteristic curves), and calibration (by comparison of the mean observed to predicted outcomes and calibration slopes). The highest discrimination was found in the Trauma Audit and Research Network trauma registry (area under the receiver operating characteristic curves between 0.83 and 0.87), and the lowest discrimination in the Pharmos trial (area under the receiver operating characteristic curves between 0.65 and 0.71). Although differences in predictor effects between development and validation populations were found (calibration slopes varying between 0.58 and 1.53), the differences in discrimination were largely explained by differences in case mix in the validation studies. Calibration was good, the fraction of observed outcomes generally agreed well with the mean predicted outcome. No meaningful differences were noted in performance between the International Mission on Prognosis and Analysis of Clinical Trials and Corticoid Randomisation After Significant Head injury models. More complex models discriminated slightly better than simpler variants.Since both the International Mission on Prognosis and Analysis of Clinical Trials and the Corticoid Randomisation After Significant Head injury prognostic models show good generalizability to more recent data, they are valid instruments to quantify prognosis in traumatic brain injury.

Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both.We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270).Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13-0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20-0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5% CI 0·12-0·43; p<0·0001). The proportion of patients with a 50% increase in alanine aminotransferase activity did not differ between the standard (9/110) and shorter modified (13/112) regimens (adjusted odds ratio 0·60, 97·5% CI 0·20-1·83); however, the proportion was higher with ondansetron (16/111) than with placebo (6/111; 3·30, 1·01-10·72; p=0·024).In patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine regimen.Chief Scientist Office of the Scottish Government.

Outcome following traumatic brain injury (TBI) is not only dependent on the nature and severity of injury and subsequent treatment, but also on constituent characteristics of injured individuals. We aimed to describe and quantify the relationship between demographic characteristics and six month outcome assessed by the Glasgow Outcome Scale (GOS) after TBI. Individual patient data on age (n = 8719), gender (n = 8720), race (n = 5320), and education (n = 2201) were extracted from eight therapeutic Phase III randomized clinical trials and three surveys in moderate or severe TBI, contained in the IMPACT database. The strength of prognostic effects was analyzed with binary and proportional odds regression analysis and expressed as an odds ratio. Age was analyzed as a continuous variable with spline functions, and the odds ratio calculated over the difference between the 75 th and 25 th percentiles. Associations with other predictors were explored. Increasing age was strongly related to poorer outcome (OR 2.14; 95% CI 2.00–2.28) in a continuous fashion that could be approximated by a linear function. No gender differences in outcome were found (OR: 1.01; CI 0.92–1.11), and exploratory analysis failed to show any gender/age interaction. The studies included predominantly Caucasians (83%); outcome in black patients was poorer relative to this group (OR 1.30; CI 1.09–1.56). This relationship was sustained on adjusted analyses, and requires further study into mediating factors. Higher levels of education were weakly related to a better outcome (OR: 0.70; CI 0.52–0.94). On multivariable analysis adjusting for age, motor score, and pupils, the prognostic effect of race and education were sustained. We conclude that outcome following TBI is dependent on age, race, to a lesser extent on education, but not on gender.

Computerized tomography (CT) scanning provides an objective assessment of the structural damage to the brain following traumatic brain injury (TBI). We aimed to describe and quantify the relationship between CT characteristics and 6-month outcome, assessed by the Glasgow Outcome Scale (GOS). Individual patient data from the IMPACT database were available on CT classification (N = 5209), status of basal cisterns ( N = 3861), shift ( N = 4698), traumatic subarachnoid hemorrhage (tSAH) ( N = 7407), and intracranial lesions ( N = 7613). We used binary logistic and proportional odds regression for prognostic analyses. The CT classification was strongly related to outcome, with worst outcome for patients with diffuse injuries in CT class III (swelling; OR 2.50; CI 2.09–3.0) or CT class IV (shift; OR 3.03; CI 2.12–4.35). The prognosis in patients with mass lesions was better for patients with an epidural hematoma (OR 0.64; CI 0.56–0.72) and poorer for an acute subdural hematoma (OR 2.14; CI 1.87–2.45). Partial obliteration of the basal cisterns (OR 2.45; CI 1.88–3.20), tSAH (OR 2.64; CI 2.42–2.89), or midline shift (1–5 mm—OR 1.36; CI 1.09–1.68); >5 mm—OR 2.20; CI 1.64–2.96) were strongly related to poorer outcome. Discrepancies were found between the scoring of basal cisterns/shift and the CT classification, indicating observer variation. These were less marked in studies that had used a central review process. Multivariable analysis indicated that individual CT characteristics added substantially to the prognostic value of the CT classification alone. We conclude that both the CT classification and individual CT characteristics are important predictors of outcome in TBI. For clinical trials, a central review process is advocated to minimize observer variability in CT assessment.

The objective of this report is to describe the design and content of the International Mission for Prognosis And Clinical Trial (IMPACT) database of traumatic brain injury which contains the complete dataset from most clinical trials and organized epidemiologic studies conducted over the past 20 years. This effort, funded by the U.S. National Institutes of Health, has led to the accumulation thus far of data from 9205 patients with severe and moderate brain injuries from eight randomized placebo controlled trials and three observational studies. Data relevant to the design and analysis of pragmatic Phase III clinical trials, including pre-hospital, admission, and post-resuscitation assessments, information on the acute management, and short-and long-term outcome were merged into a top priority data set (TPDS). The major emphasis during the first phase of study is on information from time of injury to post-resuscitation and outcome at 6 months thereby providing a unique resource for prognostic analysis and for studies aimed at optimizing the design and analysis of Phase III trials in traumatic brain injury.

Abnormalities in laboratory parameters are frequent following traumatic brain injury (TBI), but few studies have investigated their predictive value. We aimed to describe and quantify the relation between laboratory parameters that are routinely determined on admission and final outcome following TBI. Individual patient data were available in the IMPACT database from six Phase III randomized controlled trials and one observational study in TBI. We studied glucose (N = 4834), sodium ( N = 5270), pH ( N = 3398), hemoglobin (Hb, N = 3875), platelet count ( N = 1629), and prothrombin time (PT; N = 840) for their associations with outcome at 6 months (Glasgow Outcome Scale [GOS]). We used logistic regression models with linear, quadratic, and restricted cubic spline functions. The strength of the associations was expressed as an unadjusted odds ratio, calculated over the shift in outcome between the 25th and 75th percentiles. Proportional odds methodology was further applied to quantify the strength of the associations across the full range of the GOS. All parameters were consistently associated with outcome in a continuous relationship: glucose and prothrombin time showed a positive linear relation to outcome (i.e., increasing values associated with poorer outcome) and Hb, platelets, and pH an inverse linear relation (i.e., low values associated with poorer outcome). Sodium demonstrated a U-shaped relation to outcome, with low levels being more strongly related to poorer outcome. Effects were strongest for increasing levels of glucose (odds ratio 1.7; 95% CI 1.54–1.83) and decreasing levels of Hb (odds ratio 0.7; CI 0.60–0.78). Higher glucose values were associated with increasing age, but on adjusted analysis, the strength of the association with outcome remained. Whether treatment of abnormal values may improve outcome needs further rigorous study.

