Seizure first aid training for people with epilepsy attending emergency departments and their significant others: the SAFE intervention and feasibility RCT

Background No seizure first aid training intervention exists for people with epilepsy who regularly attend emergency departments and their significant others, despite such an intervention’s potential to reduce clinically unnecessary and costly visits. Objectives The objectives were to (1) develop Seizure first Aid training For Epilepsy (SAFE) by adapting a broader intervention and (2) determine the feasibility and optimal design of a definitive randomised controlled trial to test SAFE’s efficacy. Design The study involved (1) the development of an intervention informed by a co-design approach with qualitative feedback and (2) a pilot randomised controlled trial with follow-ups at 3, 6 and 12 months and assessments of treatment fidelity and the cost of SAFE’s delivery. Setting The setting was (1) third-sector patient support groups and professional health-care organisations and (2) three NHS emergency departments in England. Participants Participants were (1) people with epilepsy who had visited emergency departments in the prior 2 years, their significant others and emergency department, paramedic, general practice, commissioning, neurology and nursing representatives and (2) people with epilepsy aged ≥ 16 years who had been diagnosed for ≥ 1 year and who had made two or more emergency department visits in the prior 12 months, and one of their significant others. Emergency departments identified ostensibly eligible people with epilepsy from attendance records and patients confirmed their eligibility. Interventions Participants in the pilot randomised controlled trial were randomly allocated 1 : 1 to SAFE plus treatment as usual or to treatment as usual only. Main outcome measures Consent rate and availability of routine data on emergency department use at 12 months were the main outcome measures. Other measures of interest included eligibility rate, ease with which people with epilepsy could be identified and routine data secured, availability of self-reported emergency department data, self-reported emergency department data’s comparability with routine data, SAFE’s effect on emergency department use, and emergency department use in the treatment as usual arm, which could be used in sample size calculations. Results (1) Nine health-care professionals and 23 service users provided feedback that generated an intervention considered to be NHS feasible and well positioned to achieve its purpose. (2) The consent rate was 12.5%, with 53 people with epilepsy and 38 significant others recruited. The eligibility rate was 10.6%. Identifying people with epilepsy from attendance records was resource intensive for emergency department staff. Those recruited felt more stigmatised because of epilepsy than the wider epilepsy population. Routine data on emergency department use at 12 months were secured for 94.1% of people with epilepsy, but the application process took 8.5 months. Self-reported emergency department data were available for 66.7% of people with epilepsy, and people with epilepsy self-reported more emergency department visits than were captured in routine data. Most participants (76.9%) randomised to SAFE received the intervention. The intervention was delivered with high fidelity. No related serious adverse events occurred. Emergency department use at 12 months was lower in the SAFE plus treatment as usual arm than in the treatment as usual only arm, but not significantly so. Calculations indicated that a definitive trial would need ≈ 674 people with epilepsy and ≈ 39 emergency department sites. Limitations Contrary to patient statements on recruitment, routine data secured at the pilot trial’s end indicated that ≈ 40% may not have satisfied the inclusion criterion of two or more emergency department visits. Conclusions An intervention was successfully developed, a pilot randomised controlled trial conducted and outcome data secured for most participants. The consent rate did not satisfy a predetermined ‘stop/go’ level of ≥ 20%. The time that emergency department staff needed to identify eligible people with epilepsy is unlikely to be replicable. A definitive trial is currently not feasible. Future work Research to more easily identify and recruit people from the target population is required. Trial registration Current Controlled Trials ISRCTN13871327. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 39. See the NIHR Journals Library website for further project information

Alpha-defensin and the Synovasure lateral flow device for the diagnosis of prosthetic joint infection: a systematic review and meta-analysis

AimsThe aim of this review is to evaluate the available literature and to calculate a pooled diagnostic sensitivity and specificity for the different alpha-defensin test systems to diagnose peri-prosthetic infection.Materials and MethodsStudies using alpha-defensin or Synovasure to diagnose periprosthetic joint infection were identified from systematic searches of electronic databases. Study quality was evaluated using the QUADAS tool. Meta-analysis was completed using a bivariate model.ResultsEleven eligible studies were included. Median QUADAS score was 13 [I.Q.R. 13-13] out of 14. Significant conflicts of interest were identified in five studies. Pooled sensitivity for the laboratory alpha-defensin test was 0.95 (95% CI 0.91-0.98) and specificity 0.97 (95% CI 0.95-0.98) for four studies with a threshold level of 5.2mgl-a. Pooled sensitivity for the lateral flow cassette test was 0.85 (95% CI 0.74-0.92) and specificity was 0.90 (95% CI 0.91-0.98). There was a statistically significant difference in sensitivity but not specificity.ConclusionLaboratory based alpha-defensin testing remains a promising tool for diagnosing periprosthetic joint infection. The lateral flow cassette has a significantly lower performance and pooled results are comparable to the leucocyte esterase test. Further studies are essential before the widespread adoption of the lateral flow cassette alpha-defensin test. Take home messageAlpha defensin testing for periprosthetic joint infection has excellent sensitivity and specificity when performed in a laboratory. The pooled sensitivity and specificity is much lower when results are combined for the lateral flow cassette (Synovasure devise

