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Abstract Following the approval of Epidiolex® (cannabidiol; CBD) for the treatment of seizures associated with Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC), healthcare professionals (HCPs) have had substantial experience in treating patients with Epidiolex. However, confusion still remains among HCPs, caregivers, and patients regarding dosing, drug interactions, safety monitoring, and differentiation between Epidiolex and nonapproved CBD products. To establish consensus recommendations for Epidiolex treatment optimization in LGS, DS, and TSC, a panel of seven HCPs with expertise in epilepsy was convened. Panelists participated in a premeeting survey based on a literature review of Epidiolex for the treatment of LGS, DS, and TSC, and survey responses were compiled for discussion. A modified Delphi method was used to assess agreement among panelists regarding recommendation statements following two rounds of discussion. Panelists identified two broad themes – overcoming barriers to initiation and optimization of treatment for seizures associated with LGS, DS, and TSC – for consensus guidelines. Accurate identification of patients with these rare epilepsies is critical for optimization of Epidiolex treatment. Providers should differentiate Epidiolex from nonapproved CBD products and set expectations for the therapeutic effect and safety/tolerability of Epidiolex. Initial target dose and titration rate should be individualized by baseline variables, prior response to antiseizure medications, and therapeutic goals. Awareness of strategies to manage adverse events and concomitant medications, including drug–drug interactions, is critical. Tracking response to the maximum tolerated dose is an important measure of effectiveness. These consensus recommendations provide real‐world experience from neurology HCPs with experience in prescribing Epidiolex and can inform optimal use of Epidiolex for the treatment of seizures associated with LGS, DS, and TSC. Plain language summary Epidiolex® (cannabidiol) is approved for treating seizures in Lennox–Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Although healthcare professionals have experience in treating patients with Epidiolex, there is a need for better understanding of dosing, drug interactions, and safety of this drug. Therefore, a group of epilepsy experts developed guidelines for best practices in Epidiolex treatment. Two main areas were identified: overcoming barriers to starting Epidiolex and considerations related to Epidiolex dosing. Within these areas, topics, including correct disease identification, managing adverse events, and determining individualized dose, were discussed. These guidelines provide real‐world experience to inform optimal Epidiolex use.

The pulmonary system represents a unique lipidomic environment as it contains cellular membrane-bound lipid species and a specialized reservoir of lipids in the airway epithelial lining fluid. As a major initial point of defense, airway lipids react to inhaled contaminants such as volatile organic compounds, oxides of nitrogen, or ozone (O3), creating lipokine signaling that is crucial for both the initiation and resolution of inflammation within the lung. Dietary modulation of eicosanoids has gained increased attention in recent years for improvements to cardiovascular health. The current study sought to examine how dietary supplementation with eicosanoid precursors (i.e, oils rich in saturated or polyunsaturated fatty acids) might alter the lung lipid composition and subsequently modify the inflammatory response to ozone inhalation. Our study demonstrated that mice fed a diet high in saturated fatty acids resulted in diet-specific changes to lung lipid profiles and increased cellular recruitment to the lung following ozone inhalation. Bioinformatic analysis revealed an ozone-dependent upregulation of several lipid species, including phosphoserine 37:5. Pathway analysis of lipid species revealed the process of lateral diffusion of lipids within membranes to be significantly altered due to ozone exposure. These results show promising data for influencing pulmonary lipidomic profiles via diet, which may provide a pragmatic therapeutic approach to protect against lung inflammation and damage following pulmonary insult.

The gut microbiota modulates dopamine levels in vivo, but the bacteria and biochemical processes responsible remain incompletely characterized. A potential precursor of bacterial dopamine production is 3-methoxytyramine (3MT); 3MT is produced when dopamine is O-methylated by host catechol O-methyltransferase (COMT), thereby attenuating dopamine levels. This study aimed to identify whether gut bacteria are capable of reverting 3MT to dopamine. Human faecal bacterial communities O-demethylated 3MT and yielded dopamine. Gut bacteria that mediate this transformation were identified as acetogens Eubacterium limosum and Blautia producta. Upon exposing these acetogens to propyl iodide, a known inhibitor of cobalamin-dependent O-demethylases, 3MT O-demethylation was inhibited. Culturing E. limosum and B. producta with 3MT afforded increased acetate levels as compared with vehicle controls. Gut bacterial acetogens E. limosum and B. producta synthesized dopamine from 3MT. This O-demethylation of 3MT was likely performed by cobalamin-dependent O-demethylases implicated in reductive acetogenesis. This is the first report that gut bacteria can synthesize dopamine by O-demethylation of 3MT. Owing to 3MT being the product of host COMT attenuating dopamine levels, gut bacteria that reverse this transformation-converting 3MT to dopamine-may act as a counterbalance for dopamine regulation by COMT.

