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Abstract Background The optimal management for severe sprains (Grades II and III) of the lateral ligament complex of the ankle is unclear. The aims of this randomised controlled trial are to estimate (1) the clinical effectiveness of three methods of providing mechanical support to the ankle (below knee cast, Aircast® brace and Bledsoe® boot) in comparison to Tubigrip®, and (2) to compare the cost of each strategy, including subsequent health care costs. Methods/design Six hundred and fifty people with a diagnosis of severe sprain are being identified through emergency departments. The study has been designed to complement routine practice in the emergency setting. Outcomes are recovery of mobility (primary outcome) and usual activity, residual symptoms and need for further medical, rehabilitation or surgical treatment. Parallel economic and qualitative studies are being conducted to aid interpretation of the results and to evaluate the cost-effectiveness of the interventions. Discussion This paper highlights the design, methods and operational aspects of a clinical trial of acute injury management in the emergency department.

Background This study used national data to determine if violent child death rates fell between 1974 and 2008. Design Using mortality data from the Office of National Statistics, categories potentially containing violent child deaths were analysed for children aged <1, 1-14 and 15-19 years. These data were compared with Home Office data on recorded homicides in children aged <1 and 1-15 years. Results Annual rates of infant deaths registered as due to assault fell between 1974 and 2008 from 5.6 to 0.7 per 100 000 infants; those in children (1-14 years) fell from 0.6 to 0.2 per 100 000. When these deaths are combined with those registered as undetermined intent, rates are higher but still show a decline in both groups. There is a slight fall in the rates of police recorded homicides in infants, but no observable change in childhood rates. In adolescents, the rates of death from assault fell during the 1970s and have since remained static in females but have risen in males. When these deaths are combined with those registered as undetermined intent, the rates for adolescent women have remained static at 2.0 per 100 000, while for young men they increased from 3.3 to 5.7 per 100 000 before declining to 4.2 per 100 000. Conclusion These data provide evidence that rates of violent death in infancy and middle childhood have fallen over the past 30 years. In contrast, rates in adolescence have remained static or risen over the same period. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Hemming K, Bonellie S, Hutton J. Fetal growth and birthweight standards as screening tools: methods for evaluating performance. BJOG 2011;118:1477-1483. Objective To discuss different methods for evaluating fetal growth and population-based birthweight standards relevant to different uses: either in antenatal care or in epidemiology. Design Population-based cohort study. Setting Routinely collected data in Scotland. Population A total of 540 849 singletons born after 24 weeks between 1980 and 2003. Methods The performance of a fetal growth standard and a population-based birthweight standard are compared in two ways. First, we consider the accuracy of estimated risks of stillbirth at any point during the remaining pregnancy, a measure that is relevant in antenatal care. Second, the rates of stillbirth at each gestation, which are measures relevant in epidemiology, are compared with the actual rates. Main outcome measures Standard measures of screening and diagnostic performance: sensitivity, specificity, and positive and negative predictive values. Results In clinical care, the evidence points towards using fetal growth standards: sensitivity at term is about 30%, increasing to 43% for preterm births (24-31 weeks of gestation), compared with about 29% across all ages under the birthweight standard. Positive predictive values are about 1% across gestations. For epidemiology, the evidence is not so clear-cut: preterm, the population birthweight standard has higher sensitivity and specificity, but this is not the case in the full-term weeks. Conclusions The performance of fetal growth and birthweight standards should be evaluated in different ways, depending on whether they are intended for use in antenatal care or in epidemiological investigations. [ABSTRACT FROM AUTHOR]

RATIONALE, AIMS AND OBJECTIVES: Many studies have investigated response issues to postal questionnaires in educational and market research surveys. Behavioural theories have been applied to survey research to understand response decisions. Little attention has focussed specifically on response issues to postal questionnaires used to collect data in clinical trials. This qualitative study, nested within an acute injury RCT, examines factors affecting response and non-response from the clinical trial participant's perspective. METHODS: Qualitative study comprising of 22 semi-structured interviews with a purposeful sample of clinical trial participants. The sample consisted of 14 'responders' and 8 'non-responders' to postal questionnaire follow-up. Data were analysed using the Framework Method. RESULTS: Prevalent reasons for responding to the questionnaires were the perceived personal benefit, commitment to the trial and perceived obligation to respond. Altruism was also a strong motivator. There was an association between the participant's understanding of the trial and their likelihood of responding. Most non-responders were happy with the trial and gave reasons for non-response such as being 'lazy' and 'forgetful'. Participants who considered themselves to be fully recovered were less likely to respond. There also emerged a relationship between response and treatment preference. CONCLUSIONS: Saliency of the questionnaire topic is one of the most prevalent influences on response in clinical trials. This is not evident in the survey literature. Improvements in response rates may be gained by ensuring participants fully understand the trial procedures and stressing the importance of responding even if a full recovery has been made. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate long-term survival and examine causes of death in adult patients with cerebral palsy (CP). A 1940-1950 birth cohort based on paediatric case referral allows for long-term survival follow-up. Survival is analyzed by birth characteristics and severity of disability from age 20 years (and age 2y for a subset of the data). Survival outcome compared with that expected in the general population based on English life tables. The main cohort consisted of 341 individuals, with 193 males and 148 females. Conditional on surviving to age 20 years, almost 85% of the cohort survived to age 50 years (a comparable estimate for the general population is 96%). Very few deaths were attributed to CP for those people dying over 20 years of age. Females survived better than males. However, females faced a greater increase in risk relative to the general population than did males. We conclude that survival outlook is good though lower than in the general population. The relative risk of death compared with the UK population decreases with age, although it shows some indication of rising again after age 50 years. Many more deaths were caused by diseases of the respiratory system among those dying in their 20s and 30s than would be expected in the general population. Many fewer deaths than expected in this age group are caused by injuries and accidents. For those people who die in their 40s and 50s, an increase in deaths due to diseases of the circulatory system and neoplasms is observed. More deaths than expected in this age group are due to diseases of the nervous system. [ABSTRACT FROM AUTHOR]

Aims of the study. To measure how effective foam swabs are at removing dental plaque when compared with using a toothbrush and to quantify any difference in ability. Background. Few nursing studies have aimed to determine the effectiveness of different mouth care tools to remove plaque which is associated with the tooth/gingival margin and, therefore, with gingivitis and chronic inflammatory periodontal disease. Findings from a previous case study of two people that compared the ability of foam swabs and toothbrushes to remove plaque at the gum/tooth margin (gingival crevice) and plaque from between teeth (approximal plaque) suggested that the success of a toothbrush is affected by user technique and that foam swabs are not able to remove plaque from some 'sheltered' areas of teeth. Methods. A time-series, cross-over controlled trial with 34 volunteers was used to determine the ability of foam swabs and toothbrushes to remove dental plaque which had been allowed to accumulate overnight. Plaque accumulations were scored at each approximal and crevice site for the buccal surfaces of the eight upper and eight lower teeth after each treatment of either toothbrushing or swabbing. Results. Plaque frequency distributions in the form of boxplots, together with results from summary statistics demonstrate that toothbrushes performed substantially better than foam swabs in the ability to remove plaque from the sites studied in this larger sample of people. Conclusions. The trial verified the findings from the previous study. The conclusions can be generalized to a wider population because of the magnitude and direction of the differences measured. The implications for nurse education and the development of nursing in practice settings include the need to teach effective toothbrushing skills to nurses, and to support clinical staff in developing mouthcare practice, particularly in relation to the use of assessment strategies that include the choice of effective tools. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effect of motor and cognitive disabilities on the survival of people on the North of England Collaborative Cerebral Palsy Survey, and compare this with other published results.Methods: The cerebral palsy cohort consists of 1960-1990 births in Northumberland, Newcastle, and North Tyneside health districts. Survival and cause of death were analysed in relation to data on birth, disabilities, and a unique measure of the impact of disability.Results: Disability strongly influences survival. More than a third of those with a severe disability die before age 30. Fewer than a third of deaths are attributed to cerebral palsy on death certificates. Of those with severe cognitive disability, 63% live to age 35 (58% with severe ambulatory disability and 53% with severe manual disability), whereas at least 98% without severe disabilities live to age 35. The Lifestyle Assessment Score (LAS) allows a finer categorisation of impact of disability, and is strongly associated with survival: a ten point increase in LAS is associated with a doubling of the hazard rate. People who had LAS of at least 70, and had survived to age 5 have a 39% chance of dying before age 35.Conclusions: The majority of people with cerebral palsy attain adulthood. There appears to be more variation in survival rates associated with severe disability between regions of England, than between north east England, British Columbia, and California. Instantaneous risks of dying vary widely between England and California. This variation is not obviously attributable to differing rates of severe disability. [ABSTRACT FROM AUTHOR]

Shows the localization of the G-protein alpha 1 homologue in the moss, Physcomitrella patens. Specificity of guanosine triphosphate gamma S binding to P. patens microsomal fraction membranes; Immunolocalization of G-protein alpha 1 homologues in protonemal filaments.

A descriptive survey of current reported practice by 146 community nurses for their nursing treatment of leg ulcers was undertaken. Sixty-four per cent of nurses reported they would apply compression bandages to only venous ulcers; in only 23% of cases could the products described achieve an adequate level of compression. A variety of modern wound dressings were used by the nurses; 89% of nurses reported using a combination of different products layered over the ulcer. There is no evidence that this has any beneficial effect and could therefore be a potential waste of money, as well as contributing to allergic skin reactions. It would be useful if primary-health-care teams and Family Health Service Authority information pharmacists formulated protocols based upon effective treatments for patients with chronic leg ulcers. [ABSTRACT FROM AUTHOR]

Background and Objectives: Deviations in birth weight from an optimum, thought to be just above average for gestational age, are known to increase both the risk of developing cerebral palsy and the risk of developing cerebral palsy of a more severe form. Influences on survival of such deviations from average birth weight for gestational age are not known.Methods: Using a well-established, well-defined and large UK cohort of children and adults with cerebral palsy, followed from birth for nearly 25 years, we investigate the influence of deviations from average birth weight for gestational age, on survival duration, after allowing for severity of impairments.Results: A total of 3946 cases, born between 1980 and 1996 were included. For those born much lighter than average for gestational age, more than 30% (n = 313) had a severe motor or cognitive impairment, rising to as much as 40% (n = 239) for extremely low weights. For female infants, the proportions severely impaired increased to as much as 35% (n = 49) among those born much heavier than average; no such increase was observed for heavier than average male infants. For those with four severe impairments and a birth weight close to average for gestational age, around 60% (n = 140) survived to age 15 years, compared with less than 40% (n = 9) of those born much heavier than average for gestational age. A 2-year-old child with four severe impairments and born heavy for gestational age has a predicted median life expectancy of 79% (95% CI 70% to 88%) of the average.Conclusions: Infants with a birth weight lighter than average for gestational age have an increased likelihood of developing a more severe form of cerebral palsy. Surprisingly, among the infants who are very severely impaired, those born much lighter than average for gestational age have the longest life expectancy, and those born much heavier than average for gestational age have the shortest life expectancy. [ABSTRACT FROM AUTHOR]

Aims: To determine the differential effects of preterm birth and being small for gestational age on the cognitive and motor ability of the child.Methods: A longitudinal cohort of all infants of gestational age < or = 32 weeks born to mothers resident in the counties of Cheshire and Merseyside in 1980-1 was studied. The children were assessed at the age of 8 to 9 years using the Wechsler Intelligence Scale for Children, the Neale analysis of reading ability, and the Stott-Moyes-Henderson test of motor impairment. Adequacy of fetal growth was determined by the birthweight ratio--that is, the ratio of the observed birthweight to the expected birthweight for a given gestational age. Children with clinically diagnosed motor, learning or sensory disabilities were excluded. Information on social variables was obtained by a questionnaire completed by the parents. Of the 182 children, 158 were assessed.Results: IQ was positively correlated with birthweight ratio but not with birthweight or gestational age. Motor ability was associated with birthweight, gestational age, and birthweight ratio. Reading comprehension was associated with birthweight ratio, but reading rate and accuracy were best explained by social variables and sex. IQ remained associated with birthweight ratio, after adjusting for maternal education, housing status, and number of social service benefits received. Reading ability was related to these social variables but motor ability was not.Conclusions: The effects of SGA and preterm birth differed: SGA was associated with cognitive ability, as measured by IQ and reading comprehension; motor ability was additionally associated with preterm birth. Reading rate and accuracy were not associated with SGA or preterm birth but were socially determined. [ABSTRACT FROM AUTHOR]

Background: This is an updated version of the Cochrane Review previously published in 2018. Epilepsy is a common neurological disorder characterised by recurrent seizures. Most people with epilepsy have a good prognosis and their seizures are well controlled by a single antiepileptic drug, but up to 30% develop drug-resistant epilepsy, especially people with focal seizures. In this review, we summarised the evidence from randomised controlled trials (RCTs) of gabapentin, when used as an add-on treatment for drug-resistant focal epilepsy., Objectives: To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for people with drug-resistant focal epilepsy., Search Methods: For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) on 11 August 2020. CRS Web includes randomised or quasi-randomised, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups including Epilepsy. We imposed no language restrictions., Selection Criteria: Randomised, placebo-controlled, double-blind, add-on trials of gabapentin in people with drug-resistant focal epilepsy. We also included trials using an active drug control group or comparing different doses of gabapentin., Data Collection and Analysis: Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: seizure frequency, seizure freedom, treatment withdrawal (any reason) and adverse effects. Primary analyses were intention-to-treat. We also undertook sensitivity best-case and worst-case analyses. We estimated summary risk ratios (RR) for each outcome and evaluated dose-response in regression models., Main Results: We identified no new studies for this update, therefore, the results and conclusions are unchanged. In the previous update of this review, we combined data from six trials in meta-analyses of 1206 randomised participants. The overall risk ratio (RR) for reduction in seizure frequency of 50% or more compared to placebo was 1.89 (95% confidence interval (CI) 1.40 to 2.55; 6 studies, 1206 participants; moderate-certainty evidence). Dose regression analysis (for trials in adults) showed increasing efficacy with increasing dose, with 25.3% (95% CI 19.3 to 32.3) of people responding to gabapentin 1800 mg compared to 9.7% on placebo, a 15.5% increase in response rate (95% CI 8.5 to 22.5). The RR for treatment withdrawal compared to placebo was 1.05 (95% CI 0.74 to 1.49; 6 trials, 1206 participants; moderate-certainty evidence). Adverse effects were significantly associated with gabapentin compared to placebo. RRs were as follows: ataxia 2.01 (99% CI 0.98 to 4.11; 3 studies, 787 participants; low-certainty evidence), dizziness 2.43 (99% CI 1.44 to 4.12; 6 studies, 1206 participants; moderate-certainty evidence), fatigue 1.95 (99% CI 0.99 to 3.82; 5 studies, 1161 participants; low-certainty evidence) and somnolence 1.93 (99% CI 1.22 to 3.06; 6 studies, 1206 participants; moderate-certainty evidence). There was no evidence of a difference for the adverse effects of headache (RR 0.79, 99% CI 0.46 to 1.35; 6 studies, 1206 participants; moderate-certainty evidence) or nausea (RR 0.95, 99% CI 0.52 to 1.73; 4 trials, 1034 participants; moderate-certainty evidence). Overall, the studies were at low to unclear risk of bias due to information on each risk of bias domain not being available. We judged the overall certainty of the evidence (using the GRADE approach) as low to moderate due to potential attrition bias resulting from missing outcome data and imprecise results with wide CIs., Authors' Conclusions: Gabapentin has efficacy as an add-on treatment in people with drug-resistant focal epilepsy, and seems to be fairly well-tolerated. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of gabapentin beyond a three-month period. The results cannot be extrapolated to monotherapy or to people with other epilepsy types. Further trials are needed to assess the long-term effects of gabapentin, and to compare gabapentin with other add-on drugs., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Nausea and vomiting are experienced by most women during pregnancy. The onset is usually related to Last Menstrual Period (LMP) the date of which is often unreliable. This study describes the time to onset of nausea and vomiting symptoms from date of ovulation and compares this to date of last menstrual period METHODS: Prospective cohort of women seeking to become pregnant, recruited from 12 May 2014 to 25 November 2016, in the United Kingdom. Daily diaries of nausea and vomiting were kept by 256 women who were trying to conceive. The main outcome measure is the number of days from last menstrual period (LMP) or luteinising hormone surge until onset of nausea or vomiting., Results: Almost all women (88%) had Human Chorionic Gonadotrophin rise within 8 to 10 days of ovulation; the equivalent interval from LMP was 20 to 30 days. Many (67%) women experience symptoms within 11 to 20 days of ovulation., Conclusions: Onset of nausea and vomiting occurs earlier than previously reported and there is a narrow window for onset of symptoms. This indicates that its etiology is associated with a specific developmental stage at the foetal-maternal interface., Trial Registration: NCT01577147 . Date of registration 13 April 2012.

Background: Nausea and vomiting in pregnancy is usually called 'morning sickness'. This is felt by sufferers to trivialise the condition. Symptoms have been described as occurring both before and after noon, but daily symptom patterns have not been clearly described and statistically modelled to enable the term 'morning sickness' to be accurately analysed., Aim: To describe the daily variation in nausea and vomiting symptoms during early pregnancy in a group of sufferers., Design and Setting: A prospective cohort study of females recruited from 15 May 2014 to 17 February 2017 by Swiss Precision Diagnostics (SPD) Development Company Limited, which was researching hormone levels in early pregnancy and extended its study to include the description of pregnancy symptoms., Method: Daily symptom diaries of nausea and vomiting were kept by females who were trying to conceive. They also provided daily urine samples, which when analysed enabled the date of ovulation to be determined. Data from 256 females who conceived during the first month of the study are included in this article. Daily symptom patterns and changes in daily patterns by week of pregnancy were modelled. Functional data analysis was used to produce estimated symptom probability functions., Results: There was a peak probability of nausea in the morning, a lower but sustained probability of nausea throughout the day, and a slight peak in the evening. Vomiting had a defined peak incidence in the morning., Conclusion: Referring to nausea and vomiting in pregnancy as simply 'morning sickness' is inaccurate, simplistic, and therefore unhelpful., (© British Journal of General Practice 2020.)