Seizure first aid training for people with Epilepsy (SAFE) frequently attending emergency departments and their significant others : results of a UK multi-centre randomised controlled pilot trial

Objective To determine the feasibility and optimal design of a randomised controlled trial (RCT) of Seizure First Aid Training For Epilepsy (SAFE). Design Pilot RCT with embedded microcosting. Setting Three English hospital emergency departments (EDs). Participants Patients aged ≥16 with established epilepsy reporting ≥2 ED visits in the prior 12 months and their significant others (SOs). Interventions Patients (and their SOs) were randomly allocated (1:1) to SAFE plus treatment-as-usual (TAU) or TAU alone. SAFE is a 4-hour group course. Main outcome measures Two criteria evaluated a definitive RCT’s feasibility: (1) ≥20% of eligible patients needed to be consented into the pilot trial; (2) routine data on use of ED over the 12 months postrandomisation needed securing for ≥75%. Other measures included eligibility, ease of obtaining routine data, availability of self-report ED data and comparability, SAFE’s effect and intervention cost. Results Of ED attendees with a suspected seizure, 424 (10.6%) patients were eligible; 53 (12.5%) patients and 38 SOs consented. Fifty-one patients (and 37 SOs) were randomised. Routine data on ED use at 12 months were secured for 94.1% patients. Self-report ED data were available for 66.7% patients. Patients reported more visits compared with routine data. Most (76.9%) patients randomised to SAFE received it and no related serious adverse events occurred. ED use at 12 months was lower in the SAFE+TAU arm compared with TAU alone, but not significantly (rate ratio=0.62, 95% CI 0.33 to 1.17). A definitive trial would need ~674 patient participants and ~39 recruitment sites. Obtaining routine data was challenging, taking ~8.5 months. Conclusions In satisfying only one predetermined ‘stop/go’ criterion, a definitive RCT is not feasible. The low consent rate in the pilot trial raises concerns about a definitive trial’s finding’s external validity and means it would be expensive to conduct. Research is required into how to optimise recruitment from the target population

Equity, diversity and inclusion (EDI) in organ transplantation: an ESOT survey about EDI within ESOT as an organization and its educational activities, and transplantation research and science

The European Society of Organ Transplantation (ESOT) strives to promote equity, diversity, and inclusion (EDI) across all its activities. We surveyed the transplant community’s experiences and perspectives regarding EDI within ESOT as an organization and its educational activities, and research in general. A total of 299 respondents completed the questionnaire. About half agreed that ESOT’s Executive Committee, Council, and Sections/Committees are diverse and inclusive (51%) and that ESOT promotes EDI in its live and digital educational activities (54%). Forty percent of respondents agreed that scientific and clinical trials in the field of transplantation are diverse and inclusive. Despite the wide distribution of the survey, most of the respondents self-identified as White and were either physician or surgeon. However, the results contribute a unique insight into the experiences and perspectives of the transplantation community regarding EDI. Whilst ESOT is committed to the principles of EDI, perceptions and the high number of proposals show the apparent need to prioritize efforts to embed EDI across ESOT and transplantation science. These data should constitute a starting point for change and provide guidance for future efforts to promote EDI within the transplantation community

Measurements of CFTR-Mediated Cl- Secretion in Human Rectal Biopsies Constitute a Robust Biomarker for Cystic Fibrosis Diagnosis and Prognosis