Functional (psychogenic or somatoform) symptoms are common in neurology clinics. Cognitive-behavioral therapy (CBT) can be an effective treatment, but there are major obstacles to its provision in practice. We tested the hypothesis that adding CBT-based guided self-help (GSH) to the usual care (UC) received by patients improves outcomes.We conducted a randomized trial in 2 neurology services in the United Kingdom. Outpatients with functional symptoms (rated by the neurologist as "not at all" or only "somewhat" explained by organic disease) were randomly allocated to UC or UC plus GSH. GSH comprised a self-help manual and 4 half-hour guidance sessions. The primary outcome was self-rated health on a 5-point clinical global improvement scale (CGI) at 3 months. Secondary outcomes were measured at 3 and 6 months.In this trial, 127 participants were enrolled, and primary outcome data were collected for 125. Participants allocated to GSH reported greater improvement on the primary outcome (adjusted common odds ratio on the CGI 2.36 [95% confidence interval 1.17-4.74; p = 0.016]). The absolute difference in proportion "better" or "much better" was 13% (number needed to treat was 8). At 6 months the treatment effect was no longer statistically significant on the CGI but was apparent in symptom improvement and in physical functioning.CBT-based GSH is feasible to implement and efficacious. Further evaluation is indicated.This study provides Class III evidence that CBT-based GSH therapy improves self-reported general health, as measured by the CGI, in patients with functional neurologic symptoms.

To determine whether circulating levels of the inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha are associated with cognitive ability and estimated lifetime cognitive decline in an elderly population with type 2 diabetes.A cross-sectional study of 1,066 men and women aged 60-75 years with type 2 diabetes and living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study), was performed. Seven cognitive tests were used to measure abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility. The results were used to derive a general intelligence factor (g). A vocabulary-based test was administered as an estimate of peak prior cognitive ability. Results on the cognitive tests were assessed for statistical association with inflammatory markers measured in a venous blood sample at the time of cognitive testing.Higher IL-6 and TNF-alpha levels were associated with poorer age- and sex-adjusted scores on the majority of the individual cognitive tests. They were also associated with g using standardized regression coefficients -0.074 to -0.173 (P < 0.05). After adjusting for vocabulary, education level, cardiovascular dysfunction, duration of diabetes, and glycemic control, IL-6 remained associated with three of the cognitive tests and with g.In this representative population of people with type 2 diabetes, elevated circulating levels of inflammatory markers were associated with poorer cognitive ability. IL-6 levels were also associated with estimated lifetime cognitive decline.

Hypotension following traumatic brain injury (TBI) is recognized as an important secondary insult that is associated with adverse outcome. We aimed to describe the relationship between actual levels of admission blood pressure and Glasgow Outcome Scale (GOS) at 6 months. Individual patient data from the IMPACT database were available on systolic (N = 6801) and mean arterial (N = 6647) blood pressure. Regression models with restricted cubic spline functions were used to explore the shape of the relationships between blood pressure and outcome in unadjusted and adjusted analyses. Proportional odds methodology was applied to quantify the strength of the associations across the full range of the GOS. Analyses were performed to search for threshold values. A smooth U-shaped relationship was observed between systolic (SBP) and mean arterial (MABP) blood pressures and outcome, without any evidence of an abrupt threshold effect. Best outcomes were observed for values of SBP of the order of 135 mm Hg and for values of MABP of the order of 90 mm Hg. Both lower (OR 1.53; 95% CI: 1.31–1.80) and higher levels (OR 1.42; CI: 1.20–1.68) of SBP and lower (OR 1.30; CI 1.12–1.51) and higher levels of MABP (OR 1.45; CI 1.19–1.76) were associated with poorer outcome. These findings were consistent across studies. The relationship between high blood pressure level and poorer outcome largely disappeared on adjusted analysis. Current guidelines for the management of blood pressure in TBI focus on the avoidance of hypotension as defined by SBP < 90 mm Hg. Our finding of a smooth relationship with improving outcome as SBP increases up to 135 mm Hg, while not supporting a strong causal inference, does suggest that current guidelines need to be reconsidered.

Systematic screening for depression has been recommended for patients who have medical conditions like cancer. The 9-item Patient Health Questionnaire (PHQ-9) is becoming widely used, but its diagnostic accuracy has not yet been tested in a cancer patient population. In this article, the authors report on the performance of the PHQ-9 as a screening instrument for major depressive disorder (MDD) in patients with cancer.Data obtained from a depression screening service for patients who were attending clinics of a Regional Cancer Centre in Edinburgh, United Kingdom were used. Patients had completed both the PHQ-9 and a 2-stage procedure to identify cases of MDD. Performance of the PHQ-9 in identifying cases of MDD was determined using receiver operating characteristic (ROC) analysis.Data were available on 4264 patients. When scored as a continuous measure, the PHQ-9 performed well with an area under the ROC curve of 0.94 (95% confidence interval [CI], 0.93-0.95). A cutoff score of ≥ 8 provided a sensitivity of 93% (95% CI, 89%-95%), a specificity of 81% (95% CI, 80%-82%), a positive predictive value (PPV) of 25%, and a negative predictive value (NPV) of 99% and could be considered optimum in a screening context. The PHQ-9 did not perform as well when it was scored using an algorithm with a sensitivity of 56% (95% CI, 55%-57%), a specificity of 96% (95% CI, 95%-97%), a PPV of 52%, and an NPV of 97%.The PHQ-9 scored as a continuous measure with a cutoff score of ≥ 8 performed well in identifying MDD in cancer patients and should be considered as a screening instrument in this population.

Research in traumatic brain injury (TBI) is challenging for several reasons; in particular, the heterogeneity between patients regarding causes, pathophysiology, treatment, and outcome. Advances in basic science have failed to translate into successful clinical treatments, and the evidence underpinning guideline recommendations is weak. Because clinical research has been hampered by non-standardised data collection, restricted multidisciplinary collaboration, and the lack of sensitivity of classification and efficacy analyses, multidisciplinary collaborations are now being fostered. Approaches to deal with heterogeneity have been developed by the IMPACT study group. These approaches can increase statistical power in clinical trials by up to 50% and are also relevant to other heterogeneous neurological diseases, such as stroke and subarachnoid haemorrhage. Rather than trying to limit heterogeneity, we might also be able to exploit it by analysing differences in treatment and outcome between countries and centres in comparative effectiveness research. This approach has great potential to advance care in patients with TBI.

Clinical trials in traumatic brain injury (TBI) pose complex methodological challenges, largely related to the heterogeneity of the population. The International Mission on Prognosis and Clinical Trial Design in TBI study group has explored approaches for dealing with this heterogeneity with the aim to optimize clinical trials in TBI. Extensive prognostic analyses and simulation studies were conducted on individual patient data from eight trials and three observational studies. Here, we integrate the results of these studies into the International Mission on Prognosis and Clinical Trial Design in TBI recommendations for design and analysis of trials in TBI: Broad inclusion criteria, prespecified covariate adjustment, and an ordinal analysis will promote an efficient trial, yielding gains in statistical efficiency of more than 40%. This corresponds to being able to detect a 7% treatment effect with the same number of patients needed to demonstrate a 10% difference with an unadjusted analysis based on the dichotomized Glasgow outcome scale.

