Faculty Bibliography

BACKGROUND:To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). METHODS:once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. RESULTS:Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. CONCLUSION/CONCLUSIONS:Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.

BACKGROUND:The terminology and classification of seizures and epilepsy has undergone multiple revisions in the last several decades, which can lead to confusion and miscommunication amongst physicians and researchers. In 2017, the International League Against Epilepsy (ILAE) revised the classification of both seizures and epilepsy types in an effort to use less ambiguous terminology. Over time, definitions for status epilepticus, febrile seizures, and neonatal seizures have also evolved, as has the delineation of various epilepsy syndromes by age. METHODS:Review of the literature for old and new terminology and various epilepsy syndromes was accomplished using the PubMed database system. RESULTS:In the following article, we review old terminology for classifying seizures and epilepsy as compared to the new (2017) ILAE guidelines. We discuss neonatal seizures, status epilepticus, febrile seizures, autoimmune epilepsy and various epilepsy syndromes by age of onset. CONCLUSION/CONCLUSIONS:Adopting a classification system that uses plain language allows for more effective and efficient communication between individuals and across specialties. Definitions of various syndromes and seizure types have evolved over time and are reviewed.

Deep brain stimulation (DBS) is a surgical treatment for advanced Parkinson's disease (PD) that has undergone technological evolution that parallels an expansion in clinical phenotyping, neurophysiology, and neuroimaging of the disease state. Machine learning (ML) has been successfully used in a wide range of healthcare problems, including DBS. As computational power increases and more data become available, the application of ML in DBS is expected to grow. We review the literature of ML in DBS and discuss future opportunities for such applications. Specifically, we perform a comprehensive review of the literature from PubMed, the Institute for Scientific Information's Web of Science, Cochrane Database of Systematic Reviews, and Institute of Electrical and Electronics Engineers' (IEEE) Xplore Digital Library for ML applications in DBS. These studies are broadly placed in the following categories: (1) DBS candidate selection; (2) programming optimization; (3) surgical targeting; and (4) insights into DBS mechanisms. For each category, we provide and contextualize the current body of research and discuss potential future directions for the application of ML in DBS.

An important need exists to better understand and stratify kidney disease according to its underlying pathophysiology in order to develop more precise and effective therapeutic agents. National collaborative efforts such as the Kidney Precision Medicine Project are working towards this goal through the collection and integration of large, disparate clinical, biological and imaging data from patients with kidney disease. Ontologies are powerful tools that facilitate these efforts by enabling researchers to organize and make sense of different data elements and the relationships between them. Ontologies are critical to support the types of big data analysis necessary for kidney precision medicine, where heterogeneous clinical, imaging and biopsy data from diverse sources must be combined to define a patient's phenotype. The development of two new ontologies - the Kidney Tissue Atlas Ontology and the Ontology of Precision Medicine and Investigation - will support the creation of the Kidney Tissue Atlas, which aims to provide a comprehensive molecular, cellular and anatomical map of the kidney. These ontologies will improve the annotation of kidney-relevant data, and eventually lead to new definitions of kidney disease in support of precision medicine.

We present a radiology-pathology case series of 3 patients with coronavirus disease 2019 (COVID-19) with acute ischemic stroke due to fulminant carotid thrombosis overlying mild atherosclerotic plaque and propose a novel stroke mechanism: COVID-associated carotid atherothrombosis.

OBJECTIVE:To evaluate whether multiple sessions of transcranial direct current stimulation (tDCS) applied to the primary motor (M1) cortex paired with aerobic exercise can improve walking functions in multiple sclerosis (MS). METHODS:MS participants were recruited for a double-blind, parallel-arm, randomized, sham-controlled trial and assigned to 10 sessions (5 d/wk for 2 weeks) of either active or sham tDCS paired with unloaded cycling for 20 minutes. Stimulation was administered over the left M1 cortex (2.5 mA; anode over C3/cathode over FP2). Gait spatiotemporal parameters were assessed using a wearable inertial sensor (10-meter and 2-minute walking tests). Measurements were collected at baseline, end of tDCS intervention, and 4-week postintervention to test for duration of any benefits. RESULTS:A total of 15 participants completed the study, nine in the active and six in the sham condition. The active and sham groups were matched according to gender (50% vs. 40% female), neurologic disability (median EDSS 5.5 vs. 5), and age (mean 52.1 ± 12.9 vs. 53.7 ± 9.8 years). The active group had a significantly greater increase in gait speed (0.87 vs. 1.20 m/s, p < 0.001) and distance covered during the 2-minute walking test (118.53 vs. 133.06 m, p < 0.001) at intervention end compared to baseline. At 4-week follow-up, these improvements were maintained (baseline vs. follow-up: gait speed 0.87 vs. 1.18 m/s, p < 0.001; distance traveled 118.53 vs. 143.82 m, p < 0.001). INTERPRETATION/CONCLUSIONS:Multiple sessions of tDCS paired with aerobic exercise lead to cumulative and persisting improvements in walking and endurance in patients with MS.

Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.