Two-tailed significance tests for 2 × 2 contingency tables: What is the alternative?

Two-tailed significance testing for 2 × 2 contingency tables has remained controversial. Within the medical literature, different tests are used in different papers and that choice may decide whether findings are adjudged to be significant or nonsignificant; a state of affairs that is clearly undesirable. In this paper, it is argued that a part of the controversy is due to a failure to recognise that there are two possible alternative hypotheses to the Null. It is further argued that, while one alternative hypothesis can lead to tests with greater power, the other choice is more applicable in medical research. That leads to the recommendation that, within medical research, 2 × 2 tables should be tested using double the one-tailed exact probability from Fisher's exact test or, as an approximation, the chi-squared test with Yates' correction for continuity.

A pharmacist-led information technology intervention for medication errors (PINCER): a multicentre, cluster randomised, controlled trial and cost-effectiveness analysis.

BACKGROUND: Medication errors are common in primary care and are associated with considerable risk of patient harm. We tested whether a pharmacist-led, information technology-based intervention was more effective than simple feedback in reducing the number of patients at risk of measures related to hazardous prescribing and inadequate blood-test monitoring of medicines 6 months after the intervention. METHODS: In this pragmatic, cluster randomised trial general practices in the UK were stratified by research site and list size, and randomly assigned by a web-based randomisation service in block sizes of two or four to one of two groups. The practices were allocated to either computer-generated simple feedback for at-risk patients (control) or a pharmacist-led information technology intervention (PINCER), composed of feedback, educational outreach, and dedicated support. The allocation was masked to researchers and statisticians involved in processing and analysing the data. The allocation was not masked to general practices, pharmacists, patients, or researchers who visited practices to extract data. [corrected]. Primary outcomes were the proportions of patients at 6 months after the intervention who had had any of three clinically important errors: non-selective non-steroidal anti-inflammatory drugs (NSAIDs) prescribed to those with a history of peptic ulcer without co-prescription of a proton-pump inhibitor; ß blockers prescribed to those with a history of asthma; long-term prescription of angiotensin converting enzyme (ACE) inhibitor or loop diuretics to those 75 years or older without assessment of urea and electrolytes in the preceding 15 months. The cost per error avoided was estimated by incremental cost-effectiveness analysis. This study is registered with Controlled-Trials.com, number ISRCTN21785299. FINDINGS: 72 general practices with a combined list size of 480,942 patients were randomised. At 6 months' follow-up, patients in the PINCER group were significantly less likely to have been prescribed a non-selective NSAID if they had a history of peptic ulcer without gastroprotection (OR 0·58, 95% CI 0·38-0·89); a ß blocker if they had asthma (0·73, 0·58-0·91); or an ACE inhibitor or loop diuretic without appropriate monitoring (0·51, 0·34-0·78). PINCER has a 95% probability of being cost effective if the decision-maker's ceiling willingness to pay reaches £75 per error avoided at 6 months. INTERPRETATION: The PINCER intervention is an effective method for reducing a range of medication errors in general practices with computerised clinical records. FUNDING: Patient Safety Research Portfolio, Department of Health, England.

Thrombocytopenia and platelet transfusion in UK critical care: a multicenter observational study.

BACKGROUND: Platelet (PLT) transfusions are widely used, but few studies have described patterns of use in critical care. STUDY DESIGN AND METHODS: As part of a prospective multicenter observational study of all sequentially admitted patients to UK general intensive care units (ICUs) over 8 weeks, daily data were collected throughout admission on frequency of thrombocytopenia and use of PLT transfusions, in addition to clinical outcomes, including bleeding. RESULTS: There were 1923 admissions recruited across 29 ICUs for analysis (96.6% of all eligible admissions). The period prevalences of severe thrombocytopenia (<50 × 10(9) /L) for the entire ICU stay were 12.4% (234/1881) and 13.7% (263/1914) when the 24 hours before admission was also included. A total of 35.4% of patients who experienced severe thrombocytopenia died in the ICU. A total of 169 patients (9% of study population) received 534 units of transfused PLTs (median number of units per patient admission was 2; interquartile range, 1-3; maximum, 38). Pretransfusion PLT counts were more than 50 × 10(9) for 40% of PLT transfusions overall, and even when no clinically significant bleeding was recorded on the day of transfusion, the lowest recorded PLT count was more than 50 × 10(9) for 34% of transfusions. There was evidence of only modest increments in PLT count. CONCLUSION: Thrombocytopenia is common in critical care, but there is wide variation in PLT transfusion use. Patients commonly received PLT transfusions on days without clinically significant hemorrhage. The high prevalence of thrombocytopenia in the critically ill population and inconsistent patterns of PLT transfusions indicate the importance of improving the evidence base for PLT use.