The American Academy of Pediatrics recommends a permissive hypoxaemic target for an oxygen saturation of 90% for children with bronchiolitis, which is consistent with the WHO recommendations for targets in children with lower respiratory tract infections. No evidence exists to support this threshold. We aimed to assess whether the 90% or higher target for management of oxygen supplementation was equivalent to a normoxic 94% or higher target for infants admitted to hospital with viral bronchiolitis.We did a parallel-group, randomised, controlled, equivalence trial of infants aged 6 weeks to 12 months of age with physician-diagnosed bronchiolitis newly admitted into eight paediatric hospital units in the UK (the Bronchiolitis of Infancy Discharge Study [BIDS]). A central computer randomly allocated (1:1) infants, in varying length blocks of four and six and without stratification, to be clipped to standard oximeters (patients treated with oxygen if pulse oxygen saturation [SpO2] <94%) or modified oximeters (displayed a measured value of 90% as 94%, therefore oxygen not given until SpO2 <90%). All parents, clinical staff, and outcome assessors were masked to allocation. The primary outcome was time to resolution of cough (prespecified equivalence limits of plus or minus 2 days) in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN28405428.Between Oct 3, and March 30, 2012, and Oct 1, and March 29, 2013, we randomly assigned 308 infants to standard oximeters and 307 infants to modified oximeters. Cough resolved by 15·0 days (median) in both groups (95% CI for difference -1 to 2) and so oxygen thresholds were equivalent. We recorded 35 serious adverse events in 32 infants in the standard care group and 25 serious adverse events in 24 infants in the modified care group. In the standard care group, eight infants transferred to a high-dependency unit, 23 were readmitted, and one had a prolonged hospital stay. In the modified care group, 12 infants were transferred to a high-dependency unit and 12 were readmitted to hospital. Recorded adverse events did not differ significantly.Management of infants with bronchiolitis to an oxygen saturation target of 90% or higher is as safe and clinically effective as one of 94% or higher. Future research should assess the benefits and risks of different oxygen saturation targets in acute respiratory infection in older children, particularly in developing nations where resources are scarce.National Institute for Health Research, Health Technology Assessment programme.

The Glasgow Outcome Scale (GOS) is firmly established as the primary outcome measure for use in Phase III trials of interventions in traumatic brain injury (TBI). However, the GOS has been criticized for its lack of sensitivity to detect small but clinically relevant changes in outcome. The Glasgow Outcome Scale-Extended (GOSE) potentially addresses this criticism, and in this study we estimate the efficiency gain associated with using the GOSE in place of the GOS in ordinal analysis of 6-month outcome. The study uses both simulation and the reanalysis of existing data from two completed TBI studies, one an observational cohort study and the other a randomized controlled trial. As expected, the results show that using an ordinal technique to analyze the GOS gives a substantial gain in efficiency relative to the conventional analysis, which collapses the GOS onto a binary scale (favorable versus unfavorable outcome). We also found that using the GOSE gave a modest but consistent increase in efficiency relative to the GOS in both studies, corresponding to a reduction in the required sample size of the order of 3–5%. We recommend that the GOSE be used in place of the GOS as the primary outcome measure in trials of TBI, with an appropriate ordinal approach being taken to the statistical analysis.

The susceptibility to type 2 diabetes of people of south Asian descent is established, but there is little trial-based evidence for interventions to tackle this problem. We assessed a weight control and physical activity intervention in south Asian individuals in the UK.We did this non-blinded trial in two National Health Service (NHS) regions in Scotland (UK). Between July 1, 2007, and Oct 31, 2009, we recruited men and women of Indian and Pakistani origin, aged 35 years or older, with waist circumference 90 cm or greater in men or 80 cm or greater in women, and with impaired glucose tolerance or impaired fasting glucose determined by oral glucose tolerance test. Families were randomised (using a random number generator program, with permuted blocks of random size, stratified by location [Edinburgh or Glasgow], ethnic group [Indian or Pakistani], and number of participants in the family [one vs more than one]) to intervention or control. Participants in the same family were not randomised separately. The intervention group received 15 visits from a dietitian over 3 years and the control group received four visits in the same period. The primary outcome was weight change at 3 years. Analysis was by modified intention to treat, excluding participants who died or were lost to follow-up. We used linear regression models to provide mean differences in baseline-adjusted weight at 3 years. This trial is registered, number ISRCTN25729565.Of 1319 people who were screened with an oral glucose tolerance test, 196 (15%) had impaired glucose tolerance or impaired fasting glucose and 171 entered the trial. Participants were in 156 family clusters that were randomised (78 families with 85 participants were allocated to intervention; 78 families with 86 participants were allocated to control). 167 (98%) participants in 152 families completed the trial. Mean weight loss in the intervention group was 1.13 kg (SD 4.12), compared with a mean weight gain of 0.51 kg (3.65) in the control group, an adjusted mean difference of -1.64 kg (95% CI -2.83 to -0.44).Modest, medium-term changes in weight are achievable as a component of lifestyle-change strategies, which might control or prevent adiposity-related diseases.National Prevention Research Initiative, NHS Research and Development; NHS National Services Scotland; NHS Health Scotland.

BACKGROUND: Differences between centers in patient outcome after traumatic brain injury are of importance for multicenter studies and have seldom been studied. OBJECTIVE: To quantify the differences in centers enrolling patients in randomized clinical trials (RCTs) and surveys. METHODS: We analyzed individual patient data from 9578 patients with moderate and severe traumatic brain injury enrolled in 10 RCTs and 3 observational studies. We used random-effects logistic regression models to estimate the between-center differences in unfavorable outcome (dead, vegetative state, or severe disability measured with the Glasgow Outcome Scale) at 6 months adjusted for differences in patient characteristics. We calculated the difference in odds of unfavorable outcome between the centers at the higher end vs those at the lower end of the outcome distribution. We analyzed the total database, Europe and the United States separately, and 4 larger RCTs. RESULTS: The 9578 patients were enrolled at 265 centers, and 4629 (48%) had an unfavorable outcome. After adjustment for patient characteristics, there was a 3.3-fold difference in the odds of unfavorable outcome between the centers at the lower end of the outcome distribution (2.5th percentile) vs those at the higher end of the outcome distribution (97.5th percentile; P < .001). In the 4 larger RCTs, the differences between centers were similar. However, differences were smaller between centers in the United States (2.4-fold) than between centers in Europe (3.8-fold). CONCLUSION: Outcome after traumatic brain injury differs substantially between centers, particularly in Europe. Further research is needed to study explanations for these differences to suggest where quality of care might be improved.

<b>Objective</b> To determine the effects of low dose aspirin on cognitive function in middle aged to elderly men and women at moderately increased cardiovascular risk. <b>Design</b> Randomised double blind placebo controlled trial. <b>Setting</b> Central Scotland. <b>Participants</b> 3350 men and women aged over 50 participating in the aspirin for asymptomatic atherosclerosis trial. <b>Intervention</b> Low dose aspirin (100 mg daily) or placebo for five years. <b>Main outcome measures</b> Tests of memory, executive function, non-verbal reasoning, mental flexibility, and information processing five years after randomisation, with scores used to create a summary cognitive score (general factor). <b>Results</b> At baseline, mean vocabulary scores (an indicator of previous cognitive ability) were similar in the aspirin (30.9, SD 4.7) and placebo (31.1, SD 4.7) groups. In the primary intention to treat analysis, there was no significant difference at follow-up between the groups in the proportion achieving over the median general factor cognitive score (32.7% and 34.8% respectively, odds ratio 0.91, 95% confidence interval 0.79 to 1.05, P=0.20) or in mean scores on the individual cognitive tests. There were also no significant differences in change in cognitive ability over the five years in a subset of 504 who underwent detailed cognitive testing at baseline. <b>Conclusion</b> Low dose aspirin does not affect cognitive function in middle aged to elderly people at increased cardiovascular risk. <b>Trial registration</b> ISRCTN 66587262.