BACKGROUND: Cystic Fibrosis (CF) is caused by ∼1,900 mutations in the CF transmembrane conductance regulator (CFTR) gene encoding for a cAMP-regulated chloride (Cl(-)) channel expressed in several epithelia. Clinical features are dominated by respiratory symptoms, but there is variable organ involvement thus causing diagnostic dilemmas, especially for non-classic cases. METHODOLOGY/PRINCIPAL FINDINGS: To further establish measurement of CFTR function as a sensitive and robust biomarker for diagnosis and prognosis of CF, we herein assessed cholinergic and cAMP-CFTR-mediated Cl(-) secretion in 524 freshly excised rectal biopsies from 118 individuals, including patients with confirmed CF clinical diagnosis (n=51), individuals with clinical CF suspicion (n=49) and age-matched non-CF controls (n=18). Conclusive measurements were obtained for 96% of cases. Patients with "Classic CF", presenting earlier onset of symptoms, pancreatic insufficiency, severe lung disease and low Shwachman-Kulczycki scores were found to lack CFTR-mediated Cl(-) secretion (<5%). Individuals with milder CF disease presented residual CFTR-mediated Cl(-) secretion (10-57%) and non-CF controls show CFTR-mediated Cl(-) secretion ≥ 30-35% and data evidenced good correlations with various clinical parameters. Finally, comparison of these values with those in "CF suspicion" individuals allowed to confirm CF in 16/49 individuals (33%) and exclude it in 28/49 (57%). Statistical discriminant analyses showed that colonic measurements of CFTR-mediated Cl(-) secretion are the best discriminator among Classic/Non-Classic CF and non-CF groups. CONCLUSIONS/SIGNIFICANCE: Determination of CFTR-mediated Cl(-) secretion in rectal biopsies is demonstrated here to be a sensitive, reproducible and robust predictive biomarker for the diagnosis and prognosis of CF. The method also has very high potential for (pre-)clinical trials of CFTR-modulator therapies.This work was supported by grants TargetScreen2 (EU/FP6/LSH/2005/037365), PIC/IC/83103/2007; PTDC/MAT/118335/2010; PEstOE/BIA/UI4046/2011 (to BioFIG) and PEstOE/MAT/UI0006/2011 (to CEAUL) from FCT (Portugal); and FAPESP (SPRF, Brazil), CNPq (40.8924/2006/3, Brazil) and Mukoviszidose e.V. S02/10 (Germany). MS and IU are recipients of SFRH/BD/35936/2007 and SFRH/BD/69180/2010 PhD fellowships (FCT, Portugal), respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Out to sea: ocean currents and patterns of asymmetric gene flow in an intertidal fish species

Passive dispersal via wind or ocean currents can drive asymmetric gene flow, which influences patterns of genetic variation and the capacity of populations to evolve in response to environmental change. The mangrove rivulus fish (Kryptolebias marmoratus), hereafter “rivulus,” is an intertidal fish species restricted to the highly fragmented New World mangrove forests of Central America, the Caribbean, the Bahamas, and Florida. Mangrove patches are biological islands with dramatic differences in both abiotic and biotic conditions compared to adjacent habitat. Over 1,000 individual rivulus across 17 populations throughout its range were genotyped at 32 highly polymorphic microsatellites. Range-wide population genetic structure was evaluated with five complementary approaches that found eight distinct population clusters. However, an analysis of molecular variance indicated significant population genetic structure among regions, populations within regions, sampling locations within populations, and individuals within sampling locations, indicating that rivulus has both broad- and fine-scale genetic differentiation. Integrating range-wide genetic data with biophysical modeling based on 10 years of ocean current data showed that ocean currents and the distance between populations over water drive gene flow patterns on broad scales. Directional migration estimates suggested some significant asymmetries in gene flow that also were mediated by ocean currents and distance. Specifically, populations in the center of the range (Florida Keys) were identified as sinks that received migrants (and alleles) from other populations but failed to export individuals. These populations thus harbor genetic variation, perhaps even from extirpated populations across the range, but ocean currents and complex arrangements of landmasses might prevent the distribution of that genetic variation elsewhere. Hence, the inherent asymmetry of ocean currents shown to impact both genetic differentiation and directional migration rates may be responsible for the complex distribution of genetic variation across the range and observed patterns of metapopulation structure

Importance of competing risks in the analysis of anti-epileptic drug failure

BACKGROUND: Retention time (time to treatment failure) is a commonly used outcome in antiepileptic drug (AED) studies. METHODS: Two datasets are used to demonstrate the issues in a competing risks analysis of AEDs. First, data collection and follow-up considerations are discussed with reference to information from 15 monotherapy trials. Recommendations for improved data collection and cumulative incidence analysis are then illustrated using the SANAD trial dataset. The results are compared to the more common approach using standard survival analysis methods. RESULTS: A non-significant difference in overall treatment failure time between gabapentin and topiramate (logrank test statistic = 0.01, 1 degree of freedom, p-value = 0.91) masked highly significant differences in opposite directions with gabapentin resulting in fewer withdrawals due to side effects (Gray's test statistic = 11.60, 1 degree of freedom, p = 0.0007) but more due to poor seizure control (Gray's test statistic = 14.47, 1 degree of freedom, p-value = 0.0001). The significant difference in overall treatment failure time between lamotrigine and carbamazepine (logrank test statistic = 5.6, 1 degree of freedom, p-value = 0.018) was due entirely to a significant benefit of lamotrigine in terms of side effects (Gray's test statistic = 10.27, 1 degree of freedom, p = 0.001). CONCLUSION: Treatment failure time can be measured reliably but care is needed to collect sufficient information on reasons for drug withdrawal to allow a competing risks analysis. Important differences between the profiles of AEDs may be missed unless appropriate statistical methods are used to fully investigate treatment failure time. Cumulative incidence analysis allows comparison of the probability of failure between two AEDs and is likely to be a more powerful approach than logrank analysis for most comparisons of standard and new anti-epileptic drugs

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one&nbsp;kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells