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The aim of this study was to assess potential drug-drug interactions between highly purified cannabidiol (CBD) and anti-seizure medications (ASMs). Our group previously reported that in a sample of adults and children receiving CBD in an open-label expanded access program, there were several ASMs noted to increase in serum levels with increasing doses of CBD. We analyzed if an increased number of observations over time resulted in changes in potential interactions and if potential interactions were associated with time since enrollment, demographics, or the overall rating of adverse effects. In 169 participants (80 adults), with increasing weight-based CBD dose, there were associated increases in serum levels of clobazam and N-desmethylclobazam, free valproate, felbamate, and topiramate in the adult and pediatric arms combined, levetiracetam in the pediatric arm only, and permapanel in the adult arm only. There were no associations noted in these level changes with time since enrollment, biological sex, and adverse events profile scores. This study confirms some previously identified interactions with CBD and identifies other potential pharmacokinetic interactions; however, the clinical significance of these observations is likely minor, and there is no effect of time on these findings.

Purpose of ReviewFor millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy.Recent FindingsWhile the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD’s inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD.SummaryUnderstanding of CBD’s efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.

Objective To further evaluate the relationship between the clinical profiles and limbic and motor brain regions and their connecting pathways in psychogenic nonepileptic seizures (PNES). Neurite Orientation Dispersion and Density Indices (NODDI) multicompartment modeling was used to test the relationships between tissue alterations in patients with traumatic brain injury (TBI) and multiple psychiatric symptoms. Methods The sample included participants with prior TBI (TBI; N = 37) but no PNES, and with TBI and PNES (TBI + PNES; N = 34). Participants completed 3T Siemens Prisma MRI high angular resolution imaging diffusion protocol. Statistical maps, including fractional anisotropy (FA), mean diffusivity (MD), neurite dispersion [orientation dispersion index (ODI)] and density [intracellular volume fraction (ICVF), and free water (i.e., isotropic) volume fraction (V‐ISO)] signal intensity, were generated for each participant. Linear mixed‐effects models identified clusters of between‐group differences in indices of white matter changes. Pearson’s r correlation tests assessed any relationship between signal intensity and psychiatric symptoms. Results Compared to TBI, TBI + PNES revealed decreases in FA, ICVF, and V‐ISO and increases in MD for clusters within cingulum bundle, uncinate fasciculus, fornix/stria terminalis, and corticospinal tract pathways (cluster threshold α = 0.05). Indices of white matter changes for these clusters correlated with depressive, anxiety, PTSD, psychoticism, and somatization symptom severity (FDR threshold α = 0.05). A follow‐up within‐group analysis revealed that these correlations failed to reach the criteria for significance in the TBI + PNES group alone. Interpretation The results expand support for the hypothesis that alterations in pathways comprising the specific PNES network correspond to patient profiles. These findings implicate myelin‐specific changes as possible contributors to PNES, thus introducing novel potential treatment targets.

Late-onset unexplained epilepsy (LoUE), defined as epilepsy onset after age 55 without an obvious cause, is an important risk factor for dementia. Studies have shown that 10%-25% of individuals with LoUE develop dementia within 3-4 years following their first seizure. However, the mechanisms underlying progression from LoUE to dementia remain poorly understood. The goals of the ELUCID study are to identify risk factors associated with the development of cognitive decline and dementia in LoUE and to develop tools to identify patients at a high risk for these outcomes and thereby establish a foundation for dementia prevention strategies in this population. ELUCID is a multi-center prospective longitudinal observational study that will enroll 600 participants aged 55 or older with LoUE across seven U.S. medical centers. Participants will undergo a baseline evaluation that includes a detailed clinical history, cognitive testing, brain MRI, overnight scalp EEG, and blood biomarkers. Participants will be followed at 6-month intervals for up to 5 years, to record cognitive and neurological changes, with the primary outcomes of interest being the development of mild cognitive impairment and/or dementia. This study aims to establish LoUE disease subtypes based on biomarkers, cognitive trajectories, and imaging features and to develop a risk stratification tool for predicting cognitive decline and dementia in patients presenting with LoUE. ELUCID has obtained IRB approval (no. 2023P001566, August 2023), with the Mass General Brigham IRB serving as the single IRB of record. All de-identified study data will be made publicly available on completion of the study. The ELUCID study is a research project involving several medical centers across the U.S. It will focus on older adults who have recently developed seizures without a clear cause. Participants undergo an initial evaluation that includes questions about their medical history, a brain MRI, an overnight scalp EEG (brain wave study), and a blood draw. They will be followed over time with health questionnaires and yearly tests of memory and thinking. The purpose of the study is to learn what factors increase the risk of dementia in this population and to develop tools to predict which individuals are at the highest risk.