Background Clinical trials in traumatic brain injury have a disappointing track record, with a long history of ‘negative’ Phase III trials. One contributor to this lack of success is almost certainly the low efficiency of the conventional approach to the analysis, which discards information by dichotomizing an ordinal outcome scale. Purpose Our goal was to evaluate the potential efficiency gains, which can be achieved by using techniques, which extract additional information from ordinal outcome data — the proportional odds model and the sliding dichotomy. In addition, we evaluated the additional efficiency gains, which can be achieved through covariate adjustment. Methods The study was based on simulations, which were built around a database of patient-level data extracted from eight Phase III trials and three observational studies in traumatic brain injury. Two different putative treatment effects were explored, one which followed the proportional odds model, and the other which assumed that the effect of the intervention was to reduce the risk of death without changing the distribution of outcomes within survivors. The results are expressed as efficiency gains, reported as the percentage reduction in sample size that can be used with the ordinal analyses without loss of statistical power relative to the conventional binary analysis. Results The simulation results show substantial efficiency gains. Use of the sliding dichotomy allows sample sizes to be reduced by up to 40% without loss of statistical power. The proportional odds model gives modest additional gains over and above the gains achieved by use of the sliding dichotomy. Limitations As with any simulation study, it is difficult to know how far the findings may be extrapolated beyond the actual situations that were modeled. Conclusions Both ordinal techniques offer substantial efficiency gains relative to the conventional binary analysis. The choice between the two techniques involves subtle value judgments. In the situations examined, the proportional odds model gave efficiency gains over and above the sliding dichotomy, but arguably, the sliding dichotomy is more intuitive and clinically appealing. Clinical Trials 2010; 7: 44—57. http://ctj.sagepub.com

Diabet. Med. 29, 328–336 (2012) Abstract Objective To determine the association between lifetime severe hypoglycaemia and late‐life cognitive ability in older people with Type 2 diabetes. Methods Cross‐sectional, population‐based study of 1066 men and women aged 60–75 years, with Type 2 diabetes. Frequency of severe hypoglycaemia over a person’s lifetime and in the year prior to cognitive testing was assessed using a previously validated self‐completion questionnaire. Results of age‐sensitive neuropsychological tests were combined to derive a late‐life general cognitive ability factor, ‘ g ’. Vocabulary test scores, which are stable during ageing, were used to estimate early life (prior) cognitive ability. Results After age‐ and sex‐ adjustment, ‘ g ‘ was lower in subjects reporting at least one prior severe hypoglycaemia episode ( n = 113), compared with those who did not report severe hypoglycaemia (mean ‘ g ’−0.34 vs. 0.05, P &lt; 0.001). Mean vocabulary test scores did not differ significantly between the two groups (30.2 vs. 31.0, P = 0.13). After adjustment for vocabulary, difference in ‘ g ’ between the groups persisted (means −0.25 vs. 0.04, P &lt; 0.001), with the group with severe hypoglycaemia demonstrating poorer performance on tests of Verbal Fluency (34.5 vs. 37.3, P = 0.02), Digit Symbol Testing (45.9 vs. 49.9, P = 0.002), Letter–Number Sequencing (9.1 vs. 9.8, P = 0.005) and Trail Making ( P &lt; 0.001). These associations persisted after adjustment for duration of diabetes, vascular disease and other potential confounders. Conclusions Self‐reported history of severe hypoglycaemia was associated with poorer late‐life cognitive ability in people with Type 2 diabetes. Persistence of this association after adjustment for estimated prior cognitive ability suggests that the association may be attributable, at least in part, to an effect of hypoglycaemia on age‐related cognitive decline.

Patients with serious medical illnesses, such as cancer, are at increased risk of suicide but are also often facing death. The Patient Health Questionnaire-9 (PHQ-9) is widely used to screen patients for depression. It includes an item that asks about thoughts of death and hurting yourself (Item-9). To describe the nature of thoughts of death and suicide reported in clinical interviews carried out to further assess suicidal ideation of cancer outpatients who had endorsed the “suicidal thoughts item” (Item-9) of the PHQ-9 during routine depression screening. Secondary analysis of anonymized service data (with ethical approval) derived from the routine clinical administration of self-report questionnaires and telephone interviews to outpatients attending a Cancer Centre in the UK. Complete data were available on 330/463 (71%) of patients who had endorsed Item-9. In a subsequent structured telephone interview, approximately one-third of these patients denied any thoughts that they would be better off dead, another third acknowledged having thoughts that they would be better off dead, but not of suicide, and the remaining third reported clear thoughts of committing suicide. Only one-third of cancer outpatients who endorse the “suicidal thoughts item” of the PHQ-9 report suicidal thoughts at a subsequent interview. Services planning to set up depression screening with the PHQ-9 need to carefully consider the relative benefits and burden to their service and patients of including Item-9 and interviewing all those who endorse it.

BackgroundThe purpose of the study was to determine the prevalence and associations of clinically relevant fatigue (CRF) in men with biochemically controlled prostate cancer on long-term androgen deprivation therapy (ADT).Patients and methodsOne hundred and ninety-eight men were surveyed and the prevalence of CRF (Brief Fatigue Inventory score >3) determined. Associations with other measures (Hospital Anxiety and Depression Scale; International Prostate Symptom Score; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; Brief Pain Inventory worst pain; clinical and demographic information) were explored in univariate and multivariate analyses.ResultsEight-one per cent (160 of 198) of questionnaires were analysable. CRF prevalence was 43% (68 of 160). CRF associations included moderate/severe urinary symptoms, anxiety and medical co-morbidities; the strongest associations were depression [odds ratio (OR) 9.8, 95% confidence interval (CI) 4.3–22.8] and pain (OR 9.2, 95% CI 4.0–21.5). After controlling for other factors, the independent associations were depression (OR 4.7, 95% CI 1.6–14.0) and pain (OR 3.1, 95% CI 1.0–8.9). There was no association with age, disease burden or treatment duration.ConclusionsTwo-fifths of men with biochemically controlled prostate cancer on long-term ADT report CRF that interferes with function. Management aimed at improving CRF should address depression and pain.

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.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.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.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.An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.

We aimed to describe and quantify the relationship between cause of injury and final outcome following traumatic brain injury (TBI). Individual patient data (N = 8708) from eight therapeutic Phase III randomized clinical trials in moderate or severe TBI, and three TBI surveys were used to investigate the relationship between cause of injury and outcome, as assessed by the Glasgow Outcome Scale (GOS) at 6 months. Proportional odds methodology was applied to quantify the strength of the association and expressed as an odds ratio in a meta-analysis. Heterogeneity across studies was assessed and associations with other predictive factors explored. In a univariate analysis, a strong association between the cause of injury and long-term outcome in moderate to severe TBI patients was observed, with consistent results across the studies. Road traffic accidents (OR 0.66, 95% CI 0.60–0.73), assaults (OR 0.66, 95% CI 0.52–0.84), and injuries sustained during sporting or recreational activities (OR 0.45, 95% CI 0.28–0.71) were all associated with better outcomes than the reference category of falls. Falls were found to be associated with an older age and with a higher incidence of mass lesions. Following adjustment for age in the analysis, the relationship between cause of injury and outcome was lost.

