This study aimed to implement genome sequencing using an automated pipeline for critically ill pediatric patients within a real-world healthcare system. Twenty patients under 36 months of age, admitted to the NICU/PICU or suspected of having rapidly progressive genetic disorders, were enrolled. Trio-based genome sequencing was performed using an optimized processing pipeline, which automatically performed mapping, variant calling, annotation, and in silico pathogenicity assessment. Among 20 enrolled patients, 11 (55%) were from the NICU, and 16 (80%) presented with neurological manifestations as their chief complaint. The median time from symptom onset to study enrollment was 73 days for 18 patients referred from other hospitals and less than a week for 2 in-hospital patients. The median turnaround time (TAT) for rWGS was 10 days, with the shortest being 5 days. A definite or presumed genetic diagnosis was made in 11 patients (55%), including 10 of 16 with neurological symptoms (62.5%) and 1 of 4 with non-neurologic symptoms (25%). Management plans were modified for 8 of the 11 patients (72.7%), including medication changes, diet modifications, and preimplantation genetic testing for future pregnancies. This study highlights the feasibility and clinical utility of WGS in critically ill pediatric patients in Korea, demonstrating a high diagnostic yield and significant impact on patient management, particularly among those presenting with neurologic symptoms. Establishing a nationwide fast-track system and providing detailed testing indications are required for effective implementation. Further automation and resource optimization could reduce the TAT and improve the efficacy of rWGS in critical care settings.
This study investigated the seizure recurrence rate and potential predictors of seizure recurrence following antiepileptic drug (AED) withdrawal after resective epilepsy surgery in children with focal cortical dysplasia (FCD).We retrospectively analyzed the records of 70 children and adolescents with FCD types I, II, and IIIa who underwent resective epilepsy surgery between 2004 and 2015 and were followed for at least 2 years after surgery.We attempted AED withdrawal in 40 patients. The median time of starting the AED reduction was 10.8 months after surgery. Of these 40 patients, 14 patients (35%) experienced seizure recurrence during AED reduction or after AED withdrawal. Half of the 14 patients who experienced recurrence regained seizure freedom after AED reintroduction and optimization. Compared with their preoperative status, the AED dose or number was decreased in 57.1% of patients, and remained unchanged in 14.3% after surgery. A multivariate analysis found that incomplete resection (p=0.004) and epileptic discharges on the postoperative EEG (p=0.025) were important predictors of seizure recurrence after AED withdrawal. Over the mean follow-up duration of 4.5 years after surgery, 34 patients (48.6% of the entire cohort) were seizure-free with and without AEDs.Children with incomplete resection and epileptic discharges on postoperative EEG are at a high risk of seizure recurrence after drug withdrawal. Complete resection of FCD may lead to a favorable surgical outcome and successful AED withdrawal after surgery.
The myelin oligodendrocyte glycoprotein (MOG) antibody is detected at a high rate in childhood acquired demyelinating syndrome (ADS). This study aimed to determine the diagnostic value of the MOG antibody in ADS and the spectrum of MOG-antibody-positive demyelinating diseases in children.This study included 128 patients diagnosed with ADS (n=94) or unexplained encephalitis (n=34). The MOG antibody in serum was tested using an in-house live-cell-based immunofluorescence assay.The MOG antibody was detected in 48 patients (46 ADS patients and 2 encephalitis patients, comprising 23 males and 25 females). Acute disseminated encephalomyelitis (ADEM) (35.4%) was the most-common diagnosis, followed by the unclassified form (17.4%), isolated optic neuritis (ON) (15.2%), neuromyelitis optica spectrum disorder (13.0%), multiple sclerosis (MS) (10.8%), other clinically isolated syndromes [monophasic event except ADEM, isolated ON, or transverse myelitis (TM)] (8.7%), and unexplained encephalitis (4.3%). At the initial presentation, 35 out of the 46 patients with ADS had brain lesions detected in magnetic resonance imaging, and 54% of these 35 patients had encephalopathy. Nine of the 11 patients without brain lesions exhibited only ON. Thirty-nine percent of the patients experienced a multiphasic event during the mean follow-up period of 34.9 months (range 1.4-169.0 months). Encephalopathy at the initial presentation was frequently confirmed in the monophasic group (p=0.011).MOG antibodies were identified in all pediatric ADS phenotypes except for monophasic TM. Therefore, the MOG antibody test is recommended for all pediatric patients with ADS, especially before a diagnosis of MS and for patients without a clear diagnosis.
Abstract Objective Antiseizure drugs (ASDs) are known to cause a wide range of adverse drug reactions (ADRs). Recently, electronic health care data using the common data model (CDM) have been introduced and commonly adopted in pharmacovigilance research. We aimed to analyze ASD‐related ADRs using CDM and to assess the feasibility of CDM analysis in monitoring ADR in a single tertiary hospital. Methods We selected five ASDs: oxcarbazepine (OXC), lamotrigine (LTG), levetiracetam (LEV), valproic acid (VPA), and topiramate (TPM). Patients diagnosed with epilepsy and exposed to monotherapy with one of the ASDs before age 18 years were included. We measured four ADR outcomes: (1) hematologic abnormality, (2) hyponatremia, (3) elevation of liver enzymes, and (4) subclinical hypothyroidism. We performed a subgroup analysis to exclude the effects of concomitant medications. Results From the database, 1344 patients were included for the study. Of the 1344 patients, 436 were receiving OXC, 293 were receiving LTG, 275 were receiving LEV, 180 were receiving VPA, and 160 were receiving TPM. Thrombocytopenia developed in 14.1% of patients taking VPA. Hyponatremia occurred in 10.5% of patients taking OXC. Variable ranges of liver enzyme elevation were detected in 19.3% of patients taking VPA. Subclinical hypothyroidism occurred in approximately 21.5% to 28% of patients with ASD monotherapy, which did not significantly differ according to the type of ASD. In a subgroup analysis, we observed similar ADR tendencies, but with less thrombocytopenia in the TPM group. Significance The incidence and trends of ADRs that were evaluated by CDM were similar to the previous literature. CDM can be a useful tool for analyzing ASD‐related ADRs in a multicenter study. The strengths and limitations of CDM should be carefully addressed.
The aim of this study was to expand the understanding of the genotype-phenotype spectrum of ATP1A3-related disorders and to evaluate the therapeutic effect of a ketogenic diet in patients with alternating hemiplegia of childhood (AHC).The clinical information of 13 patients with ATP1A3 mutations was analyzed by performing retrospective chart reviews. Patients with the AHC phenotype who consented to ketogenic diet were included in the trial.Ten patients presented with the clinical phenotype of AHC, two patients presented with rapid-onset dystonia parkinsonism, and one patient presented with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. Two novel mutations of the AHC phenotype were identified: p.Ile363Thr and p.Asn743Ser. The clinical phenotypes of three mutations differed from those in previous reports: p.Arg597Pro, p.Thr769Pro, and p.Arg756Cys. One of the two patients who started a ketogenic diet experienced seizure provocation and so immediate stopped consuming the diet, while the other patient continued the ketogenic diet for 1 year, but this produced no clear benefit such as reduction of paroxysmal symptoms.Our study is the first case series of ATP1A3-related disorders to be described in Korea and which further expands the understanding of its genotype-phenotype spectrum. A ketogenic diet showed no clear benefit for the patients with AHC.
We propose a reinforcement learning framework where an agent uses an internal nominal model for stochastic model predictive control (MPC) while compensating for a disturbance. Our work builds on the existing risk-aware optimal control with stochastic differential equations (SDEs) that aims to deal with such disturbance. However, the risk sensitivity and the noise strength of the nominal SDE in the riskaware optimal control are often heuristically chosen. In the proposed framework, the risk-taking policy determines the behavior of the MPC to be risk-seeking (exploration) or risk-averse (exploitation). Specifically, we employ the risk-aware path integral control that can be implemented as a Monte-Carlo (MC) sampling with fast parallel simulations using a GPU. The MC sampling implementations of the MPC have been successful in robotic applications due to their real-time computation capability. The proposed framework that adapts the noise model and the risk sensitivity outperforms the standard model predictive path integral in simulation environments that have disturbances.
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