Registration evaluation of dynamic breast MR images

The interpretation of dynamic contrast-enhanced breast MR images is predicated on the assumption of minimal voxel movement during the time course of the image acquisition. Misalignment of the dynamic image sequence as a result of movement during image acquisition can lead to potentially misleading diagnostic conclusions. In this paper a new methodology is presented for assessing the degree of in-plane (intra-slice) movement in a dynamic image sequence. The method is demonstrated on data from six subjects. The conclusion is that the method makes it possible to quantitatively qualify the accuracy of computed enhancement curves and more importantly to identify unacceptably poor registration

Enhancing practitioners’ confidence in recruitment and consent in the EcLiPSE trial: A mixed-method evaluation of site training – a Paediatric Emergency Research in the United Kingdom and Ireland (PERUKI) study

Background: EcLiPSE (Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children) is a randomised controlled trial (RCT) in the United Kingdom. Challenges to success include the need to immediately administer an intervention without informed consent and changes in staffing during trial conduct, mainly due to physician rotations. Using literature on parents' perspectives and research without prior consent (RWPC) guidance, we developed an interactive training package (including videos, simulation and question and answer sessions) and evaluated its dissemination and impact upon on practitioners' confidence in recruitment and consent. Methods: Questionnaires were administered before and immediately after training followed by telephone interviews (mean 11 months later), focus groups (mean 14 months later) and an online questionnaire (8 months before trial closure).Results: One hundred and twenty-five practitioners from 26/30 (87%) participating hospitals completed a questionnaire before and after training. We conducted 10 interviews and six focus groups (comprising 36 practitioners); 199 practitioners working in all recruiting hospitals completed the online questionnaire. Before training, practitioners were concerned about recruitment and consent. Confidence increased after training for explaining (all scale 0-5, 95% CIs above 0 and p values < 0.05): the study (66% improved mean score before 3.28 and after 4.52), randomisation (47% improvement, 3.86 to 4.63), RWPC (72% improvement, 2.98 to 4.39), and addressing parents' objections to randomisation (51% improvement, 3.37 to 4.25). Practitioners rated highly the content and clarity of the training, which was successfully disseminated. Some concerns about staff availability for training and consent discussions remained.Conclusions: Training improved practitioners' confidence in recruitment and RWPC. Our findings highlight the value of using parents' perspectives to inform training and to engage practitioners in trials that are at high risk of being too challenging to conduct

Seizures and Encephalitis in Myelin Oligodendrocyte Glycoprotein IgG Disease vs Aquaporin 4 IgG Disease

Importance: Antibodies to myelin oligodendrocyte glycoprotein IgG (MOG-IgG) are increasingly detected in patients with non–multiple sclerosis–related demyelination, some of whom manifest a neuromyelitis optica (NMO) phenotype. Cortical involvement, encephalopathy, and seizures are rare in aquaporin 4 antibody (AQP4-IgG)–related NMO in the white European population. However, the authors encountered several patients with seizures associated with MOG-IgG disease. Objective: To compare incidence of seizures and encephalitis-like presentation, or both between AQP4-IgG–positive and MOG-IgG–positive patients. Design, Setting, and Participants: Retrospective case series of all patients who were seropositive for MOG-IgG (n = 34) and the last 100 patients with AQP4-IgG disease (NMO spectrum disorder) seen in the NMO service between January 2013 and December 2016, and analysis was completed January 4, 2017. All patients were seen in a tertiary neurological center, The Walton Centre NHS Foundation Trust in Liverpool, England. Main Outcomes and Measures: The difference in seizure frequency between the AQP4-IgG–positive and MOG-IgG–positive patient groups was determined. Results: Thirty-four patients with MOG-IgG disease (20 female) with a median age at analysis of 30.5 years (interquartile range [IQR], 15-69 years), and 100 AQP4-IgG–positive patients (86 female) with a median age at analysis of 54 years (IQR, 12-91 years) were studied. Most patients were of white race. Five of the 34 patients with MOG-IgG (14.7%) had seizures compared with 1 patient with AQP4-IgG (2-sided P < .008, Fisher test). On magnetic resonance imaging, all 5 MOG-IgG–positive patients had inflammatory cortical brain lesions associated with the seizures. In 3 of the 5 MOG-IgG–positive patients, seizures occurred as part of the index event. Four of the 5 presented with encephalopathy and seizures, and disease relapsed in all 5 patients. Four of these patients were receiving immunosuppressant medication at last follow-up, and 3 continued to take antiepileptic medication. In contrast, the only AQP4-IgG–positive patient with seizures had a diagnosis of complex partial epilepsy preceding the onset of NMO by several years and experienced no encephalitic illness; her magnetic resonance imaging results demonstrated no cortical, subcortical, or basal ganglia involvement. Conclusions and Relevance: Patients with MOG-IgG–associated disease were more likely to have seizures and encephalitis-like presentation than patients with AQP4-IgG–associated disease

Seven-step framework to enhance practitioner explanations and parental understandings of research without prior consent in paediatric emergency and critical care trials

Background: Alternatives to prospective informed consent enable the conduct of paediatric emergency and critical care trials. Research without prior consent (RWPC) involves practitioners approaching parents after an intervention has been given and seeking consent for their child to continue in the trial. As part of an embedded study in the 'Emergency treatment with Levetiracetam or Phenytoin in Status Epilepticus in children' (EcLiPSE) trial, we explored how practitioners described the trial and RWPC during recruitment discussions, and how well this information was understood by parents. We aimed to develop a framework to assist trial conversations in future paediatric emergency and critical care trials using RWPC. Methods: Qualitative methods embedded within the EcLiPSE trial processes, including audiorecorded practitioner-parent trial discussions and telephone interviews with parents. We analysed data using thematic analysis, drawing on the Realpe et al (2016) model for recruitment to trials. Results: We analysed 76 recorded trial discussions and conducted 30 parent telephone interviews. For 19 parents, we had recorded trial discussion and interview data, which were matched for analysis. Parental understanding of the EcLiPSE trial was enhanced when practitioners: provided a comprehensive description of trial aims; explained the reasons for RWPC; discussed uncertainty about which intervention was best; provided a balanced description of trial intervention; provided a clear explanation about randomisation and provided an opportunity for questions. We present a seven-step framework to assist recruitment practice in trials involving RWPC. Conclusion: This study provides a framework to enhance recruitment practice and parental understanding in paediatric emergency and critical care trials involving RWPC. Further testing of this framework is required

Predictors of Aged Residential Care Placement in Patients Newly Diagnosed with Dementia at a New Zealand Memory Service

Background: Aged residential care (ARC) is a significant cost of dementia care. However, little is known about the predictors of ARC placement in New Zealand (NZ), which is important for service planning and funding. The aim of this study was to investigate the sociodemographic and clinical characteristics that predict future ARC placement among people who received a new diagnosis of dementia at a NZ memory service. Methods: Routinely collected baseline sociodemographic and clinical data in a memory service from 14/06/13 and 14/12/19 were linked with administrative LTC admission data up to 24/1/2020. Survival analysis was carried out using multivariate Cox regression models to determine significant risk factors and their association with ARC placement. Results: A total of 657 NZ European, Māori and Pacific Islander patients were included in the analyses. There were significant differences by ethnicity including age, living situation, comorbidity and ARC placement. Adjusted analyses showed that risk of ARC placement was increased by older age (HR 1.02 per year, 95%CI:1.00–1.05), moderate dementia (HR 1.45, 95%CI:1.05–1.99), severe dementia (HR 2.25, 95%CI:1.33–3.81), and antipsychotics (HR 1.55, 95%CI:1.04–2.32); while risk was reduced in Māori (HR 0.35, 95%CI:0.18–0.68) and Pacific Islanders (HR 0.32, 95%CI:0.20–0.51). Conclusions: Despite having more severe dementia and higher comorbidity, Māori and Pacific Islanders had reduced risks of ARC placement. There is an urgent need to better understand dementia care issues and to ensure culturally safe and responsive dementia services are accessible by Māori and Pacific Islanders living in the community

Association of human cytomegalovirus proteins IRS1 and TRS1 with the viral DNA polymerase accessory subunit UL44

Multiple proteins interacting with DNA polymerases orchestrate DNA replication. Human cytomegalovirus (HCMV) encodes a DNA polymerase that includes the presumptive processivity factor UL44. UL44 is structurally homologous to the eukaryotic DNA polymerase processivity factor proliferating cell nuclear antigen (PCNA), which interacts with numerous proteins. Previous proteomic analysis has identified the HCMV protein IRS1 as a candidate protein interacting with UL44. Nuclease-resistant reciprocal co-immunoprecipitation of UL44 with IRS1 and with TRS1, which has an amino terminus identical to that of IRS1, was observed from lysate of cells infected with viruses expressing epitope-tagged UL44, epitope-tagged IRS1 or epitope-tagged TRS1. Western blotting of protein immunoprecipitated from infected cell lysate indicated that epitope-tagged IRS1 and TRS1 do not associate simultaneously with UL44. Glutathione S-transferase pull-down experiments indicated that IRS1 and TRS1 interact with UL44 via a region that is identical in both proteins. Taken together, these data suggest that IRS1 and TRS1 may compete for association with UL44 and may affect UL44 function differentially

Emergency treatment with levetiracetam or phenytoin in status epilepticus in children-the EcLiPSE study: Study protocol for a randomised controlled trial

© The Author(s). 2017. Background: Convulsive status epilepticus (CSE) is the most common life-threatening neurological emergency in childhood. These children are also at risk of significant morbidity, with acute and chronic impact on the family and the health and social care systems. The current recommended first-choice, second-line treatment in children aged 6 months and above is intravenous phenytoin (fosphenytoin in the USA), although there is a lack of evidence for its use and it is associated with significant side effects. Emerging evidence suggests that intravenous levetiracetam may be effective as a second-line agent for CSE, and fewer adverse effects have been described. This trial therefore aims to determine whether intravenous phenytoin or levetiracetam is more effective, and safer, in treating childhood CSE. Methods/design: This is a phase IV, multi-centre, parallel group, randomised controlled, open-label trial. Following treatment for CSE with first-line treatment, children with ongoing seizures are randomised to receive either phenytoin (20 mg/kg, maximum 2 g) or levetiracetam (40 mg/kg, maximum 2.5 g) intravenously. The primary outcome measure is the cessation of all visible signs of CSE as determined by the treating clinician. Secondary outcome measures include the need for further anti-seizure medications or rapid sequence induction for ongoing CSE, admission to critical care areas, and serious adverse reactions. Patients are recruited without prior consent, with deferred consent sought at an appropriate time for the family. The primary analysis will be by intention-to-treat. The primary outcome is a time to event outcome and a sample size of 140 participants in each group will have 80% power to detect an increase in CSE cessation rates from 60% to 75%. Our total sample size of 308 randomised and treated participants will allow for 10% loss to follow-up. Discussion: This clinical trial will determine whether phenytoin or levetiracetam is more effective as an intravenous second-line agent for CSE, and provide evidence for management recommendations. In addition, this trial will also provide data on which of these therapies is safer in this setting

Levetiracetam as an alternative to phenytoin for second-line emergency treatment of children with convulsive status epilepticus: the EcLiPSE RCT.

BACKGROUND:Convulsive status epilepticus is the most common neurological emergency in children. Its management is important to avoid or minimise neurological morbidity and death. The current first-choice second-line drug is phenytoin (Epanutin, Pfizer Inc., New York, NY, USA), for which there is no robust scientific evidence. OBJECTIVE:To determine whether phenytoin or levetiracetam (Keppra, UCB Pharma, Brussels, Belgium) is the more clinically effective intravenous second-line treatment of paediatric convulsive status epilepticus and to help better inform its management. DESIGN:A multicentre parallel-group randomised open-label superiority trial with a nested mixed-method study to assess recruitment and research without prior consent. SETTING:Participants were recruited from 30 paediatric emergency departments in the UK. PARTICIPANTS:Participants aged 6 months to 17 years 11 months, who were presenting with convulsive status epilepticus and were failing to respond to first-line treatment. INTERVENTIONS:Intravenous levetiracetam (40 mg/kg) or intravenous phenytoin (20 mg/kg). MAIN OUTCOME MEASURES:Primary outcome - time from randomisation to cessation of all visible signs of convulsive status epilepticus. Secondary outcomes - further anticonvulsants to manage the convulsive status epilepticus after the initial agent, the need for rapid sequence induction owing to ongoing convulsive status epilepticus, admission to critical care and serious adverse reactions. RESULTS:Between 17 July 2015 and 7 April 2018, 286 participants were randomised, treated and consented. A total of 152 participants were allocated to receive levetiracetam and 134 participants to receive phenytoin. Convulsive status epilepticus was terminated in 106 (70%) participants who were allocated to levetiracetam and 86 (64%) participants who were allocated to phenytoin. Median time from randomisation to convulsive status epilepticus cessation was 35 (interquartile range 20-not assessable) minutes in the levetiracetam group and 45 (interquartile range 24-not assessable) minutes in the phenytoin group (hazard ratio 1.20, 95% confidence interval 0.91 to 1.60; p = 0.2). Results were robust to prespecified sensitivity analyses, including time from treatment commencement to convulsive status epilepticus termination and competing risks. One phenytoin-treated participant experienced serious adverse reactions. LIMITATIONS:First, this was an open-label trial. A blinded design was considered too complex, in part because of the markedly different infusion rates of the two drugs. Second, there was subjectivity in the assessment of 'cessation of all signs of continuous, rhythmic clonic activity' as the primary outcome, rather than fixed time points to assess convulsive status epilepticus termination. However, site training included simulated demonstration of seizure cessation. Third, the time point of randomisation resulted in convulsive status epilepticus termination prior to administration of trial treatment in some cases. This affected both treatment arms equally and had been prespecified at the design stage. Last, safety measures were a secondary outcome, but the trial was not powered to demonstrate difference in serious adverse reactions between treatment groups. CONCLUSIONS:Levetiracetam was not statistically superior to phenytoin in convulsive status epilepticus termination rate, time taken to terminate convulsive status epilepticus or frequency of serious adverse reactions. The results suggest that it may be an alternative to phenytoin in the second-line management of paediatric convulsive status epilepticus. Simple trial design, bespoke site training and effective leadership were found to facilitate practitioner commitment to the trial and its success. We provide a framework to optimise recruitment discussions in paediatric emergency medicine trials. FUTURE WORK:Future work should include a meta-analysis of published studies and the possible sequential use of levetiracetam and phenytoin or sodium valproate in the second-line treatment of paediatric convulsive status epilepticus. TRIAL REGISTRATION:Current Controlled Trials ISRCTN22567894 and European Clinical Trials Database EudraCT number 2014-002188-13. FUNDING:This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 58. See the NIHR Journals Library website for further project information

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial

Background Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus.Methods This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.Findings Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Interpretation Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus