Long-term neuropsychological outcomes in children with febrile infection-related epilepsy syndrome (FIRES) treated with anakinra.

Background: Febrile-infection related epilepsy syndrome (FIRES) is a rare epilepsy syndrome in which a previously healthy individual develops refractory status epilepticus in the setting of a preceding febrile illness. There are limited data regarding detailed long-term outcomes. This study aims to describe the long-term neuropsychological outcomes in a series of pediatric patients with FIRES. Methods: This is a retrospective multi-center case series of pediatric patients with a diagnosis of FIRES treated acutely with anakinra who had neuropsychological testing at least 12 months after status epilepticus onset. Each patient underwent comprehensive neuropsychological evaluation as part of routine clinical care. Additional data collection included the acute seizure presentation, medication exposures, and outcomes. Results: There were six patients identified with a median age of 11.08 years (IQR: 8.19-11.23) at status epilepticus onset. Anakinra initiation was a median of 11 days (IQR: 9.25-13.50) after hospital admission. All patients had ongoing seizures and none of the patients returned to baseline cognitive function with a median follow-up of 40 months (IQR 35-51). Of the five patients with serial full-scale IQ testing, three demonstrated a decline in scores over time. Testing results revealed a diffuse pattern of deficits across domains and all patients required special education and/or accommodations for academic learning. Conclusions: Despite treatment with anakinra, neuropsychological outcomes in this series of pediatric patients with FIRES demonstrated ongoing diffuse neurocognitive impairment. Future research will need to explore the predictors of long-term neurocognitive outcomes in patients with FIRES and to evaluate if acute treatment interventions improve these outcomes.

Network Effects of the 15q13.3 Microdeletion on the Transcriptome and Epigenome in Human-Induced Neurons.

BACKGROUND: The 15q13.3 microdeletion is associated with several neuropsychiatric disorders, including autism and schizophrenia. Previous association and functional studies have investigated the potential role of several genes within the deletion in neuronal dysfunction, but the molecular effects of the deletion as a whole remain largely unknown. METHODS: Induced pluripotent stem cells, from 3 patients with the 15q13.3 microdeletion and 3 control subjects, were generated and converted into induced neurons. We analyzed the effects of the 15q13.3 microdeletion on genome-wide gene expression, DNA methylation, chromatin accessibility, and sensitivity to cisplatin-induced DNA damage. Furthermore, we measured gene expression changes in induced neurons with CRISPR (clustered regularly interspaced short palindromic repeats) knockouts of individual 15q13.3 microdeletion genes. RESULTS: In both induced pluripotent stem cells and induced neurons, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Furthermore, we observed global effects of the microdeletion on the transcriptome and epigenome, with disruptions in several neuropsychiatric disorder-associated pathways and gene families, including Wnt signaling, ribosome function, DNA binding, and clustered protocadherins. Individual gene knockouts mirrored many of the observed changes in an overlapping fashion between knockouts. CONCLUSIONS: Our multiomics analysis of the 15q13.3 microdeletion revealed downstream effects in pathways previously associated with neuropsychiatric disorders and indications of interactions between genes within the deletion. This molecular systems analysis can be applied to other chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders.

Prevalence of Colistin-resistant Gram-negative Isolates Carrying the mcr-1 Gene among Patients Visiting a Tertiary Care Center.

INTRODUCTION: Gram-negative isolates harboring mobilized colistin resistance (mcr-1) gene are a great threat to human health. They have been reported worldwide among various bacterial isolates. This work aimed to study the prevalence of colistin resistance among Gram-negative bacteria and the incidence of mcr-1 gene among these isolates. METHODS: A descriptive cross-sectional study was done at a tertiary care center from June 2016 to February 2017. An ethical approval was taken from review board of the Nepal Health Research Council (Reg. no: 274/2016). Convenience sampling was used. The data was collected and analyzed using Microsoft Excel 2010 and Statistical Package for Social Sciences (SPSS) Version 16 . Point estimate at 95% Confidence Interval was calculated along with frequency and proportion for binary data. RESULTS: Among 485 gram-negative isolates, only 13 (2.68%) (1.26-6.62 at 95% Confidence Interval) isolates were colistin-resistant and mcr-1 was present in two isolates. Predominant colistin-resistant isolates were E. coli 6 (4.1%), Enterobacter spp 2 (2.81%), and Acinetobacter spp 2 (2.81%). A high level of colistin-resistance was noted in 4 (30.7%) isolates as indicated by the very high value of colistin MIC (>256 µg/ml). ICU was the major site of isolation of colistin-resistant and mcr-1 positive pathogens. The majority of colistin-resistant isolates were highly drug-resistant and were sensitive only to polymyxin B. Antibiotics like imipenem, amikacin, gentamicin, aztreonam, ciprofloxacin, and piperacillin-tazobactam were effective for few of these isolates. CONCLUSIONS: Though the prevalence of mcr-1 gene was low among colistin-resistant gram-negative isolates, the resistant pattern was quite alarming as these isolates were highly drug-resistant.