[Posted 26/Mar/2024]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: HCN4 provides a biomarker for the genetic spectrum of mTORopathies and may present a potential therapeutic target for seizure control in mTOR-related epilepsy.

BACKGROUND: Pathogenic variants in PI3K-AKT-mTOR pathway and GATOR1 complex genes resulting in hyperactivation of mechanistic target of rapamycin (mTOR) complex 1 are a major cause of drug-resistant epilepsy and focal cortical malformations (FCM). Resective neurosurgery is often required to achieve seizure control in patients with mTORopathies due to lack of effectiveness of nonsurgical therapies, including antiseizure medication and mTOR inhibitors. Elevated hyperpolarization-activated cyclic nucleotide-gated potassium channel isoform 4 (HCN4) has been proposed as a key marker in some mTOR-related brain malformations. This study aimed to investigate HCN4 as a biomarker in the brain across the genetic spectrum of mTORopathies in humans.

DETAILS: The study investigated the relative steady-state levels and cellular localization of HCN4 in resected human brain tissue from 18 individuals with mTORopathies (3 individuals with tuberous sclerosis complex (TSC) due to TSC2 variants, 5 individuals with focal cortical dysplasia type IIA (FCD IIA) due to genetic variants in MTOR, AKT3, and PIK3CA, and 10 individuals with FCD IIB due to variants in TSC1, MTOR, RHEB, DEPDC5, or NPRL3). Elevated HCN4 was observed to be highly restricted to abnormal cell types (dysmorphic neurons and balloon cells) in brain tissue from all mTORopathy tissues (p < 0.0001) compared with those in controls, regardless of genetic cause or variant allele frequency. Elevated HCN4 was not observed in controls or individuals with non-mTOR-related focal epilepsy due to pathogenic variants in ATP1A3, SLC35A2, or FGFR1.

Copyright © American Academy of Neurology. All Rights Reserved.

Source: Coleman, M., Pinaes-Garcia, P., Stephenson, S. E., et al. (2024). Ectopic HCN4 Provides a Target Biomarker for the Genetic Spectrum of mTORopathies. Neuro Genetics. 2024; 10(2). Published: March, 2024. DOI: 10.1212/NXG.0000000000200135.

A Multinational Self-Controlled Case Series Study

[Posted 2/Apr/2026]

AUDIENCE: Internal Medicine, Neurology

KEY FINDINGS: In this multinational SCCS study, statin initiation may be associated with increased risk of new-onset MG during the first 6-12 months, with greater magnitude of risk elevation for higher intensity statin therapy. Consideration of the possibility of new-onset MG may be advisable within first 6-12 months after initiating statins, especially for medium-to-high-intensity statin therapy.

BACKGROUND: Evidence regarding the risk of new-onset myasthenia gravis (MG) following statin therapy initiation is limited. Purpose of this study is to investigate this potential adverse effect using multinational real-world population-based data.

DETAILS: A self-controlled case series (SCCS) study was conducted using electronic medical records and claims databases from Hong Kong, the United Kingdom (UK) and Japan. Individuals aged >=18 years with first diagnosis of MG and initiated statins were included. Conditional Poisson regression compared the risk of MG in different risk periods (up to 2 years after initiation) with non-exposure period, adjusted for age. Pooled results based on meta-analysis across all study sites were reported. In total, 2267 MG cases were analysed. Combined across all study sites, a significantly increased risk of incident MG was observed during the first year after statin initiation compared to non-exposure period, with a higher risk from Days 0-179 (pooled incidence rate ratio [IRR] [95% CI]: 2.662 [1.276-5.553]) than Days 180-364 (1.407 [1.014-1.954]). No increased risk of MG was observed more than 1 year after statin initiation (1.011 [0.848-1.206]). Moreover, the magnitude of MG risk elevation within the first 180 days after statin initiation was more pronounced with higher intensity statin regimens.

Copyright © John Wiley & Sons, Inc. All rights reserved

Source: Ka Chun Yan, V., Xu, W., Taniguchi, Y., et al. Myasthenia Gravis Following the Initiation of Statin Therapy: A Multinational Self-Controlled Case Series Study. Journal of Internal Medicine. 2026; 299(4):502-514. Published: April, 2026. DOI: 10.1111/joim.70072Digital Object Identifier (DOI)

[Posted 24/Mar/2026]

AUDIENCE: Infectious Disease, Endocrinology

KEY FINDINGS: In patients with surgically treated OM, nanopore sequencing can generate interpretable metagenomic data from bone specimens that are culture concordant and associated with clinical response. These findings support the feasibility and plausibility of using real-time metagenomic sequencing to improve the clinical management of OM.

BACKGROUND: Tools to predict successful response to surgery for the treatment of diabetic foot osteomyelitis (OM) are currently lacking. Recent studies in nonbone infections have revealed that nanopore sequencing can provide real-time metagenomic identification of pathogens. In a cohort of patients with diabetic foot OM, we tested the feasibility of generating interpretable metagenomic data from surgically acquired osseous tissue, comparing bacterial community features (pathogen dominance) with clinical outcomes (resolution of infection). Researchers hypothesized that nanopore-generated microbial data can be feasibly generated from surgically acquired bone, aligns with conventional culture results, and is predictive of clinical response.

DETAILS: Researchers performed a pilot feasibility study of 10 consecutive patients hospitalized with diabetic foot OM who underwent surgery for OM. We performed metagenomic sequencing of surgical bone samples using the MinION (Oxford Nanopore). The primary metagenomic index was community dominance (relative abundance of most abundant species). The primary clinical end point was the clinical response to surgery, adjudicated at 1 year. Authors successfully generated interpretable metagenomic data from all 10 specimens, including 2 with negative culture growth. Among culture-positive specimens, the culture-identified pathogen was either the first or second most abundant organism in all cases. Patients with favorable clinical response exhibited greater pathogen dominance than those with unfavorable response (P = .002).

Copyright © The Authors. Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

Source: Schmidt, B. M., Ranjan, P., Erb-Downward, J., et al. Microbial Dominance in Diabetic Foot Osteomyelitis Determined With Nanopore Sequencing Techniques Predicts Positive Response to Surgical Intervention. The Journal of Infectious Disease. 2026; 233(3): 458-464. Published: March 15, 2026. DOI: 10.1093/infdis/jiaf617

A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials

[Posted 16/Mar/2026]

AUDIENCE: Dermatology, Oncology

KEY FINDINGS: This systematic review and meta-analysis highlight the risk of dyslipidemia during treatment with JAKi, which could pose cardiovascular risks. Thus, regular assessments of cardiovascular risk factors and routine lipid monitoring in patients undergoing JAKi therapy may be essential for managing dyslipidemia and evaluating long-term cardiovascular safety.

BACKGROUND: Janus kinase inhibitors (JAKi) have sparked a new era in the treatment of immune-mediated diseases. While some studies have reported an increased incidence of dyslipidemia in JAKi-treated patients, the full extent of this adverse event is not established. The study aimed to assess the association between treatment with oral JAKi and dyslipidemia in phases 2 and 3 placebo-controlled randomized clinical trials (RCTs).

DETAILS: Janus kinase inhibitors (JAKi) have sparked a new era in the treatment of immune-mediated diseases. While some studies have reported an increased incidence of dyslipidemia in JAKi-treated patients, the full extent of this adverse event is not established. The study aimed to assess the association between treatment with oral JAKi and dyslipidemia in phases 2 and 3 placebo-controlled randomized clinical trials (RCTs). A systematic review and meta-analysis were conducted, encompassing phase 2 and 3 RCTs. The Embase, PubMed, and Web of Science databases were searched up to March 9, 2025. Only RCTs reporting lipid levels before and after treatment with JAKi were included. Data were extracted for changes in high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG) with values reported in mg/dL. A total of 13 studies were included in the analysis, comprising nine studies on rheumatoid arthritis, two on atopic dermatitis, one on Crohn's disease, and one on psoriasis. The studies encompassed a total of 3978 patients treated with JAKi and 1680 controls. Across all indications, the mean difference between JAKi and placebo for individual drug, was increased by 6.07 mg/dL (95% confidence interval [CI], 5.01-7.14) for HDL and 9.05 mg/dL (95% CI, 7.78-10.32) for LDL for baricitinib; HDL 5.4 mg/dL (95% CI, 3.2-7.7) and LDL 12.4 mg/dL (95% CI, 8.9-15.9) for upadacitinib; HDL 7.0 mg/dL (95% CI, 5.7-8.3) and LDL 15.7 mg/dL (95% CI, 12.9-18.6) for tofacitinib; and lastly HDL 3.0 mg/dL (95% CI, 0.2-5.8) and LDL 14.9 mg/dL (95% CI, 3.6-26.3) for decernotinib.

Copyright © John Wiley & Sons Ltd. All rights reserved.

Source: Isufi, D., Javanmardi, N., Jense, M. B., et al. Risk of Dyslipidemia Associated With Oral Janus Kinase Inhibitors: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials. International Journal of Dermatology. 2026; 65: 737-745. Published: March, 2026. DOI: 10.1111/ijd.70122

[Posted 6/Mar/2026]

AUDIENCE: Pediatric, Neurology

KEY FINDINGS: The safety profile and initial clinical improvement support the continued development of zorevunersen as a potential disease-modifying treatment for Dravet syndrome.

BACKGROUND: Enrolled patients 2 to 18 years of age with Dravet syndrome who were receiving standard antiseizure medications in two phase 1-2a, open-label, multicenter studies (MONARCH and ADMIRAL). Patients were included in either a single-ascending-dose cohort, in which zorevunersen (10 to 70 mg) was administered on day 1 only, or a multiple-ascending-dose cohort, in which zorevunersen (20 to 70 mg) was administered two or three times in a 3-month period. Patients eligible for rollover to the two open-label extension studies (SWALLOWTAIL and LONGWING) continued to receive zorevunersen (<=45 mg) every 4 months. The safety and pharmacokinetics of zorevunersen were assessed in the primary analysis; clinical effects were also evaluated.

DETAILS: Dravet syndrome is a severe developmental and epileptic encephalopathy caused primarily by SCN1A haploinsufficiency. Risks of sudden unexpected death in epilepsy and cognitive deficits are higher among patients with this syndrome than in the general population with epilepsy. The effects of zorevunersen, an antisense oligonucleotide designed to up-regulate NaV1.1 sodium channels, in patients with Dravet syndrome are not known. A total of 81 patients were enrolled in the phase 1-2a studies. As of May 30, 2025, a total of 75 patients had entered the extension studies. Most adverse events were mild or moderate. The most common adverse event was post-lumbar puncture syndrome (in 25% of patients) in the phase 1-2a studies and was an elevated protein level in cerebrospinal fluid (in 45%) in the extension studies. One patient had suspected unexpected serious adverse reactions, 1 had an adverse event that led to study withdrawal, 2 died from sudden unexpected death in epilepsy, and 1 died from malnutrition. Patients who received 70 mg of zorevunersen (one, two, or three doses) in the phase 1-2a studies, followed by up to 45 mg in the extension studies, had a median change from baseline in convulsive-seizure frequency ranging from -58.82% to -90.91% across 1-month intervals during the first 20 months of the extension studies. The data supported improvements in overall clinical status, quality of life, and adaptive behavior with continued treatment for up to 36 months in the extension studies.

Copyright © Massachusetts Medical Society. All rights reserved.

Source: Laux, L., Sullivan, J., Perry, S., et al. Zorevunersen in Children and Adolescents with Dravet Syndrome. The New England Journal of Medicine. 2026; 394: 969-982. Published: March 4, 2026. DOI: 10.1056/NEJMoa2506295.

A Randomized Clinical Trial.

[Posted 4/Mar/2026]

AUDIENCE: XXXXX

KEY FINDINGS: Results of this randomized clinical trial reveal that TSND-201 demonstrated statistically significant efficacy and was well tolerated, supporting its potential as a rapid-acting, durable treatment for PTSD.

BACKGROUND:

DETAILS: A Study to Assess the Use of Methylone in the Treatment of PTSD (IMPACT-1) part B was a phase 2, multicenter, double-blind, placebo-controlled, 10-week randomized clinical trial of TSND-201 in people with PTSD conducted between November 29, 2023, and February 19, 2025, across 16 sites in the US, UK, and Ireland. Adults aged 18 to 65 years who met DSM-5 criteria for current PTSD and 6 months or more of symptoms (Clinician-Administered PTSD Scales for DSM-5 [CAPS-5] >=35) were eligible. Participants were randomized 1:1 to receive TSND-201 or placebo. There were 4 once-weekly oral dosing sessions (150 mg followed by 100 mg or placebo). No psychotherapy was provided; however, dosing sessions were monitored by mental health professionals using a nondirective approach. Participants were followed up for 6 weeks after the last dose. The primary end point was change from baseline to day 64 in the CAPS-5 total severity score. Secondary end points included changes in PTSD Checklist for DSM-5 (PCL-5), Sheehan Disability Scale (SDS), and Montgomery-Asberg Depression Rating Scale (MADRS) scores. Other measures included response (>=50% improvement from baseline), remission (<=11 total severity score), loss of PTSD diagnosis, changes in CAPS-5 symptom clusters, and incidence of treatment-emergent adverse events (TEAEs). Safety was assessed by monitoring adverse events, vital signs, and Columbia-Suicide Severity Rating Scale. Among the 65 participants (mean [SD] age, 43.7 [10.5] years; 39 female [60.0%]), TSND-201 demonstrated significantly greater improvement in CAPS-5 total score than placebo (least-squares mean difference, 9.64; 90% CI, -16.48 to -2.80; P = .01). PCL-5 (-28.46 vs -19.47; LS mean treatment difference, -8.99; 90% CI, -17.81 to -0.17), SDS (-8.29 vs -3.57; LS mean treatment difference, -4.72; 90% CI, -8.84 to -0.61), and MADRS (-13.94 vs -7.73; LS mean treatment difference, -6.21; 90% CI, -12.41 to -0.27) scores were also improved. Common TEAEs in the TSND-201 group included headache, decreased appetite, nausea, dizziness, blood pressure increased, dry mouth, insomnia.

Copyright © American Medical Association. All Rights Reserved.

Source: Jones, A., Warner-Schmidt,J., Kwak, H., et al. Efficacy and Safety of the Neuroplastogen TSND-201 for the Treatment of PTSD: A Randomized Clinical Trial. JAMA Psychiatry. 2026; Published: February 18, 2026. DOI: 10.1001/jamapsychiatry.2025.4625