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Importance Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system. Objective To determine the time to onset of symptoms consistent with MS. Design, Setting, and Participants From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144. Interventions Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred. Main outcomes Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs. Results Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant. Conclusion and Relevance Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum. Trial Registration ClinicalTrials.gov Identifier: NCT03122652

With more than 6000 attendees between in-person and virtual offerings, the American Epilepsy Society Meeting 2022 in Nashville, felt as busy as in prepandemic times. An ever-growing number of physicians, scientists, and allied health professionals gathered to learn a variety of topics about epilepsy. The program was carefully tailored to meet the needs of professionals with different interests and career stages. This article summarizes the different symposia presented at the meeting. Basic science lectures addressed the primary elements of seizure generation and pathophysiology of epilepsy in different disease states. Scientists congregated to learn about anti-seizure medications, mechanisms of action, and new tools to treat epilepsy including surgery and neurostimulation. Some symposia were also dedicated to discuss epilepsy comorbidities and practical issues regarding epilepsy care. An increasing number of patient advocates discussing their stories were intertwined within scientific activities. Many smaller group sessions targeted more specific topics to encourage member participation, including Special Interest Groups, Investigator, and Skills Workshops. Special lectures included the renown Hoyer and Lombroso, an ILAE/IBE joint session, a spotlight on the impact of Dobbs v. Jackson on reproductive health in epilepsy, and a joint session with the NAEC on coding and reimbursement policies. The hot topics symposium was focused on traumatic brain injury and post-traumatic epilepsy. A balanced collaboration with the industry allowed presentations of the latest pharmaceutical and engineering advances in satellite symposia.

AbstractBACKGROUNDDelirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long‐term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology.METHODSThe Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts.RESULTSMeeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium‐spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations.DISCUSSIONThe DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes.Highlights Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning.

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Institute of Health Research St George's, University of London Background SCN5A-E1784K (c.5350G>A) is the most common variant associated with the LQT3 long QT syndrome (LQTS) and Brugada syndrome (BrS). It exhibits incomplete penetrance and can manifest variably as a mixed clinical phenotype of LQTS, BrS and/or conduction disorders (1-4). This presents a challenge for risk stratification and optimal management. We aimed to describe the clinical characteristics and risk markers in a large, well characterised international cohort of SCN5A-E1784K subjects and identify demographic and/or ECG parameters associated with event free survival. Methods Comprehensive clinical data, including initial presentation and follow-up data, were collected from SCN5A-E1784K subjects. Outcome ‘events’ included sudden death, aborted cardiac arrest, and documented VF or VT or arrhythmic syncope. ‘Lethal events’ included sudden death, aborted cardiac arrest or documented VF or VT. Associations between clinical characteristics and event free survival were investigated using Cox proportional hazard regression models. Results SCN5A-E1784K subjects (n=231) were recruited from 16 centres. Median follow up was 24.9 years (15.2 - 43.3) and 45 individuals (19%) experienced an event. Lethal events were observed in 14 subjects (6%). Figure 1 shows event (A) and lethal event (B) free survival in SCN5A-E1784K subjects. Higher QRS duration (corrected for age) was associated with shorter event-free interval. QRS duration was the only characteristic associated with increased risk with a hazard ratio (HR) of 1.04 or 1.05 per ms for events and lethal events, respectively. The observed survival for events and lethal events for QRS tertiles are shown in Figure 2. Discussion Ventricular myocardial conduction, as evidenced by QRS duration, appears to play a role in the risk of arrhythmic events in patients with SCN5A-E1784K. Corrected QT interval and BrS phenotype were, however, not associated with risk. This provides an important opportunity for the personalisation of risk stratification of these patients, whose management can otherwise be very challenging. Figures

Importance Preventing relapse for adults with acute myeloid leukemia (AML) in first remission is the most common indication for allogeneic hematopoietic cell transplant. The presence of AML measurable residual disease (MRD) has been associated with higher relapse rates, but testing is not standardized. Objective To determine whether DNA sequencing to identify residual variants in the blood of adults with AML in first remission before allogeneic hematopoietic cell transplant identifies patients at increased risk of relapse and poorer overall survival compared with those without these DNA variants. Design, Setting, and Participants In this retrospective observational study, DNA sequencing was performed on pretransplant blood from patients aged 18 years or older who had undergone their first allogeneic hematopoietic cell transplant during first remission for AML associated with variants in FLT3, NPM1, IDH1, IDH2, or KIT at 1 of 111 treatment sites from 2013 through 2019. Clinical data were collected, through May 2022, by the Center for International Blood and Marrow Transplant Research. Exposure Centralized DNA sequencing of banked pretransplant remission blood samples. Main Outcomes and Measures The primary outcomes were overall survival and relapse. Day of transplant was considered day 0. Hazard ratios were reported using Cox proportional hazards regression models. Results Of 1075 patients tested, 822 had FLT3 internal tandem duplication ( FLT3- ITD) and/or NPM1 mutated AML (median age, 57.1 years, 54% female). Among 371 patients in the discovery cohort, the persistence of NPM1 and/or FLT3 -ITD variants in the blood of 64 patients (17.3%) in remission before undergoing transplant was associated with worse outcomes after transplant (2013-2017). Similarly, of the 451 patients in the validation cohort who had undergone transplant in 2018-2019, 78 patients (17.3%) with residual NPM1 and/or FLT3 -ITD variants had higher rates of relapse at 3 years (68% vs 21%; difference, 47% [95% CI, 26% to 69%]; HR, 4.32 [95% CI, 2.98 to 6.26]; P < .001) and decreased survival at 3 years (39% vs 63%; difference, −24% [2-sided 95% CI, −39% to −9%]; HR, 2.43 [95% CI, 1.71 to 3.45]; P < .001). Conclusions and Relevance Among patients with acute myeloid leukemia in first remission prior to allogeneic hematopoietic cell transplant, the persistence of FLT3 internal tandem duplication or NPM1 variants in the blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without these variants. Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with acute myeloid leukemia.