Validation of a modified Care and Comfort Score and responsiveness to hip surgery in children with cerebral palsy in Gross Motor Function Classification System levels IV and V.

Aims: The purpose of this study was to assess the reliability and responsiveness to hip surgery of a four-point modified Care and Comfort Hypertonicity Questionnaire (mCCHQ) scoring tool in children with cerebral palsy (CP) in Gross Motor Function Classification System (GMFCS) levels IV and V. Methods: This was a population-based cohort study in children with CP from a national surveillance programme. Reliability was assessed from 20 caregivers who completed the mCCHQ questionnaire on two occasions three weeks apart. Test-retest reliability of the mCCHQ was calculated, and responsiveness before and after surgery for a displaced hip was evaluated in a cohort of children. Results: Test-retest reliability for the overall mCCHQ score was good (intraclass correlation coefficient 0.78), and no dimension demonstrated poor reliability. The surgical intervention cohort comprised ten children who had preoperative and postoperative mCCHQ scores at a minimum of six months postoperatively. The mCCHQ tool demonstrated a significant improvement in overall score from preoperative assessment to six-month postoperative follow-up assessment (p < 0.001). Conclusion: The mCCHQ demonstrated responsiveness to intervention and good test-retest reliability. The mCCHQ is proposed as an outcome tool for use within a national surveillance programme for children with CP.

Responsiveness of the Foot Profile Score in children with hemiplegia.

BACKGROUND: The Foot Profile Score (FPS) is a single score that summarises foot posture and dynamic foot motion during the gait cycle based on the kinematic data of the Oxford Foot Model. The FPS enables clinicians and researchers to quantify foot abnormalities during gait, to monitor change in foot/ankle motion over time, and to measure the outcome of intervention. With the creation of a new outcome measure, it is important to test its responsiveness in a clinical population for whom it may be sensitive to change. AIM: To evaluate the responsiveness of the FPS in a clinical population following isolated foot and ankle surgery. METHODS: Using previous work completed to validate the FPS, we defined the minimal clinically important difference (MCID) for the FPS. Using this MCID, we applied it to a clinical population of 37 children with cerebral palsy, spastic hemiplegia, comparing their FPS before and after foot and ankle surgery. A regression analysis looked at potential relationships between the change in FPS and their pre-operative FPS, age at surgery, and time since surgery. RESULTS: An MCID of 2.4 degrees was calculated through regression analysis. The mean change from the pre-operative FPS to the post-operative FPS was 4.6 (SD 3.7 with a range from -0.1 to 13.4). Twenty-eight children (76%) had a change in their FPS greater than the MCID. A regression analyses only showed a clear regression between pre-operative FPS and change in FPS (R2 = 0.58 p < 0.01).

A national study of plasma use in critical care: clinical indications, dose and effect on prothrombin time.

INTRODUCTION: Fresh frozen plasma (FFP) is widely used, but few studies have described patterns of plasma use in critical care. We carried out a multicentre study of coagulopathy in intensive care units (ICUs) and here describe overall FFP utilisation in adult critical care, the indications for transfusions, factors indicating the doses used and the effects of FFP use on coagulation. METHODS: We conducted a prospective, multicentre, observational study of all patients sequentially admitted to 29 adult UK general ICUs over 8 weeks. Daily data throughout ICU admission were collected concerning coagulation, relevant clinical outcomes (including bleeding), coagulopathy (defined as international normalised ratio (INR) >1.5, or equivalent prothrombin time (PT)), FFP and cryoprecipitate use and indications for transfusion. RESULTS: Of 1,923 admissions, 12.7% received FFP in the ICU during 404 FFP treatment episodes (1,212 FFP units). Overall, 0.63 FFP units/ICU admission were transfused (0.11 units/ICU day). Reasons for FFP transfusion were bleeding (48%), preprocedural prophylaxis (15%) and prophylaxis without planned procedure (36%). Overall, the median FFP dose was 10.8 ml kg⁻¹, but doses varied widely (first to third quartile, 7.2 to 14.4 ml kg⁻¹). Thirty-one percent of FFP treatments were to patients without PT prolongation, and 41% were to patients without recorded bleeding and only mildly deranged INR (<2.5). Higher volumes of FFP were administered when the indication was bleeding (median doses: bleeding 11.1 ml kg⁻¹, preprocedural prophylaxis 9.8 ml kg⁻¹, prophylaxis without procedure 8.9 ml kg⁻¹; P = 0.009 across groups) and when the pretransfusion INR was higher (ranging from median dose 8.9 ml kg⁻¹ at INR ≤ 1.5 to 15.7 ml kg⁻¹ at INR >3; P < 0.001 across ranges). Regression analyses suggested bleeding was the strongest predictor of higher FFP dose. Pretransfusion INR was more frequently normal when the transfusion indication was bleeding. Overall, posttransfusion corrections of INR were consistently small unless the pretransfusion INR was >2.5, but administration during bleeding was associated with greater INR corrections. CONCLUSIONS: There is wide variation in FFP use by ICU clinicians, and a high proportion of current FFP transfusions are of unproven clinical benefit. Better evidence from clinical trials could significantly alter patterns of use and modify current treatment costs.

Experiences of outreach workers in promoting smoking cessation to Bangladeshi and Pakistani men: longitudinal qualitative evaluation.

BACKGROUND: Despite having high smoking rates, there have been few tailored cessation programmes for male Bangladeshi and Pakistani smokers in the UK. We report on a qualitative evaluation of a community-based, outreach worker delivered, intervention that aimed to increase uptake of NHS smoking cessation services and tailor services to meet the needs of Bangladeshi and Pakistani men. METHODS: This was a longitudinal, qualitative study, nested within a phase II cluster randomised controlled trial of a complex intervention. We explored the perspectives and experiences of five outreach workers, two stop smoking service managers and a specialist stop smoking advisor. Data were collected through focus group discussions, weekly diaries, observations of management meetings, shadowing of outreach workers, and one-to-one interviews with outreach workers and their managers. Analysis was undertaken using a modified Framework approach. RESULTS: Outreach workers promoted cessation services by word of mouth on the streets, in health service premises, in local businesses and at a wide range of community events. They emphasised the reasons for cessation, especially health effects, financial implications, and the impact of smoking on the family. Many smokers agreed to be referred to cessation services, but few attended, this in part being explained by concerns about the relative inflexibility of existing service provision. Although outreach workers successfully expanded service reach, they faced the challenges of perceived lack of awareness of the health risks associated with smoking in older smokers and apathy in younger smokers. These were compounded by perceptions of "lip service" being given to their role by community organisations and tensions both amongst the outreach workers and with the wider management team. CONCLUSIONS: Outreach workers expanded reach of the service through taking it to diverse locations of relevance to Pakistani and Bangladeshi communities. The optimum method of outreach to retain and treat Bangladeshi and Pakistani smokers effectively in cessation programmes needs further development.

A comparison of conventional and minimally invasive multilevel surgery for children with diplegic cerebral palsy.

AIMS: To compare changes in gait kinematics and walking speed 24 months after conventional (C-MLS) and minimally invasive (MI-MLS) multilevel surgery for children with diplegic cerebral palsy (CP). METHODS: A retrospective analysis of 19 children following C-MLS, with mean age at surgery of 12 years five months (seven years ten months to 15 years 11 months), and 36 children following MI-MLS, with mean age at surgery of ten years seven months (seven years one month to 14 years ten months), was performed. The Gait Profile Score (GPS) and walking speed were collected preoperatively and six, 12 and 24 months postoperatively. Type and frequency of procedures as part of MLS, surgical adverse events, and subsequent surgery were recorded. RESULTS: In both groups, GPS improved from the preoperative gait analysis to the six-month assessment with maintenance at 12 and 24 months postoperatively. While reduced at six months in both groups, walking speed returned to preoperative speed by 12 months. The overall pattern of change in GPS and walking speed was similar over time following C-MLS and MI-MLS. There was a median of ten procedures per child as part of both C-MLS (interquartile range (IQR) 8.0 to 11.0) and MI-MLS (IQR 7.8 to 11.0). Surgical adverse events occurred in seven (37%) and 13 (36%) children, with four (21%) and 13 (36%) patients requiring subsequent surgery following C-MLS and MI-MLS, respectively. CONCLUSION: This study indicates similar improvements in gait kinematics and walking speed 24 months after C-MLS and MI-MLS for children with diplegic CP. Cite this article: Bone Joint J 2021;103-B(1):192-197.

Prevalence, management, and outcomes of critically ill patients with prothrombin time prolongation in United Kingdom intensive care units.