Burnout among physicians is a syndrome of emotional exhaustion, de-personalization, and reduced sense of personal accomplishment that can negatively affect personal relationships, physician well-being, and patient outcomes. Although burnout rates of up to 50% to 60% among orthopedic surgeons have been reported, no studies have evaluated burnout among orthopedic generalists and subspecialists. The primary goal of this study was to examine the prevalence of burnout among orthopedic disciplines. We conducted a multicenter study from March 2019 through December 2019 involving 149 orthopedists. An abbreviated Maslach Burnout Inventory-Human Services Survey was used to measure burnout. Demographic information, personal characteristics, professional characteristics, family life and spousal support, and depression were also assessed. The mean rate of burnout among all respondents was 62%, whereas 16.77% screened positive for depression. Subspecialties with the highest rates of burnout were oncology (100%), sports medicine (68%), and trauma (63%). Similarly, trauma (50.00%), oncology (40.00%), and general orthopedics (20.00%) had the highest positive depression screening rates. In contrast, shoulder and elbow (50%), pediatric (52%), and foot and ankle (54%) specialists had the lowest rates of burnout, whereas shoulder and elbow (0.00%), spine (0.00%), and sports medicine (6.50%) specialists had the lowest rates of positive depression screening. Older age, higher debt load, and oncology subspecialty were associated with increased burnout risk. This study sought to determine burnout rates within each orthopedic discipline, with a secondary aim of disclosing contributing factors. Trauma and oncology had the highest rates of burnout and positive depression screening. Because this study represents a small orthopedic cohort, larger studies are needed to appropriately manage burnout in the future. [Orthopedics. 20XX;XX(X):xx–xx.]

Late-onset unexplained epilepsy (LoUE), defined as epilepsy starting after age 55 with no clearly identified cause, has emerged as a significant risk factor for dementia. Individuals presenting with LoUE have no prior history of dementia. Yet, LoUE is associated with a 2-3x increased risk of developing dementia, and up to 25% of individuals with LoUE develop dementia within 4 years after their first seizure. We have little understanding of the mechanisms that underlie development of dementia in LoUE. The ELUCID Study (Epilepsy of Late-onset Unknown etiology as a risk factor for Cognitive Impairment and Dementia) is a multi-center, prospective longitudinal observational study of LoUE, focused on understanding mechanisms and predicting outcomes of mild cognitive impairment and dementia in LoUE. ELUCID will enroll 600 participants with LoUE (and without dementia) across 7 study sites. Participants undergo a baseline evaluation with clinical history, cognitive testing, brain MRI, overnight scalp EEG, and blood draw, and are followed longitudinally with interval history every 6 months and annual cognitive testing. The primary outcomes are development of mild cognitive impairment and dementia. To date, 67 ELUCID participants have completed their initial study visit, with mean age of 67.9±7.2 years and 38.8% female. The sample includes 89.6% White, 3% Black, 1.5% Asian, 6% unreported race, and 1.5% Hispanic ethnicity. Mean level of education was 16.9±2.7 years. Vascular risk factors were common, including hypertension (51%), hyperlipidemia (58%), diabetes mellitus (6%), coronary artery disease (9%), and obstructive sleep apnea (28%). A family history of seizures was present in 23.9% of participants, and a family history of dementia in 58%. Cognitive test scores largely fell within normal range, including: MMSE: 28.7±1.5; Logical Memory Delayed: 11.9±3.4; FCSRT Free Recall: 31.6±6.4; Trails B: 94.3±54.4; Digit Symbol Substitution: 41.9±10.1; and Category Fluency (animals): 17.0±4.9. Subjectively, 32.8% of participants felt their memory had worsened compared to 6 months prior. The ELUCID Study is a large longitudinal study of LoUE that will define its relationship to Alzheimer's disease and related dementias. Here we describe the study protocol and provide an early report of the baseline demographic and clinical characteristics of the accruing ELUCID study population.