Objective: Heterogeneity of patients is a common problem in randomized controlled trials (RCTs) in various fields of clinical research. We aimed to investigate the potential benefits of different approaches for dealing with heterogeneity in a case study on traumatic brain injury (TBI). Design and Setting: Statistical modeling studies in three surveys and six randomized controlled trials. Patients: Individual patient data (n = 8033) from the IMPACT database. Interventions: We investigated the statistical power and efficiency of randomized controlled trials (RCTs) in relation to (1) selection according to baseline characteristics, (2) prognostic targeting (i.e., excluding those with a relatively extreme prognosis), and (3) covariate-adjusted analysis. Statistical power was expressed as the required sample size for obtaining 80% power and efficiency as the relative change in study duration, reflecting both gains in power and adverse effects on recruitment. Uniform and targeted treatment effects were simulated for 6 month unfavorable outcome. Results: For a uniform treatment effect, selection resulted in a sample size reduction of 33% in the surveys and 5% in the RCTs, but decreased recruitment by 65% and 41%, respectively. Hence, the relative study duration was prolonged (surveys: +95%; RCTs: +60%). Prognostic targeting resulted in sample size reductions of 28% and 17%, and increased relative study duration by +5% in surveys and +11% in the RCTs. Covariate adjustment reduced sample sizes by 30% and 16%, respectively, and did not affect recruitment. For a targeted treatment effect, the sample size reductions by selection (surveys: 47%; RCTs: 20%) and prognostic targeting (surveys: 49%; RCTs: 41%) were larger and adverse effects on recruitment smaller. Conclusions: The benefits of selection and prognostic targeting in terms of statistical power are reversed by adverse effects on recruitment. Covariate adjusted analysis in a broadly selected group of patients is advisable if a uniform treatment effect is assumed, since there is no decrease in recruitment.

<h2>ABSTRACT</h2><h3>Background</h3> Little is known about the prevalence and associations of clinically relevant fatigue (CRF) in recurrence-free prostate cancer survivors. <h3>Patients and methods</h3> Four hundred and sixteen recurrence-free prostate cancer survivors who were >1 year post-radiotherapy or radical prostatectomy were surveyed. The prevalence of CRF (defined as Brief Fatigue Inventory >3) was determined and compared with a noncancer control group. Other measures included the Hospital Anxiety and Depression Scale, International Prostate Symptom Score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Relationships between these factors and CRF were explored in univariate and multivariate analyses. <h3>Results</h3> Analyzable data were obtained from 91% (377/416) of patients. The prevalence of CRF was 29% (108/377) versus 16% (10/63) in the controls (<i>P</i> = 0.031). CRF was more common in post-radiotherapy than in post-prostatectomy 33% (79/240) versus 22% (29/133), <i>P</i> = 0.024. However, when other factors (current depression, anxiety, urinary symptoms, medical comorbidities, pain and insomnia) were controlled for, previous treatment did not predict CRF. Current depression [Hospital Anxiety and Depression Scale ≥8 was by far the strongest association [odds ratio 9.9, 95% confidence interval 4.2–23.5)]. <h3>Conclusions</h3> Almost one-third of recurrence-free prostate cancer survivors report CRF. Depression, anxiety, urinary symptoms, pain and insomnia measured at outcome are more strongly associated than type of cancer treatment previously received.

Differences in blood pressure between arms are associated with increased cardiovascular mortality in cohorts with established vascular disease or substantially elevated cardiovascular risk.To explore the association of inter-arm difference (IAD) with mortality in a community-dwelling cohort that is free of cardiovascular disease.Cohort analysis of a randomised controlled trial in central Scotland, from April 1998 to October 2008.Volunteers from Lanarkshire, Glasgow, and Edinburgh, free of pre-existing vascular disease and with an ankle-brachial index ≤0.95, had systolic blood pressure measured in both arms at recruitment. Inter-arm blood pressure differences were calculated and examined for cross-sectional associations and differences in prospective survival. Outcome measures were cardiovascular events and all-cause mortality during mean follow-up of 8.2 years.Based on a single pair of measurements, 60% of 3350 participants had a systolic IAD ≥5 mmHg and 38% ≥10 mmHg. An IAD ≥5 mmHg was associated with increased cardiovascular mortality (adjusted hazard ratio [HR] 1.91, 95% confidence interval [CI] = 1.19 to 3.07) and all-cause mortality (adjusted HR 1.44, 95% CI = 1.15 to 1.79). Within the subgroup of 764 participants who had hypertension, IADs of ≥5 mmHg or ≥10 mmHg were associated with both cardiovascular mortality (adjusted HR 2.63, 95% CI = 0.97 to 7.02, and adjusted HR 2.96, 95% CI = 1.27 to 6.88, respectively) and all-cause mortality (adjusted HR 1.67, 95% CI = 1.05 to 2.66, and adjusted HR 1.63, 95% CI = 1.06 to 2.50, respectively). IADs ≥15 mmHg were not associated with survival differences in this population.Systolic IADs in blood pressure are associated with increased risk of cardiovascular events, including mortality, in a large cohort of people free of pre-existing vascular disease.

the prevalence of all types of cognitive impairment, including dementia, is increasing but knowledge of aetiological factors is still evolving.this study aimed to evaluate the association between cardiovascular risk factors and cognitive function in older persons.a population-based cohort design involving 2,312 men and women (aged 50-75) enrolled in the University of Edinburgh Aspirin for Asymptomatic Atherosclerosis trial.cognitive tests included the Mill Hill Vocabulary Scale, auditory verbal learning test (AVLT), digit symbol test, verbal fluency test (VFT), Raven's Progressive Matrices and the trail making test. A 'g' score (measure of general intelligence) was computed for each subject. Regression analysis was used to evaluate the association between relevant variables.higher diastolic BP was negatively associated with AVLT (β = -0.153, P < 0.01), and with an estimated decline on AVLT (β = -0.125, P < 0.01). Smoking was negatively associated with all the cognitive variables except VFT. The total cholesterol level was not associated with cognitive function or estimated decline.smoking and elevated blood pressure may be risk factors for cognitive decline, and thus potential targets for preventive and therapeutic interventions.

<h3>Objectives</h3> To investigate patient characteristics of an unselected primary care population associated with risk of first hospital admission and readmission for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). <h3>Design</h3> Retrospective open cohort using pseudonymised electronic primary care data linked to secondary care data. <h3>Setting</h3> Primary care; Lothian (population approximately 800 000), Scotland. <h3>Participants</h3> Data from 7002 patients from 72 general practices with a COPD diagnosis date between 2000 and 2008 recorded in their primary care record. Patients were followed up until 2010, death or they left a participating practice. <h3>Main outcome measures</h3> First and subsequent admissions for AECOPD (International Classification of Diseases (ICD) 10 codes J44.0, J44.1 in any diagnostic position) after COPD diagnosis in primary care. <h3>Results</h3> 1756 (25%) patients had at least 1 AECOPD admission; 794 (11%) had at least 1 readmission and the risk of readmission increased with each admission. Older age at diagnosis, more severe COPD, low body mass index (BMI), current smoking, increasing deprivation, COPD admissions and interventions for COPD prior to diagnosis in primary care, and comorbidities were associated with higher risk of first AECOPD admission in an adjusted Cox proportional hazards regression model. More severe COPD and COPD admission prior to primary care diagnosis were associated with increased risk of AECOPD readmission in an adjusted Prentice-Williams-Peterson model. High BMI was associated with a lower risk of first AECOPD admission and readmission. <h3>Conclusions</h3> Several patient characteristics were associated with first AECOPD admission in a primary care cohort of people with COPD but fewer were associated with readmission. Prompt diagnosis in primary care may reduce the risk of AECOPD admission and readmission. The study highlights the important role of primary care in preventing or delaying a first AECOPD admission.