Background and objective: Commercially available cannabidiol (CBD) products are increasingly being used for medicinal purposes, including for the treatment of various neurological conditions, but there are growing concerns around adherence to quality control measures that protect consumers. This study was conducted to assess the purity and label accuracy of commercially available CBD products.Methods: Commercially available CBD products were chosen from the open stream of commerce in the United States based on formulations as a tincture, gummy, vape, or topical product. Cannabinoid concentrations were analyzed to verify label accuracy including “full spectrum,” “broad spectrum,” and “CBD isolate” claims on the product label. Analysis for the presence of contaminants included evaluation for heavy metals, pesticides, and residual solvents. Labeled and actual total amounts of CBD and levels of impurities such as heavy metals, residual solvents, and pesticides were measured.Results: A total of 202 CBD products (100 tinctures, 48 gummies, 34 vape products, and 20 topicals) were chosen to represent a broad sample in the United States. Of the products tested (full spectrum, n = 84; broad spectrum, n = 28; CBD isolate, n = 37), 26% did not meet the definition for product type claimed on the packaging. The majority of products (74%) deviated from their label claim of CBD potency by at least 10%. Heavy metals were detected 52 times across 44 of the 202 products tested, with lead being the most prevalent heavy metal. Residual solvents were detected 446 times across 181 of 202 products, with the highest concentrations reported for hexane, m/p-xylene, methanol, and o-xylene. Of 232 pesticides tested, 26 were found 55 times across 30 products. A total of 3% of heavy metals, 1% of residual solvents, and 1% of pesticides violated >1 regulatory threshold.Discussion: This study demonstrated that the majority of commercially available CBD products tested within the current study are inaccurately labeled. Heavy metals, residual solvents, and pesticides were found in several products, some of which violated regulatory thresholds. Thus, uniform compliance with CBD quality control measures is lacking and raises consumer protection concerns. Improved regulatory oversight of this industry is recommended.

BackgroundThe year 2020 marked a fundamental shift in the pediatric neurology field. An impressive positive trajectory of advances in patient care and research faced sudden global disruptions by the coronavirus disease 2019 pandemic and by an international movement protesting racial, socioeconomic, and health disparities. The disruptions revealed obstacles and fragility within the pediatric neurology research mission. However, renewed commitment offers unique opportunities for the pediatric neurology research community to enhance and prioritize research directions for the coming decades.MethodsThe Research Committee of the Child Neurology Society evaluated the challenges and opportunities facing the pediatric neurology research field, including reviewing published literature, synthesizing publically available data, and conducting a survey of pediatric neurologists.ResultsWe identified three priority domains for the research mission: funding levels, active guidance, and reducing disparities. Funding levels: to increase funding to match the burden of pediatric neurological disease; to tailor funding mechanisms and strategies to support clinical trial efforts unique to pediatric neurology; and to support investigators across their career trajectory. Active guidance: to optimize infrastructure and strategies, to leverage novel therapeutics, enhance data collection, and improve inclusion of children in clinical trials. Reducing disparities: to reduce health disparities in children with neurological disease, to develop proactive measures to enhance workforce diversity and inclusion, and increase avenues to balance work-life obligations for investigators.ConclusionsIn this uniquely challenging epoch, the pediatric neurology research community has a timely and important mission to re-engage the public and government, advancing the health of children with neurological conditions.

Eczema (atopic dermatitis, AD) is a skin disease characterized by skin barrier dysfunction due to various factors, including genetics, immune system abnormalities, and environmental triggers. Application of emollients and topical drugs such as corticosteroids and calcineurin inhibitors form the mainstay of treatments for this challenging condition. This review aims to summarize the recent advances made in phytochemical-based topical applications to treat AD and the different carriers that are being used. In this review, the clinical efficacy of several plant extracts and bioactive phytochemical compounds in treating AD are discussed. The anti-atopic effects of the herbs are evident through improvements in the Scoring Atopic Dermatitis (SCORAD) index, reduced epidermal thickness, decreased transepidermal water loss, and alleviated itching and dryness in individuals affected by AD as well as in AD mouse models. Histopathological studies and serum analyses conducted in AD mouse models demonstrated a reduction in key inflammatory factors, including thymic stromal lymphopoietin (TSLP), serum immunoglobulin E (IgE), and interleukins (IL). Additionally, there was an observed upregulation of the filaggrin (FLG) gene, which regulates the proteins constituting the stratum corneum, the outermost layer of the epidermis. Carriers play a crucial role in topical drug applications, influencing dose delivery, retention, and bioavailability. This discussion delves into the efficacy of various nanocarriers, including liposomes, ethosomes, nanoemulsions, micelles, nanocrystals, solid-lipid nanoparticles, and polymeric nanoparticles. Consequently, the potential long-term side effects such as atrophy, eruptions, lymphoma, pain, and allergic reactions that are associated with current topical treatments, including emollients, topical corticosteroids, topical calcineurin inhibitors, and crisaborole, can potentially be mitigated through the use of phytochemical-based natural topical treatments.

Plant-derived lignans, consumed daily by most individuals, are thought to protect against cancer and other diseases1; however, their bioactivity requires gut bacterial conversion to enterolignans2. Here, we dissect a four-species bacterial consortium sufficient for all five reactions in this pathway. A single enzyme (benzyl ether reductase, encoded by the gene ber) was sufficient for the first two biotransformations, variable between strains of Eggerthella lenta, critical for enterolignan production in gnotobiotic mice and unique to Coriobacteriia. Transcriptional profiling (RNA sequencing) independently identified ber and genomic loci upregulated by each of the remaining substrates. Despite their low abundance in gut microbiomes and restricted phylogenetic range, all of the identified genes were detectable in the distal gut microbiomes of most individuals living in northern California. Together, these results emphasize the importance of considering strain-level variations and bacterial co-occurrence to gain a mechanistic understanding of the bioactivation of plant secondary metabolites by the human gut microbiome.

The nature of bullying and the proliferation of bully prevention programs for schools is well-documented. Research indicates that the most effective programs are those that are implemented school-wide. Forty-nine states have passed some type of legislation that deals with bully-prevention in schools. Clearly, schools throughout the country are developing and implementing school-wide bullying prevention programs. Yet students continue to be bullied at an alarming rate, with some studies citing figures in excess of 50% (Rose, Monda-Amaya & Espelage, 2001; McNamara, 2013). Students who engage in bullying select those students who are the most vulnerable, including those with special needs. One issue about school-wide programs is that they are frequently inaccessible to all students. Therefore, students with disabilities may never be taught how to deal with bullying. This article provides recommendations that enable schools to modify their school-wide programs so that all students can feel safe in school, including those with special needs.

Cancer cell energy metabolism plays an important role in dictating the efficacy of oncolysis by oncolytic viruses. To understand the role of multiple myeloma metabolism in reovirus oncolysis, we performed semi-targeted mass spectrometry-based metabolomics on 12 multiple myeloma cell lines and revealed a negative correlation between NAD+ levels and susceptibility to oncolysis. Likewise, a negative correlation was observed between the activity of the rate-limiting NAD+ synthesis enzyme NAMPT and oncolysis. Indeed, depletion of NAD+ levels by pharmacological inhibition of NAMPT using FK866 sensitized several myeloma cell lines to reovirus-induced killing. The myelomas that were most sensitive to this combination therapy expressed a functional p53 and had a metabolic and transcriptomic profile favoring mitochondrial metabolism over glycolysis, with the highest synergistic effect in KMS12 cells. Mechanistically, U-13C-labeled glucose flux, extracellular flux analysis, multiplex proteomics, and cell death assays revealed that the reovirus + FK866 combination caused mitochondrial dysfunction and energy depletion, leading to enhanced autophagic cell death in KMS12 cells. Finally, the combination of reovirus and NAD+ depletion achieved greater antitumor effects in KMS12 tumors in vivo and patient-derived CD138+ multiple myeloma cells. These findings identify NAD+ depletion as a potential combinatorial strategy to enhance the efficacy of oncolytic virus-based therapies in multiple myeloma.

Following the approval of Epidiolex® (cannabidiol; CBD) for the treatment of seizures associated with Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC), healthcare professionals (HCPs) have had substantial experience in treating patients with Epidiolex. However, confusion still remains among HCPs, caregivers, and patients regarding dosing, drug interactions, safety monitoring, and differentiation between Epidiolex and nonapproved CBD products. To establish consensus recommendations for Epidiolex treatment optimization in LGS, DS, and TSC, a panel of seven HCPs with expertise in epilepsy was convened. Panelists participated in a premeeting survey based on a literature review of Epidiolex for the treatment of LGS, DS, and TSC, and survey responses were compiled for discussion. A modified Delphi method was used to assess agreement among panelists regarding recommendation statements following two rounds of discussion. Panelists identified two broad themes – overcoming barriers to initiation and optimization of treatment for seizures associated with LGS, DS, and TSC – for consensus guidelines. Accurate identification of patients with these rare epilepsies is critical for optimization of Epidiolex treatment. Providers should differentiate Epidiolex from nonapproved CBD products and set expectations for the therapeutic effect and safety/tolerability of Epidiolex. Initial target dose and titration rate should be individualized by baseline variables, prior response to antiseizure medications, and therapeutic goals. Awareness of strategies to manage adverse events and concomitant medications, including drug–drug interactions, is critical. Tracking response to the maximum tolerated dose is an important measure of effectiveness. These consensus recommendations provide real‐world experience from neurology HCPs with experience in prescribing Epidiolex and can inform optimal use of Epidiolex for the treatment of seizures associated with LGS, DS, and TSC. Plain language summary: Epidiolex® (cannabidiol) is approved for treating seizures in Lennox–Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Although healthcare professionals have experience in treating patients with Epidiolex, there is a need for better understanding of dosing, drug interactions, and safety of this drug. Therefore, a group of epilepsy experts developed guidelines for best practices in Epidiolex treatment. Two main areas were identified: overcoming barriers to starting Epidiolex and considerations related to Epidiolex dosing. Within these areas, topics, including correct disease identification, managing adverse events, and determining individualized dose, were discussed. These guidelines provide real‐world experience to inform optimal Epidiolex use. [ABSTRACT FROM AUTHOR]