OBJECTIVE: Coagulopathy occurs frequently in critically ill patients, but its epidemiology, current treatment, and relation to patient outcome are poorly understood. We described the prevalence, risk factors, and treatment of prolongation of the prothrombin time in critically ill patients using the international normalized ratio to standardize data and explored its association with intensive care unit survival. DESIGN: Prospective multiple center observational cohort study. SETTING: Twenty-nine adult intensive care units in the United Kingdom. PATIENTS: All sequentially admitted patients over an 8-wk period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Prospective daily data were collected concerning prevalence, predefined risk factors, and treatment of coagulopathy throughout intensive care unit admission. Of 1923 intensive care unit admissions, 30% developed abnormal international normalized ratio values (defined as an international normalized ratio > 1.5). Most international normalized ratio abnormalities were minor and short-lived (73% of worst international normalized ratio values 1.6-2.5). Male sex, chronic liver disease, sepsis, warfarin therapy, increments in Acute Physiology and Chronic Health Evaluation II score, severity of renal and hepatic dysfunction, and red cell transfusions were all independent risk factors for international normalized ratio abnormalities (all p < .001). In all regression models, there was a strong independent association between abnormal international normalized ratio values and greater intensive care unit mortality (p < .0001), particularly when international normalized ratio increased after intensive care unit admission. Among patients with abnormal international normalized ratios, 33% received fresh-frozen plasma transfusions during their intensive care unit stay, but the pretransfusion international normalized ratio value varied widely. Fifty-one percent of fresh-frozen plasma treatments were to nonbleeding patients and 40% to nonbleeding patients whose international normalized ratio was normal or only modestly deranged (≤ 2.5). The dose of fresh-frozen plasma administered was highly variable (median dose 10.8 mL/kg (first, third quartile 7.2, 14.4; range, 2.4-41.1 mL/kg). CONCLUSIONS: Prothrombin time prolongation is prevalent in critically ill patients and is independently associated with greater intensive care unit mortality. Wide variation in fresh-frozen plasma treatment exists suggesting clinical uncertainty regarding best practice, particularly as a prophylactic treatment.

Diagnostic and prognostic utility of troponin estimation in patients presenting with syncope: a prospective cohort study.

AIMS: To primarily assess the value of troponin I to identify acute myocardial infarction (AMI), and second, to predict 1-month serious outcome or all-cause death in patients presenting with syncope to the Emergency Department (ED). DESIGN: Prospective cohort study of all adult patients presenting to the ED after an episode of syncope. METHODS: In admitted patients, plasma troponin I was measured 12 h after syncope, and in discharged patients, between 12 h and 7 days following discharge. Primary endpoints were the diagnosis of AMI, and the composite endpoint of serious outcome or all-cause death at 1 month. RESULTS: Over an 8-month period, 289 patients were recruited. Troponin I was obtained in 186 admitted patients and was elevated in 13 (7%), and obtained in 103 discharged patients and was raised in only one (1%). Four patients had an AMI (1.4%) and all had ischaemic electrocardiographic (ECG) changes on their presenting ED ECG (ST segment deviation or pathological Q waves) that were 100% sensitive and 72% specific for AMI with a 100% negative predictive value. Seven of the 14 patients (50%) with a raised troponin I had a serious outcome that did not include AMI, or all-cause death compared with 16 of the 267 patients (6%) without a raised troponin (p<0.0001). CONCLUSIONS: AMI is infrequent (1.4%), and estimation of troponin I provides little additional benefit to the presenting ED ECG in identifying patients with syncope due to AMI. Troponin I should not be used to rule out AMI in adult patients presenting with isolated syncope. Troponin I may predict 1-month serious outcome or all-cause death in syncope.

Primary and secondary cases in Escherichia coli O157 outbreaks: a statistical analysis.