The aim of this study was to quantify the potential reduction in sample size that can be achieved by adjustment for predictors of outcome in traumatic brain injury (TBI) trials. We used individual patient data from seven therapeutic phase III randomized clinical trials (RCTs; n = 6166) in moderate or severe TBI, and three TBI surveys (n = 2238). The primary outcome was the dichotomized Glasgow Outcome Scale at 6 months (favorable/unfavorable). Baseline predictors of outcome considered were age, motor score, pupillary reactivity, computed tomography (CT) classification, traumatic subarachnoid hemorrhage, hypoxia, hypotension, glycemia, and hemoglobin. We calculated the potential sample size reduction obtained by adjustment of a hypothetical treatment effect for one to seven predictors with logistic regression models. The distribution of predictors was more heterogeneous in surveys than in trials. Adjustment of the treatment effect for the strongest predictors (age, motor score, and pupillary reactivity) yielded a reduction in sample size of 16-23% in RCTs and 28-35% in surveys. Adjustment for seven predictors yielded a reduction of about 25% in most studies: 20-28% in RCTs and 32-39% in surveys. A major reduction in sample size can be obtained with covariate adjustment in TBI trials. Covariate adjustment for strong predictors should be incorporated in the analysis of future TBI trials.

The univariate prognostic analysis of the IMPACT database on traumatic brain injury (TBI) poses the formidable challenge of how best to summarize a highly complex set of data in a way which is accessible without being overly simplistic. In this paper, we describe and illustrate the battery of statistical methods that have been used. Boxplots, histograms, tabulations, and splines were used for initial data checking and in identifying appropriate transformations for more formal statistical modeling. Imputation techniques were used to minimize the problems associated with the analysis of incomplete data due to missing values. The associations between covariates and outcome (Glasgow Outcome Scale [GOS] assessed at 6 months) were expressed as odds ratios with supporting confidence intervals when the GOS was collapsed to a dichotomous scale. This was extended to use common odds ratios from proportional odds models to express associations over the full range of the GOS. Forest plots were used to illustrate the consistency of results from study to study within the IMPACT database. The overall prognostic strength of the prognostic factors was expressed as the proportion of variance explained (Nagelkerke's R2 statistic). Many of our approaches are based on simple graphical displays of the data, but, where appropriate, we have also used methods that although established in the statistical literature are relatively novel in their application to TBI.

The Glasgow Outcome Scale (GOS) is the primary endpoint for efficacy analysis of clinical trials in traumatic brain injury (TBI). Accurate and consistent assessment of outcome after TBI is essential to the evaluation of treatment results, particularly in the context of multicenter studies and trials. The inconsistent measurement or interobserver variation on GOS outcome, or for that matter, on any outcome scales, may adversely affect the sensitivity to detect treatment effects in clinical trial. The objective of this study is to examine effects of nondifferential misclassification of the widely used five-category GOS outcome scale and in particular to assess the impact of this misclassification on detecting a treatment effect and statistical power. We followed two approaches. First, outcome differences were analyzed before and after correction for misclassification using a dataset of 860 patients with severe brain injury randomly sampled from two TBI trials with known differences in outcome. Second, the effects of misclassification on outcome distribution and statistical power were analyzed in simulation studies on a hypothetical 800-patient dataset. Three potential patterns of nondifferential misclassification (random, upward and downward) on the dichotomous GOS outcome were analyzed, and the power of finding treatments differences was investigated in detail. All three patterns of misclassification reduce the power of detecting the true treatment effect and therefore lead to a reduced estimation of the true efficacy. The magnitude of such influence not only depends on the size of the misclassification, but also on the magnitude of the treatment effect. In conclusion, nondifferential misclassification directly reduces the power of finding the true treatment effect. An awareness of this procedural error and methods to reduce misclassification should be incorporated in TBI clinical trials.

ContextWe know little about how many outpatients of a modern cancer center suffer from clinically significant unrelieved pain and the characteristics of these patients to guide better care.ObjectivesTo determine the prevalence of clinically significant pain (CSP) in the outpatients of a regional cancer center and the association with distress and other variables.MethodsA secondary analysis of cross-sectional, self-reported and clinical data from 2768 patients reattending selected clinics of a regional National Health Service cancer center in the U.K. Pain was measured using the pain severity scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, emotional distress was measured by the Hospital Anxiety and Depression Scale, and demographic and clinical data were taken from medical records.ResultsFifty-four percent (95% confidence interval [CI] 52–56) of patients reported pain at least “a little” in the previous week and 18% (95% CI 17–20) at least “quite a bit” (CSP). The strongest independent associations of CSP were active disease (odds ratio [OR] 1.95, 95% CI 1.5–2.5) and emotional distress (OR 4.8, 95% CI 4–6).ConclusionCSP is surprisingly common in outpatients of specialist cancer services, and it is strongly and independently associated with emotional distress. Better symptom management should consider pain and distress together.

Substantial heterogeneity exists among patients who suffer from traumatic brain injury (TBI). Strict enrollment criteria may diminish heterogeneity in randomized controlled trials (RCTs), but will also decrease recruitment and may affect the outcome distribution. The aim of this study was to investigate the influences of commonly used enrollment criteria for RCTs in TBI on potential recruitment and on outcome distribution. We used individual patient data from the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) database, including six therapeutic phase III RCTs (n = 5816) and three surveys (n = 2217) in TBI. The primary outcome was the Glasgow Outcome Scale (GOS) at 6 months after injury, which we dichotomized as favorable/unfavorable. We investigated the influences of commonly used enrollment criteria on recruitment and outcome distribution: time window between injury and admission to study hospital ≤ 8 h; age at injury ≤ 65 years; ≥ 1 reactive pupil; motor score > 1; Glasgow Coma Scale ≤ 8. Application of all enrollment criteria resulted in a large reduction of recruitment in both the surveys (up to 65%) and the RCTs (up to 41%). Among the remaining patients, fewer had an unfavorable outcome in both the surveys (original, 60%; remaining, 44%) and the RCTs (original, 43%; remaining, 38%). Applying these enrollment criteria to patients from the surveys resulted in an outcome distribution that approximated the outcome observed in the RCTs. The use of strict enrollment criteria leads to substantial reductions in the recruitment of RCTs in TBI. The outcome in TBI studies depends strongly on the enrollment criteria.