Background Late‐onset unexplained epilepsy (LoUE), defined as epilepsy starting after age 55 with no clearly identified cause, has emerged as a significant risk factor for dementia. Individuals presenting with LoUE have no prior history of dementia. Yet, LoUE is associated with a 2‐3x increased risk of developing dementia, and up to 25% of individuals with LoUE develop dementia within 4 years after their first seizure. We have little understanding of the mechanisms that underlie development of dementia in LoUE. Method The ELUCID Study (Epilepsy of Late‐onset Unknown etiology as a risk factor for Cognitive Impairment and Dementia) is a multi‐center, prospective longitudinal observational study of LoUE, focused on understanding mechanisms and predicting outcomes of mild cognitive impairment and dementia in LoUE. ELUCID will enroll 600 participants with LoUE (and without dementia) across 7 study sites. Participants undergo a baseline evaluation with clinical history, cognitive testing, brain MRI, overnight scalp EEG, and blood draw, and are followed longitudinally with interval history every 6 months and annual cognitive testing. The primary outcomes are development of mild cognitive impairment and dementia. Result To date, 67 ELUCID participants have completed their initial study visit, with mean age of 67.9±7.2 years and 38.8% female. The sample includes 89.6% White, 3% Black, 1.5% Asian, 6% unreported race, and 1.5% Hispanic ethnicity. Mean level of education was 16.9±2.7 years. Vascular risk factors were common, including hypertension (51%), hyperlipidemia (58%), diabetes mellitus (6%), coronary artery disease (9%), and obstructive sleep apnea (28%). A family history of seizures was present in 23.9% of participants, and a family history of dementia in 58%. Cognitive test scores largely fell within normal range, including: MMSE: 28.7±1.5; Logical Memory Delayed: 11.9±3.4; FCSRT Free Recall: 31.6±6.4; Trails B: 94.3±54.4; Digit Symbol Substitution: 41.9±10.1; and Category Fluency (animals): 17.0±4.9. Subjectively, 32.8% of participants felt their memory had worsened compared to 6 months prior. Conclusion The ELUCID Study is a large longitudinal study of LoUE that will define its relationship to Alzheimer's disease and related dementias. Here we describe the study protocol and provide an early report of the baseline demographic and clinical characteristics of the accruing ELUCID study population.

Background: Legumes are the third largest family of angiosperms and the second most important crop class. Legume genomes have been shaped by extensive large-scale gene duplications, including an approximately 58 million year old whole genome duplication shared by most crop legumes. Results: We report the genome and the transcription atlas of coding and non-coding genes of a Mesoamerican genotype of common bean (Phaseolus vulgaris L., BAT93). Using a comprehensive phylogenomics analysis, we assessed the past and recent evolution of common bean, and traced the diversification of patterns of gene expression following duplication. We find that successive rounds of gene duplications in legumes have shaped tissue and developmental expression, leading to increased levels of specialization in larger gene families. We also find that many long non-coding RNAs are preferentially expressed in germ-line-related tissues (pods and seeds), suggesting that they play a significant role in fruit development. Our results also suggest that most bean-specific gene family expansions, including resistance gene clusters, predate the split of the Mesoamerican and Andean gene pools. Conclusions: The genome and transcriptome data herein generated for a Mesoamerican genotype represent a counterpart to the genomic resources already available for the Andean gene pool. Altogether, this information will allow the genetic dissection of the characters involved in the domestication and adaptation of the crop, and their further implementation in breeding strategies for this important crop.

We present observations of SN 2021csp, a unique supernova (SN) which displays evidence for interaction with H- and He- poor circumstellar material (CSM) at early times. Using high-cadence spectroscopy taken over the first week after explosion, we show that the spectra of SN 2021csp are dominated by C III lines with a velocity of 1800 km s\\(^{-1}\\). We associate this emission with CSM lost by the progenitor prior to explosion. Subsequently, the SN displays narrow He lines before metamorphosing into a broad-lined Type Ic SN. We model the bolometric light curve of SN 2021csp, and show that it is consistent with the energetic (\\(4\\times10^{51}\\) erg) explosion of a stripped star, producing 0.4 M\\(_\\odot\\) of 56Ni within a \\(\\sim\\)1 M\\(_\\odot\\) shell of CSM extending out to 400 R\\(_\\odot\\).