BACKGROUND: Within outbreaks of Escherichia coli O157 (E. coli O157), at least 10-15% of cases are thought to have been acquired by secondary transmission. However, there has been little systematic quantification or characterisation of secondary outbreak cases worldwide. The aim of this study was to characterise secondary outbreak cases, estimate the overall proportion of outbreak cases that were the result of secondary transmission and to analyse the relationships between primary and secondary outbreak cases by mode of transmission, country and median age. METHODS: Published data was obtained from 90 confirmed Escherichia coli O157 outbreaks in Great Britain, Ireland, Scandinavia, Canada, the United States and Japan, and the outbreaks were described in terms of modes of primary and secondary transmission, country, case numbers and median case age. Outbreaks were tested for statistically significant differences in the number of ill, confirmed, primary and secondary cases (analysis of variance and Kruskal-Wallis) and in the rate of secondary cases between these variables (Generalised Linear Models). RESULTS: The outbreaks had a median of 13.5 confirmed cases, and mean proportion of 0.195 secondary cases. There were statistically significant differences in the numbers of ill, confirmed, primary and secondary cases between modes of primary transmission (p < 0.021), and in primary and secondary cases between median age categories (p < 0.039) and modes of secondary transmission (p < 0.001).Secondary case rates differed statistically significantly between modes of secondary and primary transmission and median age categories (all p < 0.001), but not between countries (p = 0.23). Statistically significantly higher rates of secondary transmission were found in outbreaks with a median age <6 years and those with secondary transmission via person to person spread in nurseries. No statistically significant interactions were found between country, mode of transmission and age category. CONCLUSION: Our analyses indicated that ~20% of E. coli O157 outbreak cases were the result of secondary spread, and that this spread is significantly influenced by age and modes of primary and secondary transmission, but not country. In particular, the results provide further data emphasising the importance of simple but effective preventive strategies, such as handwashing, that can reduce the risk of secondary spread, particularly amongst young children in nurseries.

Notes on the use and interpretation of radiostereometric analysis.

With increasing numbers of research groups carrying out radiostereometric analysis (RSA), it is important to reach a consensus on how the main aspects of the technique should be carried out and how the results should be presented in an appropriate and consistent way. In this collection of guidelines, we identify a number of methodological and reporting issues including: measurement error and precision, migration and migration direction data, and the use of RSA as a screening technique. Alternatives are proposed, and a statistical analysis is presented, from which a sample size of 50 is recommended for screening of newly introduced prostheses.

A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis.

BACKGROUND: Calcific aortic stenosis has many characteristics in common with atherosclerosis, including hypercholesterolemia. We hypothesized that intensive lipid-lowering therapy would halt the progression of calcific aortic stenosis or induce its regression. METHODS: In this double-blind, placebo-controlled trial, patients with calcific aortic stenosis were randomly assigned to receive either 80 mg of atorvastatin daily or a matched placebo. Aortic-valve stenosis and calcification were assessed with the use of Doppler echocardiography and helical computed tomography, respectively. The primary end points were change in aortic-jet velocity and aortic-valve calcium score. RESULTS: Seventy-seven patients were assigned to atorvastatin and 78 to placebo, with a median follow-up of 25 months (range, 7 to 36). Serum low-density lipoprotein cholesterol concentrations remained at 130+/-30 mg per deciliter in the placebo group and fell to 63+/-23 mg per deciliter in the atorvastatin group (P<0.001). Increases in aortic-jet velocity were 0.199+/-0.210 m per second per year in the atorvastatin group and 0.203+/-0.208 m per second per year in the placebo group (P=0.95; adjusted mean difference, 0.002; 95 percent confidence interval, -0.066 to 0.070 m per second per year). Progression in valvular calcification was 22.3+/-21.0 percent per year in the atorvastatin group, and 21.7+/-19.8 percent per year in the placebo group (P=0.93; ratio of post-treatment aortic-valve calcium score, 0.998; 95 percent confidence interval, 0.947 to 1.050). CONCLUSIONS: Intensive lipid-lowering therapy does not halt the progression of calcific aortic stenosis or induce its regression. This study cannot exclude a small reduction in the rate of disease progression or a significant reduction in major clinical end points. Long-term, large-scale, randomized, controlled trials are needed to establish the role of statin therapy in patients with calcific aortic stenosis.

Effect of an integrated care pathway on acute asthma/wheeze in children attending hospital: cluster randomized trial.

OBJECTIVE: To determine whether an integrated care pathway (ICP) could improve care delivered to patients coming to an emergency department only or to patients who were subsequently admitted. STUDY DESIGN: Children (age, 2-16 years; n = 298) coming to the ED with acute asthma/wheeze, were randomized by using a cluster design to either standard care or care delivered by an ICP. RESULTS: Children discharged from the ED who received care with an ICP (n = 118) received more prednisolone (81%; standard, 63%; P = .03) and increased advice to obtain primary care review (72%; standard, 33%; P < .0001). A total of 180 children were admitted (94 ICP, 86 standard). The rate of recovery was unchanged by ICP. The mean ICP length of stay (37.6 hours; range, 33.5-42.4 hours), was 93% of the mean standard length of care (40.7 hours; range, 35.9-46; P = .36). When a discharge checklist was completed (60 of 94 cases), the mean ICP length of stay was 34.2 hours (range, 30.5-38.4 hours; P = .07 versus standard). An ICP resulted in a 30% reduction in prescribing errors (mean, 10.4; standard, 14.8; P = .002). Eighty-four of 94 children with an ICP received a 48-hour discharge plan (89%) versus 35 of 86 children with standard care (41%). More clinical contacts were observed in children receiving care by an ICP (mean, 22, versus standard, 19.2: P = .0004). CONCLUSION: An acute asthma/wheeze ICP improved education and prescribing errors, modestly reduced the length of stay when discharge criteria were adhered to, but did not influence recovery time. Further consideration of the effect on staff workload is required.