Schools have the potential to influence their pupils' behaviour through the school's social organisation and culture, as well as through the formal curriculum. This paper provides the first attempt to explain the differences between schools in rates of reported heterosexual sexual experience amongst 15 and 16 year olds. It first examined whether variations in rates of sexual experience remained after controlling for the known predictors of sexual activity. It then examined whether these residuals, or 'school effects', were attributable to processes within the school, or were more likely to reflect characteristics of the neighbourhood. Longitudinal survey data from 4,926 pupils in 24 Scottish schools were linked to qualitative and quantitative data on school processes including quality of relationships (staff-pupil, etc), classroom discipline, organisation of Personal and Social Education, school appearance and pupil morale. Multi-level modelling was used to test a range of models and the resulting 'school effects' were then interpreted using the process data. Overall, 42% of girls and 33% of boys reported experience of sexual intercourse, with rates by school ranging from 23% to 61%. When individual socio-economic and socio-cultural factors were taken into account the school variation dropped sharply, though pupils' attitudes and aspirations had little effect. There was very little correlation between boys' and girls' rates of sexual experience by school, after controlling for known predictors of sexual activity. Girls were more influenced by individual socio-economic factors than boys. School-level socio-economic factors were predictive even after taking account of individual socio-cultural factors, suggesting that the wider socio-economic environment further influenced young people's sexual experience. Importantly, school processes did not explain the variation between schools in sexual experience. Rather, the variation may have been due to neighbourhood culture.

The objective of this study was to determine and compare patient and general practitioner (GP) preferences for the treatment of depression in patients with cancer.A treatment preference questionnaire was completed by 100 patients who had been diagnosed with both cancer and major depressive disorder and by 86 GPs who had had experience of at least 1 patient with cancer and depression. Participants were asked to rank options for how depression should be treated, who should deliver the treatment, and where treatment should occur.The top three preferences of patients and GPs for how depression should be treated differed (P<.001). Patients preferred talking treatment alone, whereas GPs preferred a combination of drug and talking treatment. Both patients and GPs preferred treatment to be given by the GP, with older patients having a stronger preference for this. Counselors and cancer nurses were also popular preferences; mental heath professionals were unpopular. The preferred place of treatment was primary care for both patients and GPs, although many patients preferred treatment in the cancer center.Effective and acceptable services for depressed cancer patients need to take patients and GP preferences into account. A model of service that allows a choice of initial treatment modality and collaborative care between primary care and cancer center nurse would meet this requirement.

To determine the validity of a 50% drop in the 20-item Symptom Checklist Depression Scale (SCL-20) score against the “gold standard” of no longer meeting criteria for major depression as assessed using a diagnostic interview in an outpatient cancer population and also to examine the validity of other potential cut-offs (i.e., percentage drops). Secondary analysis of data from a randomized trial which compared collaborative care with usual care for cancer patients with major depression. A total of 194 trial participants who had both SCL-20 scores and depression diagnoses on the Structured Clinical Interview for DSM-IV at both baseline and at 12-week outcome formed the analyzed sample. A 50% reduction in the SCL-20 score from baseline to 12 weeks correctly identified the patients who no longer met criteria for major depression in 153 (78.9%) of 194 (95% CI 73.1% to 84.6%) cases. Most of those misclassified had not achieved a 50% reduction in SCL-20 score despite no longer meeting criteria for major depression. Examination of the performance of percentage drops other than 50% on the SCL-20 using a receiver operating characteristics (ROC) curve and histogram of misclassification suggested that the 50% drop was best if both a low overall misclassification rate and the minimizing of false positives of improvement were required. A 50% reduction in the SCL-20 score performs well as a conservative measure of change in depression status in cancer patients.

Diabet. Med. 29, 488–491 (2012) Abstract Aims To determine the prevalence and distribution of abnormal plasma liver enzymes in a representative sample of older adults with Type 2 diabetes. Methods Plasma concentrations of alanine aminotransferase, aspartate aminotransferase and γ‐glutamyltransferase were measured in a randomly selected, population‐based cohort of 1066 men and women aged 60–75 years with Type 2 diabetes (the Edinburgh Type 2 Diabetes Study). Results Overall, 29.1% (95% CI 26.1–31.8) of patients had one or more plasma liver enzymes above the upper limit of the normal reference range. Only 10.1% of these patients had a prior history of liver disease and a further 12.4% reported alcohol intake above recommended limits. Alanine aminotransferase was the most commonly raised liver enzyme (23.1% of patients). The prevalence of abnormal liver enzymes was significantly higher in men (odds ratio 1.40, 95% CI 1.07–1.83), in the youngest 5‐year age band (odds ratio 2.02, 95% CI 1.44–2.84), in patients with diabetes duration &lt; 5 years (odds ratio 1.38, 95% CI 1.01–1.90), plasma HbA 1c ≥ 58 mmol/mol (7.5%) (odds ratio 1.43, 95% CI 1.09–1.88), obese BMI (odds ratio 2.84, 95% CI 1.59–3.06) and secondary care management for their diabetes (odds ratio 1.40, 95% CI 1.05–1.87). However, all these factors combined accounted for only 7.6% of the variation in liver enzyme abnormality. Conclusions The prevalence of elevated liver enzymes in people with Type 2 diabetes is high, with only modest variation between clinically defined patient groups. Further research is required to determine the prognostic value of raised, routinely measured liver enzymes to inform decisions on appropriate follow‐up investigations.

Abstract In this paper the grades awarded in the subject level review process that ran in England between 1995 and 2001 are examined. These grades have subsequently been used to sustain most published league tables and are often cited in debates about institutional quality. However, the grades were never subject to any moderation, either at the time of the individual visit or subsequently. Accordingly, there are substantial variations between subjects and marked grade inflation over time. This paper considers how to control for these effects and, once this is done, what the impact on the published league tables would be. The difference between the adjusted and unadjusted scores are significant and this further calls into doubt both the validity of the original process and the uses to which the outputs have subsequently been put. This serves as a warning to other quality assurance agencies who have used or are considering using audits based on subject review. Keywords: quality assessmentsubject reviewgeneral linear model

Objective: Heterogeneity of patients is a common problem in randomized controlled trials (RCTs) in various fields of clinical research. We aimed to investigate the potential benefits of different approaches for dealing with heterogeneity in a case study on traumatic brain injury (TBI). Design and Setting: Statistical modeling studies in three surveys and six randomized controlled trials. Patients: Individual patient data (n = 8033) from the IMPACT database. Interventions: We investigated the statistical power and efficiency of randomized controlled trials (RCTs) in relation to (1) selection according to baseline characteristics, (2) prognostic targeting (i.e., excluding those with a relatively extreme prognosis), and (3) covariate-adjusted analysis. Statistical power was expressed as the required sample size for obtaining 80% power and efficiency as the relative change in study duration, reflecting both gains in power and adverse effects on recruitment. Uniform and targeted treatment effects were simulated for 6 month unfavorable outcome. Results: For a uniform treatment effect, selection resulted in a sample size reduction of 33% in the surveys and 5% in the RCTs, but decreased recruitment by 65% and 41%, respectively. Hence, the relative study duration was prolonged (surveys: +95%; RCTs: +60%). Prognostic targeting resulted in sample size reductions of 28% and 17%, and increased relative study duration by +5% in surveys and +11% in the RCTs. Covariate adjustment reduced sample sizes by 30% and 16%, respectively, and did not affect recruitment. For a targeted treatment effect, the sample size reductions by selection (surveys: 47%; RCTs: 20%) and prognostic targeting (surveys: 49%; RCTs: 41%) were larger and adverse effects on recruitment smaller. Conclusions: The benefits of selection and prognostic targeting in terms of statistical power are reversed by adverse effects on recruitment. Covariate adjusted analysis in a broadly selected group of patients is advisable if a uniform treatment effect is assumed, since there is no decrease in recruitment.

Once a study is final, the creation of the Statistical Analysis Plan (SAP) can commence. Accordingly to ICH E9 a SAP contains a more technical and detailed elaboration of the principal features of the analysis described in the protocol but the level of detail is not specified. This topic is currently being discussed between UK-CRC registered Trials Units, and there is as yet no agreement on the amount of detail that should be covered in the SAP. Within the Edinburgh Clinical Trials Unit (ECTU), we created a consensus document outlining what we thought the essential aspects of a SAP should be. Briefly, we set out the essential aspects of a SAP as follows. It should be written by someone who has not seen unblinded data from the trial, and should describe analyses unambiguously and in sufficient detail for another statistician to be able to repeat them. It should include a brief description of the trial design, and the statistical methods section from the protocol. Analysis populations, e.g. ITT, per protocol, should be defined in an unambiguous fashion. The SAP should state overall level of significance, and any other relevant information that will be used in the majority of analyses (e.g. treatment of missing data, adjustment for covariates, adjustment for multiplicity, adjustment of p-value due to interim analyses). A list of analyses should describe each precise outcome, the analysis method to be used, any sensitivity analyses, any deviations from the methods listed in ‘Overall Statistical Principles', and any subgroup analyses.

In this scenario of cancer time line paralleling the human aging process there are many irrefutable biases acting on the numbers coming from population based studies such as lead time and selection biases, adding to those for treatment or tumor characteristics.It is obvious that people that score higher ages are selected from population when they fail of perishing from many other conditions.Authors have speculated more aggressive disease (e.g., faster growing tumors) in the elderly and/or less frequent use of PSA testing and further diagnostic evaluation (such as biopsy for an elevated PSA) in older men compared with younger men.Furthermore, among a compilation of possible biases, two mechanisms were well recognized: 1) over diagnosis of nonaggressive PC in younger patients and 2) delay in diagnosis of aggressive disease in the elderly.Until nowadays, PC natural history is complex and unpredictable in a large number of cases.The aging process will naturally culminate with death, and it is not surprisingly that virtually all cause of death will increase with age considering the cumulative co-morbidities and the innately decreasing functional status.While it should be viewed with caution, better understandings of the aging process as well as prostate cancer natural history will add to the understanding of the illustrated scenario.

<h3>Objectives &amp; Background</h3> Paracetamol poisoning is common worldwide. Standard intravenous N-acetylcysteine (NAC) therapy is complex, and commonly associated with concentration-related adverse effects and the potential for administration errors. We aimed to determine whether adverse effect incidence could be reduced by antiemetic pre-treatment and/or a simpler and shorter intravenous N-acetylcysteine regimen. <h3>Methods</h3> We delivered, in 3 centres, a randomised factorial trial comparing a modified 12 h (100 mg/kg over 2 h, 200 mg/kg over 10 h) with a standard 20.25 h NAC regimen (150 mg/kg 15 min, 50 mg/kg 4 h, 100 mg/kg 16 h) with and without pre-treatment with ondansetron (4 mg IV). The primary endpoint was absence of retching, vomiting or need for rescue antiemetic at 2 h; secondary endpoints included the incidence of anaphylactoid reactions, the need for medication or treatment interruption, and hepatic toxicity (ALT, INR). <h3>Results</h3> In 217 participants, retching and vomiting were less common with ondansetron than placebo (OR 0.406, 97.5% CI 0.205–0.803, p=0.0031) and with the modified compared to the conventional acetylcysteine regimen (OR 0.260, 97.5% CI 0.130–0.518, p&lt;0.0001). Frequency of anaphylactoid reactions was not affected by ondansetron, but less common with modified acetylcysteine; severe reactions 5/108 (4.6%) vs. 31/100 (31%) (p&lt;0.0001). The proportion of patients with a 50% increase in ALT was not significantly different comparing conventional with modified regimens (OR 0.603, 97.5% CI 0.199–1.831), but more common with ondansetron than placebo (OR 3.295, 97.5% CI 1.013–10.723, p=0.0235). <h3>Conclusion</h3> In patients with paracetamol poisoning requiring acetylcysteine, adverse effects were substantially reduced by ondansetron pre-treatment and by using a modified, shorter treatment regimen. Ondansetron, but not the modified regimen, increased the frequency of liver function abnormalities. If large effectiveness studies confirm the modified regimen is non-inferior to conventional then shorter and safer treatment would be possible for this common poisoning.

Alice in Wonderland syndrome (AIWS) is a perceptual disorder reported to affect 1–3 per cent of the population, usually in childhood. Autonomous sensory meridian response (ASMR) is associated with similar symptoms to AIWS, reported into adulthood. ASMR is also thought to stem from a heightened sensitivity to external stimuli. Despite similarities, there has been limited research investigating the link between these two phenomena. We sought to establish a link between AIWS and ASMR. Our findings show an increased presence of AIWS symptoms amongst a population who are aware of experiencing ASMR. We described a predictive relationship between the visual symptoms of AIWS and the age of onset of ASMR. ASMR has an increasing presence and is suggested as an intervention for a range of disorders. Despite this, there remains little understanding of its causation. These findings provide an important basis for establishing the causation of ASMR as well as furthering understanding of AIWS.

Citation for published version: Roozenbeek, B, Lingsma, HF, Lecky, FE, Lu, J, Weir, J, Butcher, I, McHugh, G, Murray, GD, Perel, P, Maas, AI, Steyerberg, EW & Trauma Audit Res Network TARN, Int Mission Prognosis Anal Clinica, Corticosteroid Randomisation After 2012, 'Prediction of outcome after moderate and severe traumatic brain injury: external validation of the International Mission on Prognosis and Analysis of Clinical Trials (IMPACT) and Corticoid Randomisation After Significant Head injury (CRASH) prognostic models' Critical Care Medicine, vol 40, no. 5, pp. 1609-1617., 10.1097/CCM.0b013e31824519ce

9044 Background: In the absence of definitive evidence of best disease control, treatment decisions for early prostate cancer should consider likely long term side effects and quality of life. Fatigue is an acute side effect of treatment but there are no data about long term clinically significant fatigue (CSF) in recurrence free prostate cancer survivors. This study presents the prevalence, associations and predictors of CSF after radical prostatectomy (RP) or radiotherapy (XRT). Methods: A postal questionnaire survey of 416 recurrence free men treated at a regional cancer centre &gt;1 year previously. CSF was defined as global Brief Fatigue Inventory score &gt;3. Other measures: Hospital Anxiety and Depression Scale (HADS), International Prostate Symptom Score (IPSS), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, clinical and demographic information. Relationships between these factors and CSF were explored in univariate and then multivariate logistic regression analyses. Results: 91% (377/416) of questionnaires were analyzable. Mean age was 72 years (SD 6.1) and median time since treatment was 56 months (range 13–233). The prevalence of CSF was 29% (108/377) overall; 22% (29/133) post RP and 33% (79/244) post XRT. Univariate and multivariate associations of CSF predictors are shown below. Patients with CSF also had poorer quality of life, physical, role, and social function (all p&lt;0.001). CSF was not associated with age, social deprivation category or time since treatment. Conclusions: Almost a third of recurrence free prostate cancer survivors have CSF. RP is associated with less CSF post treatment than XRT, but treatment type did not remain statistically significant in a multivariate analysis controlling for other factors. Depression at outcome had the strongest association with CSF. Other associated variables were IPSS&gt;7, comorbid medical conditions and anxiety. Care should focus on optimising the identification and management of these conditions to improve fatigue. [Table: see text] No significant financial relationships to disclose.