Improved ictal assessment performance in the epilepsy monitoring unit via standardization.

OBJECTIVE: To determine whether the standardization and implementation of an ictal testing protocol in the Epilepsy Monitoring Unit (EMU) leads to improvements in ictal testing performance. METHODS: Ictal assessments completed in the EMU from a single center were retrospectively reviewed over a two-month period. Each assessment was evaluated to determine whether 8 high-yield aspects of the ictal assessment were performed. Following observation of performance, a standardized ictal testing protocol was developed based on a root cause analysis and review of consensus guidelines. This protocol was disseminated to staff in conjunction with an annual epilepsy education seminar. Ictal assessment performance was re-assessed during the subsequent two months (short-term follow-up) and again during a five- to seven-month period (long-term follow-up) beyond the initial intervention. For sub-group analysis, event characteristics (event type, time of assessment) and patient characteristics (age, gender) were also evaluated and analyzed in relation to ictal testing performance. RESULTS: All eight individual ictal testing elements were more likely to be assessed in short-term and long-term follow-up periods when compared to pre-intervention assessments. The cumulative difference in ictal testing was 20.4% (95% CI 3.7-37.2, p = 0.02) greater for the short-term period and 16.7% (95% CI -0.3% to 33.8%, p = 0.05) greater in the long-term period when compared to baseline testing. CONCLUSIONS: Utilization of a standardized ictal testing battery in conjunction with staff education leads to an objective improvement in ictal assessment performance. Further research is warranted to assess the replicability of our findings.

A call for transparent reporting to optimize the predictive value of preclinical research.

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.

Futures Planning at the AAN: Approach and Initial Outcome.

We describe a process of organizational strategic future forecasting, with a horizon of 2035, as implemented by the American Academy of Neurology (AAN) on behalf of its members, and as a model approach for other organizations. The participants were members of the 2018-2020 AAN Boards of Directors and Executive Team, moderated by a consultant with expertise in future forecasting. Four predetermined model scenarios of import to our field (1 "expectable," 1 "challenging," and 2 "visionary") were discussed in small groups, with alternative scenarios developed in specific domains. Common themes emerged among all scenarios: the importance of thoughtful integration of biomedical and information technology tools into neurologic practice; continued demonstration of the value of neurologic care to society; and emphasis on population management and prevention of neurologic disease. Allowing for the inherent uncertainties of predicting the future, the AAN's integration of structured forecasting into its strategic planning process has allowed the organization to prepare more effectively for change, such as the disruptions stemming from the coronavirus disease 2019 (COVID-19) pandemic. The approaches outlined here will be integrated into future AAN operations and may be implemented to a similar effect by other organizations.

IGF-1 partially restores chemotherapy-induced reductions in neural cell proliferation in adult C57BL/6 mice.

Chemotherapeutic agents produce persistent difficulties in memory through an unknown mechanism. We tested the hypothesis that chemotherapeutic agents readily able to cross the blood-brain barrier (cyclophosphamide and fluorouracil), as opposed to those not known to readily cross the barrier (paclitaxel and doxorubicin), reduce neural cell proliferation following chemotherapy. We found that 5-bromo-2-deoxyuridine labeling following chemotherapy given to C57BL/6 mice revealed a similar reduction in neural cell proliferation in the dentate gyrus for all four agents. Insulin-like growth factor 1, a molecule implicated in promoting neurogenesis, counteracted the effects of high doses of chemotherapy on neural cell proliferation.

Leadership, recognition awards, and publication by men and women in the American Academy of Neurology.

OBJECTIVE: To study sex differences with respect to publications, leadership, and recognition awards in the American Academy of Neurology (AAN) in light of recent research highlighting inequities in these domains. METHODS: We examined medical school graduation, neurology residency (using American Medical Association and American Council for Graduate Medical Education data), membership in the AAN, first and last authorship in Neurology®, membership on AAN committees, and AAN recognition awards by sex for 1997, 2007, and 2017. RESULTS: Female medical students were less likely to enter neurology residency in 1997 only. In 2007 and 2017, there was no proportionate difference between men and women as last author, a surrogate for senior member of the author panel. In 2017, women were proportionately more likely to be first authors than men, a surrogate for principal investigator of the study. Committee membership was less for women in 1997 and 2007 (p < 0.001) but was not proportionately different in 2017 (p = 0.534). Women were proportionately more likely to receive recognition awards in all years studied (1997 p = 0.008, 2007 p < 0.001, 2017 p < 0.001), although absolute numbers of women were lower. CONCLUSIONS: Female membership, leadership (through committee membership), and publications as last author were lower in 1997 in the AAN. These same metrics demonstrated substantial proportionate changes, with no differences in last authorship in 2007 and 2017, greater likelihood for women to be first author in 2017, no differences in committee membership in 2017, and greater likelihood of receiving awards determined by merit in all 3 years.