Role of brain natriuretic peptide (BNP) in risk stratification of adult syncope.

AIMS: To assess the value of a near-patient brain natriuretic peptide (BNP) test to predict medium term (3 month) serious outcome for adult syncope patients presenting to a UK emergency department (ED). METHODS: This was a prospective cohort pilot study. Consecutive patients aged > or = 16 years presenting with syncope over a 3 month period were eligible for prospective enrolment. All patients who were medium or high risk according to our ED's existing syncope guidelines underwent near-patient BNP testing using the Triage point of care machine. RESULTS: 99 patients were recruited. 72 of 82 high and medium risk patients underwent BNP measurement. 11 patients had a serious outcome, 9 of whom had BNP measured. In 25 (35%) patients, BNP was > or = 100 pg/ml, and in 3 of these it was > 1000 pg/ml. 6 of the 25 patients (24%) with a BNP > 100 pg/ml, and all 3 patients with a BNP > 1000 pg/ml, were in the serious outcome group. BNP was raised over 100 pg/ml in 6 of the 9 serious outcome patients having a BNP measured (66%), and over 1000 pg/ml in 3 (33%). CONCLUSIONS: This early work suggests that BNP may have a role in the risk assessment of syncope patients in the ED. Further work is required to see how BNP interacts with other clinical variables. Near-patient BNP testing may be shown to be an independent predictor of adverse outcome either alone or incorporated into existing syncope clinical decision rules and scores in order to improve their sensitivity and specificity. Further studies are required to evaluate this.

The Risk stratification Of Syncope in the Emergency department (ROSE) pilot study: a comparison of existing syncope guidelines.

AIMS: This study was conducted as a feasibility pilot for the Risk stratification Of Syncope in the Emergency department (ROSE) study. The secondary aim was to compare the performance of our existing emergency department (ED) guidelines with existing clinical decision rules (Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) Score and San Francisco Syncope Rule; SFSR) at predicting short-term (1 week and 1 month) and medium-term (3 months) serious outcomes for patients with syncope presenting to the ED. METHODS: This was a prospective cohort study. All patients presenting with syncope aged > or = 16 years between 7 November 2005 and 7 February 2006 were prospectively enrolled. RESULTS: 99 patients were recruited over a 3-month period. 44 patients were admitted and 55 discharged from the ED. 11 patients had a serious outcome: 8 by 7 days and a further 3 by 3 months. Five patients died by 3 months and six others had an alternative serious outcome. All 11 patients had been admitted from the ED, 7 were at high risk, 4 were at medium risk and none were at low risk according to our existing ED guidelines. Percentages of serious outcomes were 0%, 2.9%, 8.0%, 22.7% and 37.5% for OESIL scores of 0, 1, 2, 3 and 4 respectively. 40 patients had none of the 5 SFSR high-risk factors (0 serious outcomes = 0%) and 59 patients had an SFSR high-risk factor (11 serious outcomes = 18.6%). The risk of serious outcome at 7 days, 1 month and 3 months was 8.1%, 8.1% and 11.1%, respectively. CONCLUSIONS: A study to derive and validate a UK ED syncope clinical decision rule is feasible. This pilot study has evaluated the OESIL score, the SFSR and our existing ED guidelines, and has shown that each is able to identify an increased probability of medium-term serious outcome in patients with syncope. The SFSR shows good sensitivity at the expense of an increase in admissions to hospital; however, our existing ED syncope guidelines and the OESIL Score, although being able to successfully risk stratify patients, are not sufficiently sensitive to be able to reduce admissions without missing patients at risk of a serious outcome. Undoubtedly there is a need for a simple UK-derived clinical decision rule for patients presenting with syncope to enable safe, effective clinical care and to aid less experienced decision makers.

Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease. METHODS: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15). FINDINGS: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group. INTERPRETATION: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence. FUNDING: Medical Research Council.