Background: Drug resistance is common in focal epilepsy. In this update, we summarised the current evidence regarding add-on levetiracetam in treating drug-resistant focal epilepsy. The original review was published in 2001 and last updated in 2012., Objectives: To evaluate the effectiveness of levetiracetam when used as an add-on treatment for people with drug-resistant focal epilepsy., Search Methods: We searched the Cochrane Register of Studies (CRS Web, which includes the Cochrane Epilepsy Group Specialized Register and CENTRAL), MEDLINE Ovid, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) to November 2018. We contacted the manufacturers of levetiracetam and researchers in the field to seek any ongoing or unpublished trials., Selection Criteria: Randomised, placebo-controlled trials of add-on levetiracetam treatment in people with drug-resistant focal epilepsy., Data Collection and Analysis: Two review authors independently selected trials for inclusion, assessed trials for bias, extracted data, and evaluated the overall certainty of the evidence. Outcomes investigated included 50% or greater reduction in focal seizure frequency (response), treatment withdrawal, adverse effects (including a specific analysis of changes in behaviour), cognitive effects, and quality of life (QoL). Primary analysis was intention-to-treat. We performed meta-analysis for all outcomes using a Mantel-Haenszel approach and calculated risk ratios (RR), with 95% confidence intervals (CI) for all estimates apart from adverse effects (99% CIs). We assessed heterogeneity using a Chi² test and the I² statistic., Main Results: This update included 14 trials (2455 participants), predominantly possessing low risks of bias. Participants were adults in 12 trials (2159 participants) and children in the remaining two (296 participants). The doses of levetiracetam tested were 500 mg/day to 4000 mg/day in adults, and 60 mg/kg/day in children. Treatment ranged from 12 to 24 weeks. When individual doses were examined, levetiracetam at either 500 mg/day or 4000 mg/day did not perform better than placebo for the 50% or greater reduction in seizure frequency outcome (500 mg: RR 1.60, 95% CI 0.71 to 3.62; P = 0.26; 4000 mg: RR 1.64, 95% CI 0.59 to 4.57; P = 0.34). Levetiracetam was significantly better than placebo at all other individual doses (1000 mg to 3000 mg). RR was significantly in favour of levetiracetam compared to placebo when results were pooled across all doses (RR 2.37, 95% CI 2.02 to 2.78; 14 studies, 2455 participants; moderate-certainty evidence). Dose-response analysis demonstrated that the odds of achieving response (50% or greater reduction in seizure frequency) were increased by nearly 40% (odds ratio (OR) 1.39, 95% CI 1.23 to 1.58) for each 1000 mg increase in dose of levetiracetam. There were important levels of heterogeneity across multiple comparisons. Participants were not significantly more likely to experience treatment withdrawal with levetiracetam than with placebo (pooled RR 1.11, 95% CI 0.89 to 1.40; 13 studies, 2428 participants; high-certainty evidence). Somnolence was the most common adverse effect, affecting 13% of participants, and it was significantly associated with levetiracetam compared to placebo (pooled RR 1.62, 99% CI 1.19 to 2.20; 13 studies, 2423 participants; moderate-certainty evidence). Changes in behaviour were negligible in adults (1% affected; RR 1.79, 99% CI 0.59 to 5.41), but significant in children (23% affected; RR 1.90, 99% CI 1.16 to 3.11). Levetiracetam had a positive effect on some aspects of cognition and QoL in adults and worsened certain aspects of child behaviour., Authors' Conclusions: Overall, this review update finds that in both adults and children with drug-resistant focal epilepsy, levetiracetam added on to usual care is more effective than placebo at reducing seizure frequency, it is unlikely to be stopped by patients, and it has minimal adverse effects outside of potential worsening behaviour in children. These findings are unchanged from the previous review update in 2012. This review update contributes two key additional findings: 1. a 500 mg daily dose of levetiracetam is no more effective than placebo at reducing seizures; and 2. the odds of response (50% reduction in seizure frequency) are increased by nearly 40% for each 1000 mg increase in dose of levetiracetam. It seems reasonable to continue the use of levetiracetam in both adults and children with drug-resistant focal epilepsy., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Predictive models within epilepsy are frequently developed via Cox's proportional hazards models. These models estimate risk of a specified event such as 12-month remission. They are relatively simple to produce, have familiar output, and are useful to answer questions about short-term prognosis. However, the Cox model only considers time to first event rather than all seizures after starting treatment for example. This makes assessing change in seizure rates over time difficult. Variants to the Cox model exist enabling recurrent events to be modelled. One such variant is the Prentice, Williams and Peterson - Total Time (PWP-TT) model. An alternative is the negative binomial model for event counts. This study aims to demonstrate the differences between the three approaches, and to consider the benefits of the PWP-TT approach for assessing change in seizure rates over time., Methods: Time to 12-month remission and time to first seizure after randomisation were modelled using the Cox model. Risk of seizure recurrence was modelled using the PWP-TT model, including all seizures across the whole follow-up period. Seizure counts were modelled using negative binomial regression. Differences between the approaches were demonstrated using participants recruited to the UK-based multi-centre Standard versus New Antiepileptic Drug (SANAD) study., Results: Results from the PWP-TT model were similar to those from the conventional Cox and negative binomial models. In general, the direction of effect was consistent although the variables included in the models and the significance of the predictors varied. The confidence intervals obtained via the PWP-TT model tended to be narrower due to the increase in statistical power of the model., Conclusions: The Cox model is useful for determining the initial response to treatment and potentially informing when the next intervention may be required. The negative binomial model is useful for modelling event counts. The PWP-TT model extends the Cox model to all included events. This is useful in determining the longer-term effects of treatment policy. Such a model should be considered when designing future clinical trials in medical conditions typified by recurrent events to improve efficiency and statistical power as well as providing evidence regarding changes in event rates over time.

Background: The majority of people with epilepsy have a good prognosis and their seizures are controlled by a single antiepileptic drug. However, up to 20% of patients from population-based studies, and up to 30% from clinical series (not population-based), develop drug-resistant epilepsy, especially those with focal-onset seizures. In this review, we summarise the current evidence regarding topiramate, an antiepileptic drug first marketed in 1996, when used as an add-on treatment for drug-resistant focal epilepsy.This is an update of a Cochrane Review first published in 1999, and last updated in 2014., Objectives: To evaluate the efficacy and tolerability of topiramate when used as an add-on treatment for people with drug-resistant focal epilepsy., Search Methods: For the latest update of this review we searched the following databases on 2 July 2018: Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (Ovid, 1946- ); ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We also contacted the manufacturers of topiramate and researchers in the field to identify any ongoing or unpublished studies., Selection Criteria: Randomised, placebo-controlled add-on trials of topiramate, recruiting people with drug-resistant focal epilepsy., Data Collection and Analysis: Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: (1) 50% or greater reduction in seizure frequency; (2) seizure freedom; (3) treatment withdrawal (any reason); (4) adverse effects. Primary analyses were intention-to-treat (ITT), and summary risk ratios (RRs) with 95% confidence intervals (95% CIs) are presented. We evaluated dose-response in regression models. We carried out a 'Risk of bias' assessment for each included study using the Cochrane 'Risk of bias' tool and assessed the overall certainty of evidence using the GRADE approach., Main Results: We included 12 trials, representing 1650 participants. Baseline phases ranged from four to 12 weeks and double-blind phases ranged from 11 to 19 weeks. The RR for a 50% or greater reduction in seizure frequency with add-on topiramate compared to placebo was 2.71 (95% CI 2.05 to 3.59; 12 studies; high-certainty evidence). Dose regression analysis showed increasing effect with increasing topiramate dose demonstrated by an odds ratio (OR) of 1.45 (95% CI 1.28 to 1.64; P < 0.001) per 200 mg/d increase in topiramate dosage. The proportion of participants achieving seizure freedom was also significantly increased with add-on topiramate compared to placebo (RR 3.67, 95% CI 1.79 to 7.54; 8 studies; moderate-certainty evidence). Treatment withdrawal was significantly higher for add-on topiramate compared to placebo (RR 2.37, 95% CI 1.66 to 3.37; 12 studies; high-certainty evidence). The RRs for the following adverse effects indicate that they are significantly more prevalent with topiramate, compared to placebo: ataxia 2.29 (99% CI 1.10 to 4.77; 4 studies); concentration difficulties 7.81 (99% CI 2.08 to 29.29; 6 studies; moderate-certainty evidence); dizziness 1.52 (99% CI 1.07 to 2.16; 8 studies); fatigue 2.08 (99% CI 1.37 to 3.15; 10 studies); paraesthesia 3.65 (99% CI 1.58 to 8.39; 7 studies; moderate-certainty evidence); somnolence 2.44 (99% CI 1.61 to 3.68; 9 studies); 'thinking abnormally' 5.70 (99% CI 2.26 to 14.38; 4 studies; high-certainty evidence); and weight loss 3.99 (99% CI 1.82 to 8.72; 9 studies; low-certainty evidence). Evidence of publication bias for the primary outcome was found (Egger test, P = 0.001). We rated all studies included in the review as having either low or unclear risk of bias. Overall, we assessed the evidence as moderate to high certainty due to the evidence of publication bias, statistical heterogeneity and imprecision, which was partially compensated for by large effect sizes., Authors' Conclusions: Topiramate has efficacy as an add-on treatment for drug-resistant focal epilepsy as it is almost three times more effective compared to a placebo in reducing seizures. The trials reviewed were of relatively short duration and provided no evidence for the long-term efficacy of topiramate. Short-term use of add-on topiramate was shown to be associated with several adverse events. The results of this review should only be applied to adult populations as only one study included children. Future research should consider further examining the effect of dose.

Background: This is an updated version of the Cochrane Review previously published in 2013.Most people with epilepsy have a good prognosis and their seizures are well controlled by a single antiepileptic drug, but up to 30% develop drug-resistant epilepsy, especially those with focal seizures. In this review, we summarised the evidence from randomised controlled trials (RCTs) of gabapentin, when used as an add-on treatment for drug-resistant focal epilepsy., Objectives: To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for people with drug-resistant focal epilepsy., Search Methods: For the latest update, we searched the Cochrane Register of Studies (CRS Web, 20 March 2018), which includes the Cochrane Epilepsy Group's Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946 to 20 March 2018), ClinicalTrials.gov (20 March 2018) and the World Health Organization International Clinical Trials Registry Platform (ICTRP, 20 March 2018). We imposed no language restrictions., Selection Criteria: Randomised, placebo-controlled, double-blind, add-on trials of gabapentin in people with drug-resistant focal epilepsy. We also included trials using an active drug control group or comparing different doses of gabapentin., Data Collection and Analysis: For this update, two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: seizure frequency, seizure freedom, treatment withdrawal (any reason) and adverse effects. Primary analyses were intention-to-treat. We also undertook sensitivity best-case and worst-case analyses. We estimated summary risk ratios (RR) for each outcome and evaluated dose-response in regression models., Main Results: We included 12 trials representing 2607 randomised participants. We combined data from six trials in meta-analyses of 1206 randomised participants. The overall RR for reduction in seizure frequency of 50% or more compared to placebo was 1.89 (95% confidence interval (CI) 1.40 to 2.55; 6 trials, 1206 participants; moderate-quality evidence). Dose regression analysis (for trials in adults) showed increasing efficacy with increasing dose, with 25.3% (19.3 to 32.3) of people responding to gabapentin 1800 mg compared to 9.7% on placebo, a 15.5% increase in response rate (8.5 to 22.5). The RR for treatment withdrawal compared to placebo was 1.05 (95% CI 0.74 to 1.49; 6 trials, 1206 participants; moderate-quality evidence). Adverse effects were significantly associated with gabapentin compared to placebo. RRs were as follows: ataxia 2.01 (99% CI 0.98 to 4.11; 3 studies, 787 participants; low-quality evidence), dizziness 2.43 (99% CI 1.44 to 4.12; 6 studies, 1206 participants; moderate-quality evidence), fatigue 1.95 (99% CI 0.99 to 3.82; 5 studies, 1161 participants; low-quality evidence) and somnolence 1.93 (99% CI 1.22 to 3.06; 6 studies, 1206 participants; moderate-quality evidence). There were no significant differences for the adverse effects of headache (RR 0.79, 99% CI 0.46 to 1.35; 6 studies, 1206 participants; moderate-quality evidence) or nausea (RR 0.95, 99% CI 0.52 to 1.73; 4 trials, 1034 participants; moderate-quality evidence). Overall, the studies were rated at low to unclear risk of bias due to information on each risk of bias domain not being available. We judged the overall quality of evidence (using the GRADE approach) as low to moderate due to potential attrition bias resulting from missing outcome data and imprecise results with wide confidence intervals., Authors' Conclusions: Gabapentin has efficacy as an add-on treatment in people with drug-resistant focal epilepsy. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of gabapentin beyond a three-month period. The results cannot be extrapolated to monotherapy or to people with other epilepsy types.

Aim: Hyperkinetic movement disorders (HMDs) can be assessed using impairment-based scales or functional classifications. The Burke-Fahn-Marsden Dystonia Rating Scale-movement (BFM-M) evaluates dystonia impairment, but may not reflect functional ability. The Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), and Communication Function Classification System (CFCS) are widely used in the literature on cerebral palsy to classify functional ability, but not in childhood movement disorders. We explore the concordance of these three functional scales in a large sample of paediatric HMDs and the impact of dystonia severity on these scales., Method: Children with HMDs (n=161; median age 10y 3mo, range 2y 6mo-21y) were assessed using the BFM-M, GMFCS, MACS, and CFCS from 2007 to 2013. This cross-sectional study contrasts the information provided by these scales., Results: All four scales were strongly associated (all Spearman's rank correlation coefficient rs >0.72, p<0.001), with worse dystonia severity implying worse function. Secondary dystonias had worse dystonia and less function than primary dystonias (p<0.001). A longer proportion of life lived with dystonia is associated with more severe dystonia (rs =0.42, p<0.001)., Interpretation: The BFM-M is strongly linked with the GMFCS, MACS, and CFCS, irrespective of aetiology. Each scale offers interrelated but complementary information and is applicable to all aetiologies. Movement disorders including cerebral palsy can be effectively evaluated using these scales., (© 2015 Mac Keith Press.)

DCs are potent APCs and key regulators of innate and adaptive immunity. After allo-SCT, their reconstitution in the peripheral blood (PB) to levels similar to those in healthy individuals tends to be slow. We investigate the age- and sex-dependant immune reconstitution of myeloid (mDC) and plasmacytoid DC (pDC) in the PB of 45 children with leukaemia or myelodysplastic syndrome (aged 1-17 years, median 10) after allo-SCT with regard to relapse, acute GVHD (aGVHD) and relapse-free survival. Low pDC/μL PB up to day 60 post SCT are associated with higher incidence of moderate or severe aGVHD (P=0.035), whereas high pDC/μL PB up to day 60 are associated with higher risk of relapse (P<0.001). The time-trend of DCs/μL PB for days 0-200 is a significant predictor of relapse-free survival for both mDCs (P<0.001) and pDCs (P=0.020). Jointly modelling DC reconstitution and complications improves on these simple criteria. Compared with BM, PBSC transplants tend to show slower mDC/pDC reconstitution (P=0.001, 0.031, respectively), but have no direct effect on relapse-free survival. These results suggest an important role for both mDCs and pDCs in the reconstituting immune system. The inclusion of mDCs and pDCs may improve existing models for complication prediction following allo-SCT.

The adverse effects profile of levetiracetam in epilepsy is still being fully described. We recently published a Cochrane Review evaluating the effectiveness of levetiracetam, added on to usual care, in treating drug-resistant focal epilepsy. The five most common adverse effects were reported and analysed with no scope for reporting any less common adverse effects than those. Here, we report and analyse the remaining adverse effects (including the five most common). These were (in decreasing order of frequency) somnolence; headache; asthenia; accidental injury; dizziness; infection; pharyngitis; pain; rhinitis; abdominal pain; flu syndrome; vomiting; diarrhoea; convulsion; nausea; increased cough; anorexia; upper respiratory tract infection; hostility; personality disorder; urinary tract infection; nervousness; depression; aggression; back pain; agitation; emotional liability; psychomotor hyperactivity; pyrexia; rash; ECG abnormalities; decreased appetite; nasal congestion; irritability; abnormal behaviour; epistaxis; insomnia; altered mood; anxiety; bloody urine; diplopia; dissociation; memory impairment; pruritis; increased appetite; acne; and stomach discomfort. Only somnolence and infection were significantly associated with levetiracetam. When adverse effects pertaining to infection were combined, these affected 19.7% and 15.1% of participants on levetiracetam and placebo (relative risk 1.16, CI 0.89-1.50, Chi(2) heterogeneity p = 0.13). Somnolence and infection further retained significance in adults while no single adverse effect was significant in children. This review updates the adverse effects profile data on levetiracetam use by empirically reporting its common and uncommon adverse effects and analysing their relative importance statistically using data from a group of trials that possess low Risk of Bias and high Quality of Evidence GRADE scores.

Background: The majority of people with epilepsy have a good prognosis and their seizures are controlled by a single antiepileptic drug. However, up to 20% of patients from population-based studies and up to 30% from clinical series (not population-based) develop drug-resistant epilepsy, especially those with partial onset seizures. In this review we summarise the current evidence regarding topiramate, an antiepileptic drug first marketed in 1996, when used as an add-on treatment for drug-resistant partial epilepsy. This is an updated version of the original Cochrane review published in Issue 3, 1999., Objectives: To evaluate the efficacy and safety of topiramate when used as an add-on treatment for people with drug-resistant partial epilepsy., Search Methods: We searched the Cochrane Epilepsy Group Specialised Register (June 2013); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 5); MEDLINE (1946 to 2013); SCOPUS (1823 to 2013); ClinicalTrials.gov and ICTRP. We imposed no language restrictions. We also contacted the manufacturers of topiramate and researchers in the field to identify any ongoing or unpublished studies., Selection Criteria: Randomised, placebo-controlled or active drug controlled add-on trials of topiramate, recruiting people with drug-resistant partial epilepsy., Data Collection and Analysis: Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: (a) 50% or greater reduction in seizure frequency; (b) seizure freedom; (c) treatment withdrawal (any reason); (d) side effects. Primary analyses were intention-to-treat and summary risk ratios (RR) with 95% confidence intervals (95% CI) are presented. We evaluated dose response in regression models. We carried out a 'Risk of bias' assessment for each included study using the Cochrane 'Risk of bias' tool and assessed the overall quality of evidence using the GRADE approach, which we presented in a 'Summary of findings' table., Main Results: Eleven trials were included, representing 1401 randomised participants. Baseline phases ranged from 4 to 12 weeks and double-blind phases from 11 to 19 weeks. The RR for a 50% or greater reduction in seizure frequency compared to placebo was 2.97 (95% CI 2.38 to 3.72). Dose regression analysis shows increasing effect with increasing dose, but found no advantage for doses over 300 or 400 mg per day. The RR for seizure freedom (95% CI) compared to placebo was 3.41 (95% CI 1.37 to 8.51). The RR for treatment withdrawal compared to placebo was 2.44 (95% CI 1.64 to 3.62). The RRs for the following side effects indicate that they are significantly associated with topiramate: ataxia 2.29 (99% CI 1.10 to 4.77); concentration difficulties 7.81 (2.08 to 29.29); dizziness 1.54 (99% CI 1.07 to 2.22); fatigue 2.19 (99% CI 1.42 to 3.40); paraesthesia 3.91 (1.51 to 10.12); somnolence 2.29 (99% CI 1.49 to 3.51); 'thinking abnormally' 5.70 (99% CI 2.26 to 14.38) and weight loss 3.47 (1.55 to 7.79). Evidence of publication bias was found (P-value from the Egger test was P=0.003). We rated all studies included in the review as having either low or unclear risk of bias. Overall, we assessed the evidence as moderate quality due to the evidence of publication bias., Authors' Conclusions: Topiramate has efficacy as an add-on treatment for drug-resistant partial epilepsy in that it is three times more effective compared to a placebo in reducing seizures. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of topiramate. In the short term topiramate as an add-on has been shown to be associated with several adverse events. The results of this review cannot be extrapolated to monotherapy or treatment of other epilepsy types and future research should consider examining the effect of dose.

Background: The majority of people with epilepsy have a good prognosis and their seizures are well controlled by a single antiepileptic drug, but up to 30% develop drug-resistant epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding the antiepileptic drug gabapentin, when used as an add-on treatment for drug-resistant partial epilepsy., Objectives: To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for people with drug-resistant partial epilepsy., Search Methods: This is an updated version of the original Cochrane review published in The Cochrane Library 2009, Issue 4. We searched the Cochrane Epilepsy Group's Specialised Register (14 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 4, The Cochrane Library) (April 2013) and MEDLINE (1946 to 14 May 2013). We imposed no language restrictions., Selection Criteria: Randomised, placebo-controlled, double-blind, add-on trials of gabapentin in people with drug-resistant partial epilepsy. Trials using an active drug control group or which compared doses of gabapentin were also included in the review., Data Collection and Analysis: Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: (a) seizure frequency and seizure freedom; (b) treatment withdrawal (any reason); (c) adverse effects. Primary analyses were intention-to-treat. We also undertook sensitivity best and worst-case analyses. We estimated summary risk ratios for each outcome and evaluated dose-response in regression models., Main Results: Eleven trials were included representing 2125 randomised participants. We combined data from six trials in meta-analyses of 1206 randomised participants. The overall risk ratio (RR) for 50% or greater reduction in seizure frequency compared to placebo was 1.89 (95% confidence interval (CI) 1.40 to 2.55). Dose regression analysis (for trials in adults) shows increasing efficacy with increasing dose, with 25.3% (19.3 to 32.3) of people responding to 1800 mg of gabapentin compared to 9.7% on placebo, a 15.5% increase in response rate (8.5 to 22.5). The RR for treatment withdrawal compared to placebo was 1.05 (95% CI 0.74 to 1.49). Adverse effects were significantly associated with gabapentin compared to placebo. Risk ratios were as follows: ataxia 2.01 (99% CI 0.98 to 4.11), dizziness 2.43 (99% CI 1.44 to 4.12), fatigue 1.95 (99% CI 0.99 to 3.82) and somnolence 1.93 (99% CI 1.22 to 3.06). No significant differences were found for the adverse effects of headache (RR 0.79, 99% CI 0.46 to 1.35) or nausea (RR 0.95, 99% CI 0.52 to 1.73). Overall the studies together are rated as low/unclear risk of bias due to information on each risk of bias domain not being available., Authors' Conclusions: Gabapentin has efficacy as an add-on treatment in people with drug-resistant partial epilepsy. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of gabapentin beyond a three-month period. The results cannot be extrapolated to monotherapy or to people with other epilepsy types.

Dendritic cells (DCs) are the most potent antigen-presenting cells and are the key link between the innate and adaptive immune response. Only a few reports with study populations of up to 50 individuals have been published with age-based reference values for DC subpopulations in healthy children. Therefore, we aimed to establish reference ranges in a larger study population of 100 healthy children, which allowed age-matched subgroups. Most previous studies were performed using a dual-platform approach. In this study, a single-platform approach in a lyse no-wash procedure was used. DC subpopulations were defined as follows: CD45(+) CD85k(+) HLA-DR(+) CD14(-) CD16(-) CD33(+) cells as myeloid DCs (mDCs) and CD45(+) CD85k(+) HLA-DR(+) CD14(-) CD16(-) CD123(+) cells as plasmacytoid DCs (pDCs). Reference ranges were established using a semi-parametric regression of age-matched absolute and relative DC counts. We found a significant decline with increasing age in the medians of mDCs (P = 0.0003) and pDCs per μl peripheral blood (PB) (P = 0.004) and in the 50%, 90% and 95% reference ranges. We also identified significantly lower absolute cell counts of mDCs per μl PB in girls than in boys for all age groups (P = 0.0015). Due to the larger paediatric study population and single-platform approach, this study may give a more precise overview of the normal age-matched development of DC subpopulations and may provide a basis for analyzing abnormal DC counts in different illnesses or therapies such as post stem cell transplantation., (© 2013 The Authors. Scandinavian Journal of Immunology © 2013 Blackwell Publishing Ltd.)

Background: Epilepsy is a common neurological condition which affects between 0.5% and 1% of the population. Approximately 30% of people with epilepsy do not respond to treatment with currently available drugs. The majority of these people have partial epilepsy. Vigabatrin is an antiepileptic drug licensed for use in the treatment of refractory epilepsy. No major side effects associated with the use of vigabatrin were detected by initial randomised controlled trials of the drug. However, longer-term observational studies have subsequently identified that its use is associated with asymptomatic visual field constriction., Objectives: The objective of this review was to synthesise evidence from short-term, randomised, placebo-controlled trials of vigabatrin. We summarised the effects of vigabatrin on seizures and short-term side effects when used as an add-on treatment for people with drug-resistant partial epilepsy. A review of longer-term observational studies and estimates of proportions of patients developing visual field constrictions is currently being undertaken and results will be cited in this review in due course., Search Methods: We searched the Cochrane Epilepsy Group Specialised Register (12 October 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 9), MEDLINE (1946 to October week 1, 2012) and reference lists of articles. We also contacted the manufacturers of vigabatrin (Hoechst Marion Roussel)., Selection Criteria: We included randomised, double-blind, placebo-controlled, fully published trials of vigabatrin in people with drug-resistant partial epilepsy., Data Collection and Analysis: Two review authors assessed trials for inclusion and extracted data. Primary analysis was by intention-to-treat (ITT). Outcomes evaluated included 50% or greater reduction in seizure frequency, treatment withdrawal and side effects observable in the short term. Results are presented on the risk ratio (RR) scale with 95% or 99% confidence intervals (CI)., Main Results: Eleven suitable trials that tested vigabatrin doses between 1000 mg and 6000 mg were identified and included in the analysis. There were 982 observations on 747 patients in the primary ITT analysis of treatment efficacy. Patients treated with vigabatrin were significantly more likely to obtain a 50% or greater reduction in seizure frequency compared with those treated with placebo (RR 2.58, 95% CI 1.87 to 3.57). Those treated with vigabatrin were also significantly more likely to have treatment withdrawn (RR 2.49, 95% CI 1.05 to 5.88), and were more likely to experience a number of side effects, significantly so for fatigue or drowsiness. There was some evidence of small study effect bias, with smaller studies tending to report greater estimates of RR than larger studies. It is possible, therefore, that the actual RR of obtaining 50% reduction in seizure frequency is less than that obtained by a meta-analysis of fully published studies., Authors' Conclusions: This review of randomised controlled trials showed that vigabatrin can reduce seizure frequency in people with drug-resistant partial epilepsy. Short-term follow-up of patients showed that some side effects were associated with its use. Further analysis of longer-term observational studies is required to evaluate how likely patients are to develop visual field defects and whether such side effects are associated with dose and duration of drug use.

Background: Epilepsy is an important neurological condition and drug resistance in epilepsy is particularly common in individuals with focal seizures. In this review, we summarise the current evidence regarding a new antiepileptic drug, levetiracetam, when used as add-on treatment for controlling drug-resistant focal epilepsy. This is an update to a Cochrane Review that was originally published in 2001., Objectives: To evaluate the effectiveness of levetiracetam, added on to usual care, in treating drug-resistant focal epilepsy., Search Methods: We searched the Cochrane Epilepsy Group's Specialized Register (August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 7, 2012), and MEDLINE (1946 to August week 1, 2012). We also contacted the manufacturers of levetiracetam and researchers in the field to seek any ongoing or unpublished trials., Selection Criteria: Randomised, placebo-controlled trials of add-on levetiracetam treatment in people with drug-resistant focal epilepsy., Data Collection and Analysis: Two review authors independently selected trials for inclusion, assessed trials for bias, extracted data, and evaluated the overall quality of evidence. Outcomes investigated included 50% or greater reduction in focal seizure frequency (response); less than 50% reduction in focal seizure frequency (non-response); treatment withdrawal; adverse effects (including a specific analysis of changes in behaviour); cognitive effects and quality of life (QoL). Risk ratios (RR) with 95% confidence intervals (CIs) were used as measures of effect (99% CIs for adverse effects). Primary analyses were Intention-to-Treat (ITT). Dose response and inter-trial heterogeneity were evaluated in regression models., Main Results: Eleven trials (1861 participants) were included. They predominantly possessed low risks of bias. Participants were adults in nine trials (1565 participants) and children in the remaining two trials (296 participants). The dose of levetiracetam tested was 1000 to 4000 mg/day in adults, and 60 mg/kg/day in children. Treatment ranged from 12 to 24 weeks. For the 50% or greater reduction in focal seizure frequency outcome, the RR was significantly in favour of levetiracetam at all doses. The naive estimates, ignoring dose, showed children (52% responded) as better responders than adults (39% responded) on levetiracetam. 25% of children and 16% of adults responded to placebo. The Number Needed to Treat for an additional beneficial outcome for children and adults was four (95% CI three to seven) and five (95% CI four to six), respectively. The significant levels of statistical heterogeneity between trials on adults precluded valid provision of an overall RR (ignoring dose). Results for the two trials that tested levetiracetam 2000 mg on adults were sufficiently similar to be combined to give an RR for 50% or greater reduction in focal seizure frequency of 4.91 (95% CI 2.75 to 8.77), with an RR of 0.68 (95% CI 0.60 to 0.77) for non-response. At this dose, 37% and 8% of adults were responders in the levetiracetam and placebo groups, respectively. Regression analysis demonstrated that much of the heterogeneity between adult trials was likely to be explained by different doses of levetiracetam tested and different years of trial publication. There was no evidence of statistical heterogeneity between trials on children. For these trials, the RR for 50% or greater reduction in focal seizure frequency was 1.91 (95% CI 1.38 to 2.63), with an RR of 0.68 (95% CI 0.56 to 0.81) for non-response. 27% of children responded. Participants were not significantly more likely to have levetiracetam withdrawn (RR 0.98; 95% CI 0.73 to 1.32 and RR 0.80; 95% CI 0.43 to 1.46 for adults and children, respectively). For adults, somnolence (RR 1.51; 99% CI 1.06 to 2.17) and infection (RR 1.76; 99% CI 1.03 to 3.02) were significantly associated with levetiracetam. Accidental injury was significantly associated with placebo (RR 0.60; 99% CI 0.39 to 0.92). No individual adverse effect was significantly associated with levetiracetam in children. Changes in behaviour were negligible in adults (1% affected; RR 1.79; 99% CI 0.59 to 5.41) but significant in children (23% affected; RR 1.90; 99% CI 1.16 to 3.11). Cognitive effect and QoL outcomes suggested that levetiracetam had a positive effect on cognition and some aspects of QoL in adults. In children, levetiracetam did not appear to alter cognitive function but there was evidence of worsening in certain aspects of child behaviour. The overall quality of evidence used was high., Authors' Conclusions: This update adds seven more trials to the original review, which contained four trials. At every dose analysed, levetiracetam significantly reduced focal seizure frequency relative to placebo. This indicates that levetiracetam can significantly reduce focal seizure frequency when it is used as an add-on treatment for both adults and children with drug-resistant focal epilepsy. As there was evidence of significant levels of statistical heterogeneity within this positive effect it is difficult to be precise about the relative magnitude of the effect. At a dose of 2000 mg, levetiracetam may be expected to be 3.9 times more effective than placebo; with 30% of adults being responders at this dose. At a dose of 60 mg/kg/day, levetiracetam may be expected to be 0.9 times more effective than placebo; with 25% of children being responders at this dose. When dose was ignored, children were better responders than adults by around 4% to 13%. The results grossly suggest that one child or adult may respond to levetiracetam for every four or five children or adults, respectively, that have received levetiracetam rather than placebo. The drug seems to be well tolerated in both adults and children although non-specific changes in behaviour may be experienced in as high as 20% of children. This aspect of the adverse-effect profile of levetiracetam was analysed crudely and requires further investigation and validation. It seems reasonable to continue the use of levetiracetam in both adults and children with drug-resistant focal epilepsy. The results cannot be used to confirm longer-term or monotherapy effects of levetiracetam or its effects on generalised seizures. The conclusions are largely unchanged from those in the original review. The most significant contribution of this update is the addition of paediatric data into the analysis.

Hommel (Biometrical Journal; 45:581-589) proposed a flexible testing procedure for seamless phase II/III clinical trials. Schmidli et al. (Statistics in Medicine; 26:4925-4938), Kimani et al. (Statistics in Medicine; 28:917-936) and Brannath et al. (Statistics in Medicine; 28:1445-1463) exploited the flexible testing of Hommel to propose adaptation in seamless phase II/III clinical trials that incorporate prior knowledge by using Bayesian methods. In this paper, we show that adaptation incorporating prior knowledge may lead to higher power. Other important issues to consider in such adaptive designs are the gain in power (or saving in patients) over traditional testing and how utility values used to make the adaptation may be used to stop a trial early. In contrast to the aforementioned authors, we discuss these issues in detail and propose a unified approach to address them so that implementing the aforementioned designs and proposing similar designs is clearer., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: Epilepsy is a common neurological condition, affecting almost 0.5 to 1% of the population. Nearly 30% of people with epilepsy are resistant to currently available drugs. Tiagabine is one of the newer antiepileptic drugs and its effects as an adjunct (add-on) to standard drugs are assessed in this review., Objectives: To evaluate the effects of add-on treatment with tiagabine upon seizures, adverse effects, cognition and quality of life for people with drug-resistant localisation related seizures., Search Methods: This is an updated version of the original Cochrane review published in issue 10, 2010. We searched the Cochrane Epilepsy Group's Specialised Register (December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL, issue 4, 2011 of The Cochrane Library), and MEDLINE (1948 to November 2011). No language restrictions were imposed. We also contacted the manufacturers of tiagabine and experts in the field to seek any ongoing or unpublished studies., Selection Criteria: Randomised placebo controlled add-on trials of people of any age with localisation related seizures, in which an adequate method of concealment of randomisation was used were included. The studies could be double, single or unblinded and be of parallel or crossover design. They had to have a minimum treatment period of eight weeks. Trials using an active drug control group were also included., Data Collection and Analysis: Two review authors independently selected trials for inclusion and extracted data. Any disagreements were resolved by discussion. Outcomes investigated included 50% or greater reduction in seizure frequency; treatment withdrawal; adverse effects; effects on cognition and quality of life. The primary analyses were by intention-to-treat. Worst case and best case analyses were also calculated for seizure outcomes. Dose response was evaluated in regression models., Main Results: Four parallel group and two crossover group trials were included. The overall relative risk (RR) with 95% confidence intervals (CIs) for a 50% or greater reduction in seizure frequency (tiagabine versus placebo) was 3.16 (95% CI 1.97 to 5.07). Due to differences in response rates among trials, regression models were unable to provide reliable estimates of responses to individual doses. The RR for treatment withdrawal was 1.81 (95% CI 1.25 to 2.62). The 99% CIs for the following adverse effects: dizziness; fatigue; nervousness and tremor did not include unity, indicating that they are significantly associated with tiagabine. For cognitive and quality of life outcomes the limited data available suggested that there were no significant effects on cognition and mood and adjustment., Authors' Conclusions: Tiagabine reduces seizure frequency but is associated with some adverse effects when used as an add-on for people with drug-resistant localisation-related seizures.

Rationale: This paper presents a Bayesian approach using WinBUGS for analysing survival data in which observations have missing information on some covariates. Modelling the joint density of the survival time and the covariates allows for the missing covariate data to be missing at random (MAR), as opposed to the more restrictive assumptions imposed by a complete case analysis., Methods: Here, the survival times are modelled by the accelerated failure time model and the joint covariate density is factorized as a series of conditional densities, each modelled by logistic regression. We propose a class of models to examine MAR assumption by using Bayesian informative priors or auxiliary data., Results: In the example considered, the complete case analysis underestimates the proportion of severely impaired cases. Furthermore, models evaluating sensitivity to the MAR assumption suggest that median life expectancies could be increased. Gains in precision are small in the application considered, possibly a reflection of extra uncertainty because of the inclusion of all cases, including those of unknown severity., Conclusions: Through simple Bayesian models, more realistic assumptions concerning the nature of the missing data can be made. Implementation in WinBUGS means that this model is accessible to practicing statisticians., (© 2010 Blackwell Publishing Ltd.)

'If anticoagulants had been administered sooner, my client would not have died' was a central claim put to us, as statistician expert witnesses, by a Claimant's and Defendant's lawyers. To assist other litigants, and without identifying the specific case, we set out the study types that contribute to the evidence base, and their limitations. We then explain why it is difficult to adduce evidence about the relative risk of dying from pulmonary embolism within 12 hours of admission to accident and emergency even when it is well accepted that anticoagulation reduces the risk of dying within the next seven days of patients at objectively confirmed risk of pulmonary embolism. No matter how much we may want an answer, or how tragic an individual outcome, we can only work from the available evidence or work to improve the evidence base, which needs to be resourced.

The Collaborative Ankle Support Trial (CAST) is a longitudinal trial of treatments for severe ankle sprains in which interest lies in the rate of improvement, the effectiveness of reminders and potentially informative missingness. A model is proposed for continuous longitudinal data with non-ignorable or informative missingness, taking into account the nature of attempts made to contact initial non-responders. The model combines a non-linear mixed model for the outcome model with logistic regression models for the reminder processes. A sensitivity analysis is used to contrast this model with the traditional selection model, where we adjust for missingness by modelling the missingness process. The conclusions that recovery is slower, and less satisfactory with age and more rapid with below knee cast than with a tubular bandage do not alter materially across all models investigated. The results also suggest that phone calls are most effective in retrieving questionnaires., (Copyright © 2011 John Wiley & Sons, Ltd.)

Health care interventions that use quality of life or health scores often provide data which are skewed and bounded. The scores are typically formed by adding up numerical responses to a number of questions. Different questions might have different weights, but the scores will be bounded, and are often scaled to the range 0-100. If improvement in health over time is measured, scores will tend to cluster near the 'healthy' or 'good' boundary as time progresses, leading to a skew distribution. Further, some patients will drop-out as time progresses, hence the scores reflect a selected population.We fit models based on the skew-normal distribution to data from a randomized controlled trial of treatments for sprained ankles, in which scores were recorded at baseline and at 1, 3 and 9 months after injury. We consider the extent to which skewness in the data can be explained by clustering at the boundary via a comparison between a censored normal and a censored skew-normal model.As this analysis is based on the complete data only, a formula for the bias of the treatment effects due to informative drop-out is given. This allows us to assess under what conditions the conclusions drawn from the complete data might be either reinforced or reversed, when the informative drop-out process is taken into account., (2010 John Wiley & Sons, Ltd.)

Purpose: Vigabatrin is an efficacious antiepileptic drug licensed as add-on therapy in refractory epilepsy and used in infantile spasms. Eight years after licensing, there emerged a strong and possibly causative association with bilateral visual field loss. We report a systematic review ascertaining the magnitude of risk of vigabatrin associated visual field loss (VAVFL) and any clinical predictors of risk., Methods: Electronic searches, including MEDLINE (1966-2009), EMBASE (1974-2009), and CINAHL (1982-2009), were conducted. Reports, published in full, of observational studies investigating the prevalence of visual field loss in patients with partial epilepsy treated with vigabatrin were included. Outcomes were the proportion with visual field loss, and the relative risk of VAVFL compared to similar nonexposed patients with epilepsy., Key Findings: Thirty-two studies were identified, which included 1,678 patients exposed to vigabatrin and 406 controls. Of the 1,678 exposed patients, 738 (44%) had visual field loss compared to just 30 (7%) among the 406 controls. The random-effects estimate for the proportion of adults with visual field loss was 52% [95% confidence interval (CI) 46-59]. The estimate for children was lower at 34% (95% CI 25-42). The relative risk for field loss in vigabatrin-exposed patients was 4.0 (95% CI 2.9-5.5). Larger mean cumulative dose of vigabatrin and increasing age were associated with a higher proportion of patients with visual field loss., Significance: Vigabatrin should be reserved for patients with epilepsy for whom there is no other alternative or for patients who have determined the benefit of ongoing treatment to outweigh the risk of VAVFL., (Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.)

We present a model for meta-regression in the presence of missing information on some of the study level covariates, obtaining inferences using Bayesian methods. In practice, when confronted with missing covariate data in a meta-regression, it is common to carry out a complete case or available case analysis. We propose to use the full observed data, modelling the joint density as a factorization of a meta-regression model and a conditional factorization of the density for the covariates. With the inclusion of several covariates, inter-relations between these covariates are modelled. Under this joint likelihood-based approach, it is shown that the lesser assumption of the covariates being Missing At Random is imposed, instead of the more usual Missing Completely At Random (MCAR) assumption. The model is easily programmable in WinBUGS, and we examine, through the analysis of two real data sets, sensitivity and robustness of results to the MCAR assumption., (Copyright (c) 2010 John Wiley & Sons, Ltd.)

Sec1/Munc18 (SM) proteins bind cognate soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes and stimulate vesicle membrane fusion. Before fusion, vesicles are docked to specific target membranes. Regulation of vesicle docking is attributed to some but not all SM proteins, suggesting specialization of this earlier function. Yeast Sec1p seems to function only after vesicles are docked and SNARE complexes are assembled. Here, we show that yeast Sec1p is required before and after SNARE complex assembly, in support of general requirements for SM proteins in both vesicle docking and fusion. Two classes of sec1 mutants were isolated. Class A mutants are tightly blocked in cell growth and secretion at a step before SNARE complex assembly. Class B mutants have a SNARE complex binding defect, with a range in severity of cell growth and secretion defects. Mapping the mutations onto an SM protein structure implicates a peripheral bundle of helices for the early, docking function and a deep groove, opposite the syntaxin-binding cleft on nSec1/Munc-18, for the interaction between Sec1p and the exocytic SNARE complex.

Objectives: We examined how customized birth-weight standards compare to population birth-weight references at term (> or =37 weeks), nearly term (34-36 weeks), moderately preterm (32-33 weeks) and for the very preterm births (28-31 weeks), with respect to perinatal mortality., Study Design: Data from the national Swedish Medical Births Register for the years 1992-2001, consisting of a total of 783,303 singletons born at or after 28 completed gestational weeks. Infants were classified as small for gestational age (SGA, <10th centile) according to a conventional population based birth-weight reference and a customized standard. Risk ratios (RR) for still birth and neonatal death were compared between standards by prematurity of the birth. Diagnostic performance measures of specificity, sensitivity and positive and negative predictive values were also evaluated., Results: More than half, 59% (209), of the 355 infants still-born between 28 and 31 weeks gestation were classified as SGA by the customized standard, but only 23% (80), were so classified as SGA by the population reference. However, only 14% (95%CI 13-16) of the 1461 very preterm infants classified as SGA by the customized standard were still-born, compared to 23% (95%CI 19-28) of the 348 infants classified as SGA by the population reference. Therefore, the relative risk of still birth for those classified as SGA by the customized standard is lower, 2.02 (95%CI: 1.65, 2.46), than for the population reference 2.64 (95%CI: 2.11, 3.30). Similar results were observed for the risk of neonatal death. For term weeks, customized standards showed stronger relationships than population references (RR: 4.30 (95%CI 3.82, 4.84) vs. 4.00 (95%CI 3.55, 4.51) for still births)., Conclusions: Customized standards categorize a higher absolute number of preterm infants who are still-born as SGA. However, infants classified as SGA by population references are at higher risk of perinatal mortality than infants classified as SGA by customized standards.

The inverse of the difference between rates, called the 'number needed to treat' (NNT), was suggested 20 years ago as a good way to present the results of comparisons of success or failure under different therapies. Such comparisons usually arise in randomised controlled trials and meta-analysis. This article reviews the claims made about this statistic, and the problems associated with it. Methods that have been proposed for confidence intervals are evaluated, and shown to be erroneous. We suggest that giving the baseline risk, and the difference in success or event rates, the 'absolute risk reduction', is preferable to the number needed to treat, for both theoretical and practical reasons.

Seamless phase II/III clinical trials are attractive in development of new drugs because they accelerate the drug development process. Seamless phase II/III trials are carried out in two stages. After stage 1 (phase II stage), an interim analysis is performed and a decision is made on whether to proceed to stage 2 (phase III stage). If the decision is to continue with further testing, some dose-selection procedure is used to determine the set of doses to be tested in stage 2. In this paper, we propose a dose-selection procedure for binary outcomes in adaptive seamless phase II/III clinical trials that incorporates the dose-response relationship when the experimental treatments are different dose levels of the same drug, and explicitly incorporates both efficacy and safety. The choice of the doses to continue to stage 2 is made by comparing the predictive power of the potential sets of doses, which might continue.

Objective: To estimate the clinical effectiveness and cost-effectiveness of three methods of ankle support compared with double layer tubular compression bandage., Design: A randomised controlled trial, designed to reflect practice in UK hospital emergency departments., Setting: Eight emergency departments in England., Participants: Aged 16 or over with acute severe ankle sprain, unable to weight bear, no fracture., Interventions: 584 participants were randomised to one of four treatment arms: tubular bandage, below knee cast, Aircast ankle brace or Bledsoe boot, all applied 2-3 days after presentation to allow swelling to resolve., Main Outcome Measures: Response to treatment was assessed using the Foot and Ankle Outcome Score and generic measures (Functional Limitations Profile, SF-12 and EQ-5D)., Results: When adjusted for age, sex and baseline scores, the below knee cast offered a small but statistically significant benefit at 4 weeks in terms of pain (FAOS pain difference 5.1; 95% CI 0.4-9.8), foot- and ankle-related quality of life (QoL) (FAOS QoL difference 5.9; 95% CI 0.1-11.8) and the physical component of the SF-12 (SF-12 score difference 2.2; 95% CI 0.0-4.4). Neither the Aircast brace nor the Bledsoe boot was statistically or clinically better. At 12 weeks the below knee cast was significantly better than tubular bandage in terms of pain (FAOS pain difference 5.1; 95% CI 0.3-10.0), activities of daily living (FAOS ADL difference 3.5; 95% CI 0.4-6.6), sports (FAOS sports difference 8.7; 95% CI 1.6-15.7) and QoL (FAOS QoL difference 8.7; 95% CI 2.4-15.0), and the Aircast brace was better only in terms of ankle-related QoL and mental health. The Bledsoe boot conferred no significant advantage over tubular bandage. By 9 months there were no significant differences. Based on mean direct health-care costs per participant, the Bledsoe boot was the most expensive (215 pounds) and tubular bandage the least so (1 pound 44 pence). Inclusion of indirect costs (sick leave) raised overall costs substantially and removed any significant differences between the therapies. Cost-utility analysis demonstrated that the Aircast brace [301 pounds per quality-adjusted life-year (QALY)] and below knee cast (339 pounds per QALY) were more cost-effective than the Bledsoe boot (2116 pounds per QALY). However, inclusion of indirect costs produced different rank orders, depending on the assumptions made, and results should be treated with caution., Conclusions: The below knee cast and the Aircast brace offered cost-effective alternatives to tubular bandage for acute severe ankle sprain, the former having the advantage in terms of overall recovery at 3 months. As there were no differences in long-term outcome, practitioners should consider likely compliance and acceptability to patients when choosing a brace.

Background: Improved quality of care is a policy objective of health care systems around the world. Implementation research is the scientific study of methods to promote the systematic uptake of clinical research findings into routine clinical practice, and hence to reduce inappropriate care. It includes the study of influences on healthcare professionals' behaviour and methods to enable them to use research findings more effectively. Cluster randomized trials represent the optimal design for evaluating the effectiveness of implementation strategies. Various codes of medical ethics, such as the Nuremberg Code and the Declaration of Helsinki inform medical research, but their relevance to cluster randomised trials in implementation research is unclear. This paper discusses the applicability of various ethical codes to obtaining consent in cluster trials in implementation research., Discussion: The appropriate application of biomedical codes to implementation research is not obvious. Discussion of the nature and practice of informed consent in implementation research cluster trials must consider the levels at which consent can be sought, and for what purpose it can be sought. The level at which an intervention is delivered can render the idea of patient level consent meaningless. Careful consideration of the ownership of information, and rights of access to and exploitation of data is required. For health care professionals and organizations, there is a balance between clinical freedom and responsibility to participate in research., Summary: While ethical justification for clinical trials relies heavily on individual consent, for implementation research aspects of distributive justice, economics, and political philosophy underlie the debate. Societies may need to trade off decisions on the choice between individualized consent and valid implementation research. We suggest that social sciences codes could usefully inform the consideration of implementation research by members of Research Ethics Committees.

Purpose: Open-label extension studies, or follow-on randomised controlled trials (FORCTs) are widely believed to be prone to patient selection biases which may inflate effect estimates. This study investigates the reporting and analysis of efficacy outcomes in FORCTs and critically evaluates the associated underlying assumptions. We propose an alternative method of analysis, in line with that recommended in the analysis of RCTs, the intention to treat (ITT) approach, in which it is assumed that all patients who discontinue treatment are non-responders., Methods: A systematic review of FORCTs and randomised controlled trials (RCT) of topiramate, levetiracetam and gabapentin as adjuvant therapy in refractory adult epilepsy was conducted. Sample sizes and numbers of responders, along with reported outcomes were extracted. To evaluate the feasibility of the assumptions underlying the various methods of analysis, the most common causes of discontinuation were evaluated. For each FORCT, we compared the reported outcome to the proposed ITT analysis., Results: The 10 FORCT reports identified all excluded from the analysis patients who dropped out of the RCT. Adverse events or inefficacy were the main reasons for treatment discontinuation. Analysis based on the ITT method, led to smaller effect estimates than those reported. For example, a FORCT of levetiracetam reported a responder rate of 43%, which reduced to 28% under an ITT analysis, comparable to an ITT analysis outcome of 26% for the parent RCT., Conclusions: FORCTs can provide important information about long-term efficacy and tolerability of newer therapies. However, current reporting methods are likely to be misleading as outcomes are reported for the subset of patients continuing with treatment at the end of the FORCT. Since the majority of patients who discontinue treatment do so for reasons associated with inefficacy, an analysis based on the ITT approach more closely reflects the outcomes of the patients.

Purpose: Observational studies may provide important information on the long-term effects of treatments for epilepsy, but systematic reviews of observational studies may be more prone to heterogeneity and biases. These issues were investigated in a systematic review of non-randomised add-on anti-epileptic drug studies., Methods: Searches of MEDLINE (1966-2006), EMBASE (1974-2006), CINAHL (1982-2006), the Cochrane database of systematic reviews, the Cochrane Controlled Trials register, the DARE database and hand-searching congress proceedings were conducted. Randomised controlled trials, follow-on randomised controlled trials and prospective and retrospective cohort studies of gabapentin, topiramate, or levetiracetam as add-on therapy in adults (>12 years old) were identified. Outcomes were 50% responders and proportion seizure free., Results: Thirty-eight non-randomised gabapentin studies, 82 topiramate and 84 levetiracetam studies were identified. There was marked heterogeneity of effect estimates from observational studies which prohibited the pooling of estimates in random effects models. Median effect estimates were larger and more varied for observational studies than randomised placebo-controlled trials (RCTs). For example, the median value (10th and 90th percentile) for 50% responders for gabapentin was 36% (15 and 71%) compared to 23% (19 and 38%) for gabapentin RCTs. Patient and study covariates in meta-regression models could not explain the vast heterogeneity. Publication bias was evident and a sensitivity analysis, allowing for the effects of publication bias, showed that effect estimates could increase by up to 6% for seizure freedom rates., Discussion: Reports of observational anti-epileptic studies give limited information on patient selection and characteristics. Systematic reviews of observational studies are prone to significant heterogeneity and bias which cannot adequately be explained by reported study characteristics. Reporting standards for observational studies of anti-epileptic drugs could be improved by following guidelines for reporting non-randomised studies of interventions.