Checklist for the preparation and review of pain clinical trial publications: a pain-specific supplement to CONSORT.

INTRODUCTION: Randomized clinical trials (RCTs) are considered the gold standard when assessing the efficacy of interventions because randomization of treatment assignment minimizes bias in treatment effect estimates. However, if RCTs are not performed with methodological rigor, many opportunities for bias in treatment effect estimates remain. Clear and transparent reporting of RCTs is essential to allow the reader to consider the opportunities for bias when critically evaluating the results. To promote such transparent reporting, the Consolidated Standards of Reporting Trials (CONSORT) group has published a series of recommendations starting in 1996. However, a decade after the publication of the first CONSORT guidelines, systematic reviews of clinical trials in the pain field identified a number of common deficiencies in reporting (e.g., failure to identify primary outcome measures and analyses, indicate clearly the numbers of participants who completed the trial and were included in the analyses, or report harms adequately). METHODS: Qualitative review of a diverse set of published recommendations and systematic reviews that addressed the reporting of clinical trials, including those related to all therapeutic indications (e.g., CONSORT) and those specific to pain clinical trials. RESULTS: A checklist designed to supplement the content covered in the CONSORT checklist with added details relating to challenges specific to pain trials or found to be poorly reported in recent pain trials was developed. CONCLUSIONS: Authors and reviewers of analgesic RCTs should consult the CONSORT guidelines and this checklist to ensure that the issues most pertinent to pain RCTs are reported with transparency.

Generic substitution in the treatment of epilepsy: patient and physician perceptions.

Generic substitution of branded antiepileptic drugs (AEDs) has sparked recent debates. We sought to understand perceptions about generic AED substitution and how these guide prescribing. Surveys were conducted among 550 adult patients with self-reported epilepsy and 606 physicians who treat patients with epilepsy. Physicians (88%) were concerned about an increase in breakthrough seizures in patients switched from a brand AED to a generic or among generics. Two-thirds of physicians and 34% of patients have linked breakthrough seizures to generic AED substitution. Physicians (75%) and patients (65%) were also concerned about efficacy. About half of physicians were extremely/very likely to request that brand AEDs not be substituted with a generic. In conclusion, perceptions among physicians and patients do not align with the FDA position that generic AEDs have the same clinical effect and safety profile as branded AEDs. Additional investigation on bioequivalence may help address ongoing concerns and inform policy-making decisions.

Risk of cardiac events in Long QT syndrome patients when taking antiseizure medications.

Many antiseizure medications (ASMs) affect ion channel function. We investigated whether ASMs alter the risk of cardiac events in patients with corrected QT (QTc) prolongation. The study included people from the Rochester-based Long QT syndrome (LQTS) Registry with baseline QTc prolongation and history of ASM therapy (n = 296). Using multivariate Anderson-Gill models, we assessed the risk of recurrent cardiac events associated with ASM therapy. We stratified by LQTS genotype and predominant mechanism of ASM action (Na+ channel blocker and gamma-aminobutyric acid modifier.) There was an increased risk of cardiac events when participants with QTc prolongation were taking vs off ASMs (HR 1.65, 95% confidence interval [CI] 1.36-2.00, P < 0.001). There was an increased risk of cardiac events when LQTS2 (HR 1.49, 95% CI 1.03-2.15, P = 0.036) but not LQTS1 participants were taking ASMs (interaction, P = 0.016). Na+ channel blocker ASMs were associated with an increased risk of cardiac events in participants with QTc prolongation, specifically LQTS2, but decreased risk in LQTS1. The increased risk when taking all ASMs and Na+ channel blocker ASMs was attenuated by concurrent beta-adrenergic blocker therapy (interaction, P < 0.001). Gamma-aminobutyric acid modifier ASMs were associated with an increased risk of events in patients not concurrently treated with beta-adrenergic blockers. Female participants were at an increased risk of cardiac events while taking all ASMs and each class of ASMs. Despite no change in overall QTc duration, pharmacogenomic analyses set the stage for future prospective clinical and mechanistic studies to validate that ASMs with predominantly Na+ channel blocking actions are deleterious in LQTS2, but protective in LQTS1.

Evaluation of phenytoin serum levels following a loading dose in the acute hospital setting.

PURPOSE: Due to the complex pharmacokinetic profiles of phenytoin (PHT) and fosphenytoin (FOS), achieving sustained, targeted serum PHT levels in the first day of use is challenging. METHODS: A population based approach was used to analyze total serum PHT (tPHT) level within 2-24h of PHT/FOS loading with or without supplementary maintenance or additional loading doses among PHT-naïve patients in the acute hospital setting. Adequate tPHT serum level was defined as ≥20µg/mL. RESULTS: Among 494 patients with 545 tPHT serum levels obtained in the first 2-24h after the loading dose (LD), tPHT serum levels of either

Junior faculty core curriculum to enhance faculty development.

INTRODUCTION: Senior Instructors and Assistant Professors in their first academic appointment may not have all the tools for an efficient start to their careers. Although many institutions provide access to mentoring programs and seminars on faculty development, the timing and format of the offerings often conflict with ongoing responsibilities of the faculty, particularly clinical faculty. METHODS: We established a collaboration between the Clinical and Translational Science Institute (CTSI) and the University of Rochester Medical Center Office for Faculty Development with the goal of developing a week-long Junior Faculty Core Curriculum that would better suit faculty schedules. We convened focus groups and with their help, identified themes for inclusion in the course. Speakers were identified from among local senior faculty. University leadership was enlisted in promoting the course. Individual speakers and course content were evaluated daily, at the end of the week-long course, and 6 months later. Planning for subsequent years incorporated the feedback. Yearly evaluations and subsequent course modification continued. RESULTS: Junior faculty from nearly every department in the Medical Center were represented. There was high learner satisfaction and participation however several limitations were identified and addressed in subsequent years. The focus on principles and available resources, not specific skills or content was appropriate. Daily interactions among participants from a wide variety of departments fostered networking among faculty who may not otherwise have met and discussed common interests. CONCLUSIONS: The ultimate value of such an early, intensive faculty development program will depend on whether it equips junior faculty to organize, develop, and achieve their academic goals better than alternative formats. This will require further study.

Interpretation of CIs in clinical trials with non-significant results: systematic review and recommendations.

OBJECTIVES: Interpretation of CIs in randomised clinical trials (RCTs) with treatment effects that are not statistically significant can distinguish between results that are 'negative' (the data are not consistent with a clinically meaningful treatment effect) or 'inconclusive' (the data remain consistent with the possibility of a clinically meaningful treatment effect). This interpretation is important to ensure that potentially beneficial treatments are not prematurely abandoned in future research or clinical practice based on invalid conclusions. DESIGN: Systematic review of RCT reports published in 2014 in Annals of Internal Medicine, New England Journal of Medicine, JAMA, JAMA Internal Medicine and The Lancet (n=247). RESULTS: 85 of 99 articles with statistically non-significant results reported CIs for the treatment effect. Only 17 of those 99 articles interpreted the CI. Of the 22 articles in which CIs indicated an inconclusive result, only four acknowledged that the study could not rule out a clinically meaningful treatment effect. CONCLUSIONS: Interpretation of CIs is important but occurs infrequently in study reports of trials with treatment effects that are not statistically significant. Increased author interpretation of CIs could improve application of RCT results. Reporting recommendations are provided.

Reporting of data monitoring boards in publications of randomized clinical trials is often deficient: ACTTION systematic review.

OBJECTIVE: To examine whether primary reports of randomized clinical trials (RCTs) in six high-impact, general medical journals reported (1) whether or not a Data Monitoring Committee/Data and Safety Monitoring Board (DMC/DSMB) was used and (2) the composition of the responsibilities of the reported DSMB/DMCs. STUDY DESIGN AND SETTING: Systematic review of RCTs published in 2014 in Annals of Internal Medicine, BMJ, NEJM, JAMA, JAMA Internal Medicine, and Lancet. RESULTS: Of the 294 articles identified, 174 (59%) mentioned using a DMC/DSMB. Of these 174, 126 (72%) indicated at least one responsibility of the DMC/DSMB, 26% listed the names of the DMC/DSMB members, and another 14% listed both their names and affiliations. Only one article stated that a DSMB was not used. The remaining 119 articles did not report whether or not a DMC/DSMB was used, although 59 had previously stated in a clinical trials registry entry or a published protocol that a DMC/DSMB was to be used. CONCLUSIONS: Considering the major role that DMC/DSMBs play in protecting participant safety, data quality, and interim analyses in RCTs, we recommend that authors of publications of RCTs report whether a DMC/DSMB was used and the responsibilities and members of DMC/DSMBs to increase transparency regarding study conduct.