Abstract The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1–2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.

AbstractBackgroundRNA‐seq experiments have traditionally been done with short‐read sequencing technologies that, by nature, collapse all RNA isoforms for a given gene into a single expression measurement—a major oversimplification of the underlying biology. Collapsing all RNA isoforms for a single gene severely limits our ability to characterize all RNA isoforms and determine their individual downstream functions. While computational approaches for assembling short reads into full transcripts exist, these methods are inherently structurally inaccurate, especially when compared to full‐length sequencing possible with long‐read sequencing technologies. In contrast, long‐read sequencing technologies can sequence entire RNA molecules, allowing researchers to accurately quantify expression for the complete set of RNA isoform species, including de novo RNA isoforms. Long‐read sequencing is especially well suited for discovering novel isoforms in the recently released telomere‐to‐telomere (T2T) human reference genome (CHM13). The new CHM13 genome assembly resolved highly homologous regions that are challenging to study with short‐reads. Here we sequenced post‐mortem human brain tissue with long‐reads and aligned them to CHM13 to explore novel gene bodies and transcript isoforms.MethodsWe sequenced pre‐frontal cortex tissue from four post‐mortem human brain samples using Oxford Nanopore Technologies long‐read sequencing for PCR amplified cDNA. Data were basecalled using Guppy, reads were aligned to the CHM13 human reference genome using minimap2, and transcripts were assembled and quantified with the Bambu package in R.ResultsAmong other findings, we discovered 84 new, high‐confidence gene bodies expressed in all four samples with at least 5 reads in each sample. We also found 223 novel RNA isoforms in previously annotated gene bodies. Of these 223 novel isoforms, 29 aligned to medically relevant genes such as MAOB, HLA‐DRB1, and ABO.ConclusionsOur results suggest long‐reads aligned to the CHM13 reference genome have the potential to reveal novel gene bodies and transcript isoforms that were missed in previous studies. These methods can provide a more complete picture of the transcriptomic landscape of diseases, including Alzheimer’s disease—hopefully generating information with potential to help inform future treatment and/or early diagnostic efforts.

52 Background: When combination medical therapy incorporates both IV and oral anti-cancer agents, patients may experience compound side effects and face challenges with treatment adherence. To assess how community cancer programs may improve care coordination for patients receiving combination IV/oral systemic therapy, the Association of Community Cancer Centers (ACCC) conducted a mixed-methods study that involved healthcare professionals (HCPs), patients and caregivers. Methods: The study followed a sequential quantitative-qualitative design to answer questions around the barriers or challenges associated with combination IV/oral systemic therapy. The quantitative phase included an online survey of HCPs (by ACCC) and a survey of patients and caregivers (by Edge Research, in collaboration with several patient advocacy organizations). In the quantitative phase, the survey results were contextualized through two HCP focus groups and individual HCP interviews. Results: Comparing and contrasting the patient survey (n = 113) and HCP survey (n = 157) results revealed insights around the following themes: Top Challenges: Patients felt their top challenges were side effects (57.5%); inconvenience going to medical appointments (37.2%); and financial burden (36.3%). HCPs perceived top challenges as cost of care to the patient (24.0%); coordination and delivery of oral agents (22.1%); and health insurance coverage (21.9%). In focus groups, HCPs explained how they were investing significant staffing resources to prevent and mitigate financial toxicity, especially for patients receiving oral therapies. Methods of Communication: 35.4% of patients “highly preferred” using email to communicate with HCPs about their combination regimens. However, HCPs felt that email was one of the least effective methods of communicating with patients. In focus groups, HCPs agreed that email is convenient when communicating about non-urgent matters. However, they were concerned that some patients may use email to communicate about urgent issues. Treatment-related AEs: When patients experienced treatment-related AEs, 30.1% said their clinicians tried a dose modification or hold. HCPs had mixed perceptions regarding the effectiveness of dose holidays. Those who felt this was highly effective included: advanced practice providers (42.9%), nurses (28.1%); oncologists (16.7%); and pharmacists (16.7%). Conclusions: This study identifies opportunities to improve care coordination for patients receiving combination IV/oral systemic anti-cancer regimens. These findings may inform the creation and dissemination of effective practices and quality improvement projects. These results may also help cancer programs tailor resources and incorporate proactive steps to address some of the key challenges patients may face.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P < .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P < .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P < .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.