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Objective: Epilepsy surgery is vital in managing of children with drug-resistant epilepsy. Noninvasive and invasive testing modalities allow for evaluation and treatment of children with drug-resistant epilepsy. Evidence-based algorithms for this process do not exist. This study examines expert response to a vignette of pediatric nonlesional epilepsy to assess associations in evaluation and treatment choices., Methods: We analyzed annual report data and an epilepsy practice survey reported in 2020 from 135 pediatric epilepsy center directors in the United States. Characteristics of centers along with noninvasive and invasive testing and surgical treatment strategies were collected. Multivariable logistic regression modeling was performed., Results: The response rate was 100% with 135 responses included in the analyses. Most used noninvasive testing modalities included Neuropsychology evaluation (90%), interictal brain fluorodeoxyglucose-positron emission tomography (85%), and functional magnetic resonance imaging (MRI) (72%) with nearly half obtaining genetic testing. Choosing functional MRI was associated with stereo electroencephalography (EEG) ( P  = .025) and selecting Wada with subdural grid/strips ( P  = .038). Directors from pediatric-only centers were more likely to choose stereo EEG as opposed to combined centers ( P  = .042). Laser interstitial thermal therapy was almost 7 times as likely to be chosen as a treatment modality compared with open resection in dedicated pediatric centers (OR 6.96, P  = .002)., Significance: In a vignette of nonlesional childhood drug-resistant epilepsy, epilepsy center directors' patterns of noninvasive testing, invasive testing, and treatment were examined. Management choices were associated with pediatric versus combined pediatric/adult center characteristics. Expert opinions demonstrated equipoise in evaluation and management of children with drug-resistant epilepsy and the need for evidence-based management strategies., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Pregnant people with coronavirus disease 2019 (COVID-19) experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy., Methods: IMPAACT 2032 was a phase 4 prospective, open-label, nonrandomized opportunistic study of hospitalized pregnant and nonpregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks after last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and nonpregnant women were calculated., Results: Fifty-three participants initiated remdesivir (25 pregnant; median gestational age, 27.6 weeks; interquartile range, 24.9-31.0 weeks). Plasma exposures of remdesivir, its 2 major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and nonpregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI, 1.35-3.03) with each additional infusion in nonpregnant versus pregnant participants. Three adverse events in nonpregnant participants were related to treatment (1 grade 3; 2 grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected., Conclusions: Plasma remdesivir PK parameters were comparable between pregnant and nonpregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy., Clinical Trials Registration: NCT04582266., Competing Interests: Potential conflicts of interest. K. M. B. has received consulting fees from ViiV Healthcare. K. B. has received research support from Gilead Sciences, Inc and ViiV Healthcare paid to her institution. D. S. has received research support from Gilead Sciences, Inc, Merck, and ViiV Healthcare paid to his institution. A. A. serves on scientific advisory boards for Gilead Sciences, Inc and ViiV Healthcare; is a site principal investigator for a multisite and investigator-initiated studies with Gilead Sciences, Inc; and is a consultant for Merck. E. V. C. is serving on a data and safety monitoring board for Melinta Pharmaceuticals. D. E. Y. was previously an unpaid technical advisor for the nonprofit Cover the Globe and Maipelo Trust. M. M. has received research support from Gilead Sciences, Inc, Merck, and ViiV Healthcare paid to his institution. R. H. and K. K. are employees of Gilead Sciences, Inc and hold stock in the company. J. D. M. has received research support from Gilead Sciences, Inc paid to his institution. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: To develop a pragmatic twice daily lamivudine dosing strategy for preterm infants from 24 to 37 completed weeks of gestation., Methods: Data were combined from eight pharmacokinetic studies in neonates and infants receiving lamivudine oral solution. A population pharmacokinetic model was developed using non-linear mixed effects regression. Different lamivudine dosing strategies, stratified by gestational age at birth (GA) bands, were simulated in a virtual population of preterm infants, aimed at maintaining lamivudine drug exposures (AUC0-12) within a reference target range of 2.95 to 13.25 µg·h/mL, prior to switching to WHO-weight band doses when ≥4 weeks of age and weighing ≥3 kg., Results: A total of 154 infants (59% female) contributed 858 lamivudine plasma concentrations. Median (range) GA at birth was 38 (27-41) weeks. At the time of first pharmacokinetic sampling infants were older with median postnatal age (PNA) of 6.3 (0.52-26.6) weeks. Lamivudine concentrations were described by a one-compartment model, with CL/F and V/F allometrically scaled to weight. Maturation of CL/F was described using an Emax model based on PNA. CL/F was also adjusted on GA to allow extrapolation for extreme prematurity. Simulations predicted an optimal lamivudine dosing for infants GA ≥24 to <30 weeks of 2 mg/kg twice daily from birth until weighing 3 kg; and for GA ≥30 to <37 weeks, 2 mg/kg twice daily for the first 4 weeks of life, followed by 4 mg/kg twice daily until weighing 3 kg., Conclusions: Model-based predictions support twice daily pragmatic GA band dosing of lamivudine for preterm infants, but clinical validation is warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective : Epilepsy disproportionally affects children from Hispanic/Latino backgrounds, particularly among those born outside the U.S. Longstanding health-related disparities associated with ethnicity (e.g. language use) further contribute to gaps in care. Neuropsychologists are beginning to outline best practices when working with non-English speakers; however, the lack of appropriately normed/validated measures for pre-surgical language evaluation is a limiting factor. This report informs practices among neuropsychologists by discussing atypical language organization in a non-English speaker using a multicultural framework and collaborative therapeutic assessment process. Method : The current study presents a 16-year-old, right-handed, monolingual Spanish-speaking, Latina designated female with drug-resistant focal seizures with impaired awareness. Comprehensive presurgical epilepsy workup included: CBC, video EEG, brain MRI, functional MRI, PET, MEG, baseline neuropsychological evaluation by bilingual Spanish-English providers, and Wada testing. Results : Neuropsychological testing revealed the most pronounced deficits in language, working memory, and processing speed domains. Functional MRI showed bilateral language activation, which Wada testing confirmed along with bilateral memory representation. Conclusion : Diagnosis, treatment, surgical intervention, and post-operative status are discussed. The clinical course is examined through a multicultural lens, highlighting limitations in international health services, barriers accessing health care in the U.S., and patient-specific factors that were considered as a part of the clinical decision-making process. Targeted recommendations related to culturally-informed care are offered.

Cognitive, behavioral, and disease traits are influenced by both genetic and environmental factors. Individual differences in these traits have been associated with graph theoretical properties of resting-state networks, indicating that variations in connectome topology may be driven by genetics. In this study, we establish the heritability of global and local graph properties of resting-state networks derived from functional MRI (fMRI) and magnetoencephalography (MEG) using a large sample of twins and non-twin siblings from the Human Connectome Project. We examine the heritability of MEG in the source space, providing a more accurate estimate of genetic influences on electrophysiological networks. Our findings show that most graph measures are more heritable for MEG compared to fMRI and the heritability for MEG is greater for amplitude compared to phase synchrony in the delta, high beta, and gamma frequency bands. This suggests that the fast neuronal dynamics in MEG offer unique insights into the genetic basis of brain network organization. Furthermore, we demonstrate that brain network features can serve as genetic fingerprints to accurately identify pairs of identical twins within a cohort. These results highlight novel opportunities to relate individual connectome signatures to genetic mechanisms underlying brain function., (© 2024. The Author(s).)

Introduction: Digital measures and digital health-care delivery have been rarely implemented in lower-and-middle-income countries (LMICs), contributing to worsening global disparities and inequities. Sustainable ways to implement and use digital approaches will help to improve time to access, management, and quality of life in persons with epilepsy, goals that remain unreachable in under-resourced communities. As under-resourced environments differ in human and economic resources, no one approach will be appropriate to all LMICs., Areas Covered: Digital health and tools to monitor and measure digital endpoints and metrics of quality of life will need to be developed or adapted to the specific needs of under-resourced areas. Portable technologies may partially address the urban-rural divide. Careful delineation of stakeholders and their engagement and alignment in all efforts is critically important if these initiatives are to be successfully sustained. Privacy issues, neglected in many regions globally, must be purposefully addressed., Expert Opinion: Epilepsy care in under-resourced environments has been limited by the lack of relevant technologies for diagnosis and treatment. Digital biomarkers, and investigative technological advances, may finally make it feasible to sustainably improve care delivery and ultimately quality of life including personalized epilepsy care.

Introduction: Between 20 and 40% of patients with epilepsy are considered pharmacoresistant. Stereoelectroencephalography (sEEG) is frequently used as an invasive method for localizing seizures in patients with pharmacoresistant epilepsy who are surgical candidates; however, electrode nomenclature varies widely across institutions. This lack of standardization can have many downstream consequences, including difficulty with intercenter or intracenter interpretation, communication, and reliability., Methods: The authors propose a novel sEEG nomenclature that is both intuitive and comprehensive. Considerations include clear/precise entry and target anatomical locations, laterality, distinction of superficial and deep structures, functional mapping, and relative labeling of electrodes in close proximity if needed. Special consideration was also given to electrodes approximating radiographically distinct lesions. The accuracy of electrode identification and the use of correct entry-target labels were assessed by neurosurgeons and epileptologists, not directly involved in each case., Results: The authors' nomenclature was used in 41 consecutive sEEG cases (497 electrodes total) within their institution. After reconstruction was complete, the accuracy of electrode identification was 100%, and the correct use of entry-target labels was 98%. The last 30 sEEG cases had 100% correct use of entry-target labels., Conclusions: The proposed sEEG nomenclature demonstrated both high accuracy in electrode identification and consistent use of entry-target labeling. The authors submit this nomenclature as a model for standardization across epilepsy surgery centers. They intend to improve practicability, ease of use, and specificity of this nomenclature through collaboration with other surgical epilepsy centers., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 by the American Clinical Neurophysiology Society.)

The National Association of Epilepsy Centers first published the guidelines for epilepsy centers in 1990, which were last updated in 2010. Since that update, epilepsy care and the science of guideline development have advanced significantly, including the importance of incorporating a diversity of stakeholder perspectives such as those of patients and their caregivers. Currently, despite extensive published data examining the efficacy of treatments and diagnostic testing for epilepsy, there remain significant gaps in data identifying the essential services needed for a comprehensive epilepsy center and the optimal manner for their delivery. The trustworthy consensus-based statements (TCBS) process produces unbiased, scientifically valid guidelines through a transparent process that incorporates available evidence and expert opinion. A systematic literature search returned 5937 relevant studies from which 197 articles were retained for data extraction. A panel of 41 stakeholders with diverse expertise evaluated this evidence and drafted recommendations following the TCBS process. The panel reached consensus on 52 recommendations covering services provided by specialized epilepsy centers in both the inpatient and outpatient settings in major topic areas including epilepsy monitoring unit care, surgery, neuroimaging, neuropsychology, genetics, and outpatient care. Recommendations were informed by the evidence review and reflect the consensus of a broad panel of expert opinions.

Background and Objectives: The American Academy of Neurology has developed quality measures related to various neurologic disorders. A gap exists in the implementation of these measures in the different health care systems. To date, there has been no electronic health care record nor implementation of quality measures in Antigua. Therefore, we aimed to increase the percent of patients who have epilepsy quality measures documented using standardized common data elements in the outpatient neurology clinic at Sir Lester Bird Medical Center from 0% to 80% per week by June 1, 2022 and sustain for 6 months., Methods: We used the Institute for Health care Improvement Model for Improvement methodology. A data use agreement was implemented. Data were displayed using statistical process control charts and the American Society for Quality criteria to determine statistical significance and centerline shifts., Results: Current and future state process maps were developed to determine areas of opportunity for interventions. Interventions were developed following a "Plan-Do-Study-Act cycle." One intervention was the creation of a RedCap survey and database to be used by health care providers during clinical patient encounters. Because of multiple interventions, we achieved a 100% utilization of the survey for clinical care., Discussion: Quality improvement (QI) methodology can be used for implementation of quality measures in various settings to improve patient care outcomes without use of significant resources. Implementation of quality measures can increase efficiency in clinical delivery. Similar QI methodology could be implemented in other resource-limited countries of the Caribbean and globally., Competing Interests: The authors report no relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp. TAKE-HOME POINTS → Epilepsy and Child Neurology quality measures were created by workgroups led by the American Academy of Neurology.→ A framework can be created to use quality improvement in neurology practices caring for people with epilepsy.→ Creation and implementation of standardized data entry around important quality measures in epilepsy be implemented in countries outside the United States., (© 2023 American Academy of Neurology.)

Objective: An epilepsy monitoring unit (EMU) is a specialized unit designed for capturing and characterizing seizures and other paroxysmal events with continuous video electroencephalography (vEEG). Nearly 260 epilepsy centers in the United States are accredited by the National Association of Epilepsy Centers (NAEC) based on adherence to specific clinical standards to improve epilepsy care, safety, and quality. This study examines EMU staffing, safety practices, and reported outcomes., Method: We analyzed NAEC annual report data and results from a supplemental survey specific to EMU practices reported in 2019 from 341 pediatric or adult center directors. Data on staffing, resources, safety practices and complications were collated with epilepsy center characteristics. We summarized using frequency (percentage) for categorical variables and median (inter-quartile range) for continuous variables. We used chi-square or Fisher's exact tests to compare staff responsibilities., Results: The supplemental survey response rate was 100%. Spell classification (39%) and phase 1 testing (28%) were the most common goals of the 91,069 reported admissions. The goal ratio of EEG technologist to beds of 1:4 was the most common during the day (68%) and off-hours (43%). Compared to residents and fellows, advanced practice providers served more roles in the EMU at level 3 or pediatric-only centers. Status epilepticus (SE) was the most common reported complication (1.6% of admissions), while cardiac arrest occurred in 0.1% of admissions., Significance: EMU staffing and safety practices vary across US epilepsy centers. Reported complications in EMUs are rare but could be further reduced, such as with more effective treatment or prevention of SE. These findings have potential implications for improving EMU safety and quality care., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The single equivalent current dipole (sECD) is the standard clinical procedure for presurgical language mapping in epilepsy using magnetoencephalography (MEG). However, the sECD approach has not been widely used in clinical assessments, mainly because it requires subjective judgements in selecting several critical parameters. To address this limitation, we developed an automatic sECD algorithm (AsECDa) for language mapping., Methods: The localization accuracy of the AsECDa was evaluated using synthetic MEG data. Subsequently, the reliability and efficiency of AsECDa were compared to three other common source localization methods using MEG data recorded during two sessions of a receptive language task in 21 epilepsy patients. These methods include minimum norm estimation (MNE), dynamic statistical parametric mapping (dSPM), and dynamic imaging of coherent sources (DICS) beamformer., Results: For the synthetic single dipole MEG data with a typical signal-to-noise ratio, the average localization error of AsECDa was less than 2 mm for simulated superficial and deep dipoles. For the patient data, AsECDa showed better test-retest reliability (TRR) of the language laterality index (LI) than MNE, dSPM, and DICS beamformer. Specifically, the LI calculated with AsECDa revealed excellent TRR between the two MEG sessions across all patients (Cor = 0.80), while the LI for MNE, dSPM, DICS-event-related desynchronization (ERD) in the alpha band, and DICS-ERD in the low beta band ranged lower (Cor = 0.71, 0.64, 0.54, and 0.48, respectively). Furthermore, AsECDa identified 38% of patients with atypical language lateralization (i.e., right lateralization or bilateral), compared to 73%, 68%, 55%, and 50% identified by DICS-ERD in the low beta band, DICS-ERD in the alpha band, MNE, and dSPM, respectively. Compared to other methods, AsECDa's results were more consistent with previous studies that reported atypical language lateralization in 20-30% of epilepsy patients., Discussion: Our study suggests that AsECDa is a promising approach for presurgical language mapping, and its fully automated nature makes it easy to implement and reliable for clinical evaluations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer IM declared a past co-authorship with the author DC to the handling editor., (Copyright © 2023 Babajani-Feremi, Pourmotabbed, Schraegle, Calley, Clarke and Papanicolaou.)

Objective: The evaluation to determine candidacy and treatment for epilepsy surgery in persons with drug-resistant epilepsy (DRE) is not uniform. Many non-invasive and invasive tests are available to ascertain an appropriate treatment strategy. This study examines expert response to clinical vignettes of magnetic resonance imaging (MRI)-positive lesional focal cortical dysplasia in both temporal and extratemporal epilepsy to identify associations in evaluations and treatment choice., Methods: We analyzed annual report data and a supplemental epilepsy practice survey reported in 2020 from 206 adult and 136 pediatric epilepsy center directors in the United States. Non-invasive and invasive testing and surgical treatment strategies were compiled for the two scenarios. We used chi-square tests to compare testing utilization between the two scenarios. Multivariable logistic regression modeling was performed to assess associations between variables., Results: The supplemental survey response rate was 100% with 342 responses included in the analyses. Differing testing and treatment approaches were noted between the temporal and extratemporal scenarios such as chronic invasive monitoring selected in 60% of the temporal scenario versus 93% of the extratemporal scenario. Open resection was the most common treatment choice; however, overall treatment choices varied significantly (p < .001). Associations between non-invasive testing, invasive testing, and treatment choices were present in both scenarios. For example, in the temporal scenario stereo-electroencephalography (SEEG) was more commonly associated with fluorodeoxyglucose-positron emission tomography (FDG-PET) (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.06-3.29; p = .033), magnetoencephalography (MEG) (OR 2.90; 95% CI 1.60-5.28; p = <.001), high density (HD) EEG (OR 2.80; 95% CI 1.27-6.24; p = .011), functional MRI (fMRI) (OR 2.17; 95% CI 1.19-4.10; p = .014), and Wada (OR 2.16; 95% CI 1.28-3.66; p = .004). In the extratemporal scenario, choosing SEEG was associated with increased odds of neuromodulation over open resection (OR 3.13; 95% CI 1.24-7.89; p = .016)., Significance: In clinical vignettes of temporal and extratemporal lesional DRE, epilepsy center directors displayed varying patterns of non-invasive testing, invasive testing, and treatment choices. Differences in practice underscore the need for comparative trials for the surgical management of DRE., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Objective: Nearly one-third of persons with epilepsy will continue having seizures despite trialing multiple antiseizure medications. Epilepsy surgery may be beneficial in these cases, and evaluation at a comprehensive epilepsy center is recommended. Numerous palliative and potentially curative approaches exist, and types of surgery performed may be influenced by center characteristics. This article describes epilepsy center characteristics associated with epilepsy surgery access and volumes in the United States., Methods: We analyzed National Association of Epilepsy Centers 2019 annual report and supplemental survey data obtained with responses from 206 adult epilepsy center directors and 136 pediatric epilepsy center directors in the United States. Surgical treatment volumes were compiled with center characteristics, including US Census region. We used multivariable modeling with zero-inflated Poisson regression models to present ORs and incidence rate ratios of receiving a given surgery type based on center characteristics., Results: The response rate was 100% with individual element missingness less than 4% across 352 observations undergoing univariate analysis. Multivariable models included 319 complete observations. Significant regional differences were present. The rates of laser interstitial thermal therapy (LITT) were lower at centers in the Midwest (incidence rate ratio [IRR] 0.74, 95% CI 0.59-0.92; p = 0.006) and Northeast (IRR 0.77, 95% CI 0.61-0.96; p = 0.022) compared with those in the South. Conversely, responsive neurostimulation implantation rates were higher in the Midwest (IRR 1.45, 95% CI 1.1-1.91; p = 0.008) and West (IRR 1.91, 95% CI 1.49-2.44; p < 0.001) compared with the South. Center accreditation level, institution type, demographics, and resources were also associated with variations in access and rates of potentially curative and palliative surgical interventions., Discussion: Epilepsy surgery procedure volumes are influenced by US epilepsy center region and other characteristics. These variations may affect access to specific surgical treatments for persons with drug resistant epilepsy across the United States., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose: In February 2021 a series of winter storms caused power outages for nearly 10 million people in the United States, Northern Mexico and Canada. In Texas, the storms caused the worst energy infrastructure failure in state history, leading to shortages of water, food and heat for nearly a week. Impacts on health and well-being from natural disasters are greater in vulnerable populations such as individuals with chronic illnesses, for example due to supply chain disruptions. We aimed to determine the impact of the winter storm on our patient population of children with epilepsy (CWE)., Methods: We conducted a survey of families with CWE that are being followed at Dell Children's Medical Center in Austin, Texas., Results: Of the 101 families who completed the survey, 62% were negatively affected by the storm. Twenty-five percent had to refill antiseizure medications during the week of disruptions, and of those needing refills, 68% had difficulties obtaining the medications, leading to nine patients-or 36% of those needing a refill-running out of medications and two emergency room visits because of seizures and lack of medications., Conclusions: Our results demonstrate that close to 10% of all patients included in the survey completely ran out of antiseizure medications, and many more were affected by lack of water, heat, power and food. This infrastructure failure emphasizes the need for adequate disaster preparation for vulnerable populations such as children with epilepsy for the future., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: The impact of pandemic has had worse effects in countries with already stretched healthcare resources. study's The study aimed to explore changes in epilepsy care delivery in resource-limited countries during and since the acute phase of the COVID-19 pandemic., Method: A cross-sectional survey was conducted in 22 countries among healthcare providers (HCPs) caring for persons with epilepsy (PWE), in collaboration with newly formed global collaborators, the International Epilepsy Equity Group. Findings were compared based on the World Bank Ranking (WBR) and HCPs' practice type. Data were analyzed using Chi-square tests (α = 0.05) and pairwise multiple comparisons with α = 0.017 (Bonferroni adjustment). Open-ended responses were analyzed using thematic analysis., Findings: A total of 241 HCPs participated in the study. Of these, 8.30%, 65.98%, and 21.99% were from high-income (HIC), upper-middle-income (UMIC), and lower-middle-income countries (LMICs), respectively. Among HCPs, 31.12% were adult specialists, and 43.98% were pediatric specialists. During the acute phase of the pandemic, HCPs reported that the major barrier for PWE was difficulty reaching physicians/healthcare providers. Except for difficulty reaching physicians/healthcare providers (WBR P = 0.01 HIC < LMIC), no other significant differences in barriers during the acute phase were observed. Since the acute phase of the pandemic, the major concern for PWE was fear of getting infected with the SARS-CoV-2 virus. Significant differences in concerns since the acute phase included lockdowns (WBR: P = 0.03 UMIC < LMIC), fiscal difficulties (WBR: P < 0.001 UMICs < LMICs, UMICs < HIC; practice type: P = 0.006 adult < others, pediatrics < others), clinic closure (WBR: P = 0.003 UMIC < HIC; practice type: P =< 0.001 adult < others, pediatric < others), and long waiting times (WBR: P = 0.005, LMIC < UMIC, LMIC < HIC; practice type: P = 0.006 pediatric < adults). Diagnostic services, including EEG, MRI, CT (practice type: P < 0.001, adult < others; pediatric < others), and lab work (WBR: P = 0.01 UMIC < HIC), were restricted. The telephone was the most reported teleconsultation method used. Except for SMS/texting (WBR P = 0.02 UMIC < LMIC), there were no significant differences in teleconsultation methods used., Discussion: There is a high probability that the initial wave and consequent reduction of in-person care, restriction of health services, and fiscal difficulties affecting all involved in care delivery, led to the disruption of epilepsy care. Additional support are needed in resource-limited countries to cope with future pandemics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Persons with drug-resistant epilepsy may benefit from epilepsy surgery and should undergo presurgical testing to determine potential candidacy and appropriate intervention. Institutional expertise can influence use and availability of evaluations and epilepsy surgery candidacy. This census survey study aims to examine the influence of geographic region and other center characteristics on presurgical testing for medically intractable epilepsy., Methods: We analyzed annual report and supplemental survey data reported in 2020 from 206 adult epilepsy center directors and 136 pediatric epilepsy center directors in the United States. Test utilization data were compiled with annual center volumes, available resources, and US Census regional data. We used Wilcoxon rank-sum, Kruskal-Wallis, and chi-squared tests for univariate analysis of procedure utilization. Multivariable modeling was also performed to assign odds ratios (ORs) of significant variables., Results: The response rate was 100% with individual element missingness < 11% across 342 observations undergoing univariate analysis. A total of 278 complete observations were included in the multivariable models, and significant regional differences were present. For instance, compared to centers in the South, those in the Midwest used neuropsychological testing (OR = 2.87, 95% confidence interval [CI] = 1.2-6.86; p = .018) and fluorodeoxyglucose-positron emission tomography (OR = 2.74, 95% CI = = 1.14-6.61; p = .025) more commonly. For centers in the Northeast (OR = .46, 95% CI = .23-.93; p = .031) and West (OR = .41, 95% CI = .19-.87; p = .022), odds of performing single-photon emission computerized tomography were lower by nearly 50% compared to those in the South. Center accreditation level, demographics, volume, and resources were also associated with varying individual testing rates., Significance: Presurgical testing for drug-resistant epilepsy is influenced by US geographic region and other center characteristics. These findings have potential implications for comparing outcomes between US epilepsy centers and may inject disparities in access to surgical treatment., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Objectives: Persons with epilepsy, especially those with drug resistant epilepsy (DRE), may benefit from inpatient services such as admission to the epilepsy monitoring unit (EMU) and epilepsy surgery. The COVID-19 pandemic caused reductions in these services within the US during 2020. This article highlights changes in resources, admissions, and procedures among epilepsy centers accredited by the National Association of Epilepsy Centers (NAEC)., Methods: We compared data reported in 2019, prior to the COVID-19 pandemic, and 2020 from all 260 level 3 and level 4 NAEC accredited epilepsy centers. Data were described using frequency for categorical variables and median for continuous variables and were analyzed by center level, center population category, and geographical location. Qualitative responses from center directors to questions regarding the impact from COVID-19 were summarized utilizing thematic analysis. Responses from the NAEC center annual reports as well as a supplemental COVID-19 survey were included., Results: EMU admissions declined 23% (-21,515) in 2020, with largest median reductions in level 3 centers [-55 admissions (-44%)] and adult centers [-57 admissions (-39%)]. The drop in admissions was more substantial in the East North Central, East South Central, Mid Atlantic, and New England US Census divisions. Survey respondents attributed reduced admissions to re-assigning EMU beds, restrictions on elective admissions, reduced staffing, and patient reluctance for elective admission. Treatment surgeries declined by 371 cases (5.7%), with the largest reduction occurring in VNS implantations [-486 cases (-19%)] and temporal lobectomies [-227 cases (-16%)]. All other procedure volumes increased, including a 35% (54 cases) increase in corpus callosotomies., Discussion: In the US, access to care for persons with epilepsy declined during the COVID-19 pandemic in 2020. Adult patients, those relying on level 3 centers for care, and many persons in the eastern half of the US were most affected., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Prior studies have used graph analysis of resting-state magnetoencephalography (MEG) to characterize abnormal brain networks in neurological disorders. However, a present challenge for researchers is the lack of guidance on which network construction strategies to employ. The reproducibility of graph measures is important for their use as clinical biomarkers. Furthermore, global graph measures should ideally not depend on whether the analysis was performed in the sensor or source space. Therefore, MEG data of the 89 healthy subjects of the Human Connectome Project were used to investigate test-retest reliability and sensor versus source association of global graph measures. Atlas-based beamforming was used for source reconstruction, and functional connectivity (FC) was estimated for both sensor and source signals in six frequency bands using the debiased weighted phase lag index (dwPLI), amplitude envelope correlation (AEC), and leakage-corrected AEC. Reliability was examined over multiple network density levels achieved with proportional weight and orthogonal minimum spanning tree thresholding. At a 100% density, graph measures for most FC metrics and frequency bands had fair to excellent reliability and significant sensor versus source association. The greatest reliability and sensor versus source association was obtained when using amplitude metrics. Reliability was similar between sensor and source spaces when using amplitude metrics but greater for the source than the sensor space in higher frequency bands when using the dwPLI. These results suggest that graph measures are useful biomarkers, particularly for investigating functional networks based on amplitude synchrony., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Objectives: Patients with drug-resistant epilepsy (DRE) may benefit from specialized testing and treatments to better control seizures and improve quality of life. Most evaluations and procedures for DRE in the United States are performed at epilepsy centers accredited by the National Association of Epilepsy Centers (NAEC). On an annual basis, the NAEC collects data from accredited epilepsy centers on hospital-based epilepsy monitoring unit (EMU) size and admissions, diagnostic testing, surgeries, and other services. This article highlights trends in epilepsy center services from 2012 through 2019., Methods: We analyzed data reported in 2012, 2016, and 2019 from all level 3 and level 4 NAEC accredited epilepsy centers. Data were described using frequency for categorical variables and median for continuous variables and were analyzed by center level and center population category. EMU beds, EMU admissions, epileptologists, and aggregate procedure volumes were also described using rates per population per year., Results: During the period studied, the number of NAEC accredited centers increased from 161 to 256, with the largest increases in adult- and pediatric-only centers. Growth in EMU admissions (41%), EMU beds (26%), and epileptologists (109%) per population occurred. Access to specialized testing and services broadly expanded. The largest growth in procedure volumes occurred in laser interstitial thermal therapy (LiTT) (61%), responsive neurostimulation (RNS) implantations (114%), and intracranial monitoring without resection (152%) over the study period. Corpus callosotomies and vagus nerve stimulator (VNS) implantations decreased (-12.8% and -2.4%, respectively), while growth in temporal lobectomies (5.9%), extratemporal resections (11.9%), and hemispherectomies/otomies (13.1%) lagged center growth (59%), leading to a decrease in median volumes of these procedures per center., Discussion: During the study period, the availability of specialty epilepsy care in the United States improved as the NAEC implemented its accreditation program. Surgical case complexity increased while aggregate surgical volume remained stable or declined across most procedure types, with a corresponding decline in cases per center. This article describes recent data trends and current state of resources and practice across NAEC member centers and identifies several future directions for driving systematic improvements in epilepsy care., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: A knowledge gap exists for dolutegravir (DTG) pharmacokinetics and safety during the first 4 weeks of life, preventing safe and effective DTG use in neonates., Setting: Population pharmacokinetic modeling and simulation were used to assess newborn DTG dosing requirements during the first few days of life as a function of maternal DTG dosing history before delivery., Methods: DTG PK data were obtained from pregnant women and infants enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026S study. Maternal and neonate population pharmacokinetic models were separately developed. Monte Carlo simulations were performed to simulate neonatal concentrations after 2 doses of DTG after birth for infants born to mothers either receiving or not receiving DTG before delivery., Results: In DTG-naïve infants, a 5-mg DTG dose at birth with a second dose after 48 hours maintained median concentrations above the lower bound of the target range (0.77 μg/mL) and below the upper bound of the target range (7.34 μg/mL representing 2-fold above the adult Cmax value). In DTG-exposed infants, a 5-mg DTG dose at 24 hours after birth with a second dose after 48 hours maintained median concentrations within or nearly within the target range, even if the last maternal DTG dose was taken as soon as 6 hours or as long as 24 hours before delivery., Conclusions: Newborn DTG dosing requirements during the first few days of life depend on maternal DTG dosing history before delivery. These results may help the design of future clinical studies of DTG in the neonatal population., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Data from 2 generations of participants in the San Diego Prospective Study (SDPS) were used to compare cross-sectional and prospective relationships of 5 measures of the low level of response (low LR) to alcohol to 2 key alcohol-related outcomes., Methods: The analyses used data from 373 SDPS male probands and 158 male and female offspring of these individuals to evaluate relationships of 5 LR measures to the prior 5-year maximum drinks per occasion and the number of 11 DSM-IV alcohol use disorder (AUD) criteria experienced. Probands' LR measures included responses to alcohol challenges administered 15 years previously, and ratings for both generations included measures of the number of standard drinks during four periods: the first five times of drinking (SRE-5), the prior three drinking months (SRE-3), the period of heaviest drinking (SRE-H), and a total average across all time frames (SRE-T). Analyses included zero-order correlations, correlations using covariates, and hierarchical multiple regression analyses., Results: All 5 LR measures were correlated with aspects of maximum drinks and the number of AUD criteria, but the most robust results were seen for SRE-3 and maximum drinks. Correlations were less consistent for SRE-5, a measure more closely related to outcomes in the offspring. Hierarchical regression analyses supported most of these conclusions and showed that alcohol challenge-based LRs added significant information regarding maximum drinks even when evaluated with SRE values. The close correlation between SRE-H and SRE-T argues against the need for studies to include both measures. The patterns of results were similar irrespective of whether covariates were included., Conclusions: There were significant correlations of maximum drinks and the number of AUD criteria with findings from prior alcohol challenges and all SRE scores. Challenges and SRE reports are related but not identical LR measures. All SRE scores, including SRE-5, offered useful information regarding subsequent drinking behavior., (© 2021 by the Research Society on Alcoholism.)

Pediatric human immunodeficiency virus post-exposure prophylaxis is frequently indicated, but delays in medication receipt are common. Using plan-do-study-act cycles, we developed a multidisciplinary collaboration to reduce critical process delays in our pediatric emergency department. Interruptions decreased from a median 1 per month pre-intervention to zero per month during the intervention., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Common data elements (CDEs) are standardized questions and answer choices that allow aggregation, analysis, and comparison of observations from multiple sources. Clinical CDEs are foundational for learning health care systems, a data-driven approach to health care focused on continuous improvement of outcomes. We aimed to create clinical CDEs for pediatric epilepsy., Methods: A multiple stakeholder group (clinicians, researchers, parents, caregivers, advocates, and electronic health record [EHR] vendors) developed clinical CDEs for routine care of children with epilepsy. Initial drafts drew from clinical epilepsy note templates, CDEs created for clinical research, items in existing registries, consensus documents and guidelines, quality metrics, and outcomes needed for demonstration projects. The CDEs were refined through discussion and field testing. We describe the development process, rationale for CDE selection, findings from piloting, and the CDEs themselves. We also describe early implementation, including experience with EHR systems and compatibility with the International League Against Epilepsy classification of seizure types., Results: Common data elements were drafted in August 2017 and finalized in January 2020. Prioritized outcomes included seizure control, seizure freedom, American Academy of Neurology quality measures, presence of common comorbidities, and quality of life. The CDEs were piloted at 224 visits at 10 centers. The final CDEs included 36 questions in nine sections (number of questions): diagnosis (1), seizure frequency (9), quality of life (2), epilepsy history (6), etiology (8), comorbidities (2), treatment (2), process measures (5), and longitudinal history notes (1). Seizures are categorized as generalized tonic-clonic (regardless of onset), motor, nonmotor, and epileptic spasms. Focality is collected as epilepsy type rather than seizure type. Seizure frequency is measured in nine levels (all used during piloting). The CDEs were implemented in three vendor systems. Early clinical adoption included 1294 encounters at one center., Significance: We created, piloted, refined, finalized, and implemented a novel set of clinical CDEs for pediatric epilepsy., (© 2020 International League Against Epilepsy.)

Background: Pediatric refractory epilepsy affects quality of life, clinical disability, and healthcare costs for patients and families., Objective: To show the impact of surgical treatment for pediatric epilepsy on healthcare utilization compared to medically treated pediatric epilepsy over 5 yr., Methods: The Pediatric Health Information System database was used to conduct a cohort study using 5 published algorithms. Refractory epilepsy patients treated with antiepileptic medications (AEDs) only or AEDs plus epilepsy surgery between 1/1/2008 and 12/31/2014 were included. Healthcare utilization following the index date at 2 and 5 yr including inpatient, emergency department (ED), and all epilepsy-related visits were evaluated. The propensity scores (PS) method was used to match surgically and medically treated patients. PS. SAS® 9.4 and Stata 14.0 were used for data management and statistical analysis., Results: A total of 2106 (17.1%) and 10186 (82.9%) were surgically and medically treated. A total of 4050 matched cases, 2025 per each treated group, were included. Compared to medically treated patients, utilization was reduced in the surgical group: at 2 and 5 yr postindex date, there was a reduction of 36% to 37% of inpatient visits and 47% to 50% of ED visits. The total number (inpatient, ED, ambulatory visits) of epilepsy-associated visits were reduced by 39% to 43% in the surgical group compared to the medically treated group. In those who had surgery, the average reduction in AEDs was 16% at 2 and 5 yr after treatment., Conclusion: Patients with refractory epilepsy treated with surgery had significant reductions in healthcare utilization compared with patients treated only with medications., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: HIV treatment of neonates requires identifying appropriate antiretroviral dosing regimens. Our aims were to characterize raltegravir elimination kinetics in low birth weight (LBW) neonates after maternal dosing and to develop a pharmacokinetic model to predict raltegravir plasma concentrations for term and preterm neonates., Methods: Mothers living with HIV who received raltegravir during pregnancy and their LBW neonates participated in IMPAACT P1097 study. Up to 6 serial plasma samples were collected from each infant over the first 2 postnatal weeks to characterize raltegravir elimination. Safety laboratory evaluations were obtained, and infants were monitored for 6 weeks for signs of raltegravir toxicity. An integrated maternal-neonatal pharmacokinetic model was developed to predict neonatal raltegravir plasma concentrations., Results: Sixteen mothers and their 18 LBW neonates were enrolled. The median (range) raltegravir elimination half-life was 24.4 (10.1-83) hours (N = 17 neonates). No adverse events related to raltegravir in utero exposure were observed. Pharmacokinetic modeling revealed that raltegravir clearance in full-term LBW neonates was well described by allometric scaling but clearance in preterm LBW neonates was better described using slower clearance maturation kinetics. Simulations suggest receipt of the current dosing recommendations in a 34-week gestation neonate would result in plasma concentrations up to 2.5-fold higher than those observed in full-term LBW infants., Conclusions: Modeling suggests that prematurity reduces raltegravir clearance and a modified raltegravir dosing regimen will be necessary to avoid elevated plasma raltegravir concentrations.

Background: Denial of an overarching alcohol problem despite endorsement of specific alcohol-related difficulties may be central to development and continuation of alcohol use disorders (AUDs). However, there is limited information about which characteristics of drinkers and which drinking problems relate most closely to that denial., Methods: Using data from two generations of the San Diego Prospective Study (SDPS), we compared AUD subjects who considered themselves non-problematic drinkers (Group 1) with those with AUDs who acknowledged a general alcohol problem (Group 2). Comparisons included demography, alcohol-related patterns and problems, drug use, as well as impulsivity and sensation seeking. Variables were first evaluated as univariate characteristics after which significant group differences were entered in logistic regression analyses., Results: Sixty-seven percent of 94 AUD probands and 82 % of 176 AUD offspring reported themselves as light or moderate social drinkers despite averages of up to 12 maximum drinks per occasion and four DSM problems. Regression analyses indicated deniers evidenced less intense alcohol and drug-related problems and identified DSM-IV criterion items that they were most likely to deny., Conclusions: A large majority of two generations of SDPS participants whose interviews indicated a current AUD did not characterize themselves as problem drinkers. Despite drinking amounts that far exceeded healthy limits and admitting to important life problems with alcohol, these individuals give misleading answers regarding their condition when asked general questions about drinking by health care deliverers. The authors offer suggestions regarding how to identify those drinkers in need of advice regarding dangers of their behaviors., (Published by Elsevier B.V.)

Antiepileptic drugs afford good seizure control for approximately 70% of individuals with epilepsy. Epilepsy surgery is extremely helpful for appropriate individuals with drug resistance. Since antiquity, trephination was a crude and invasive technique to manage epilepsy. The late 1800s saw the advent of a more evidence-based approach with attempts to define seizure foci and determine areas of function. Seizure localization initially required direct brain stimulation during surgery before resection. Fortunately, improved knowledge of seizure semiology and advancements in preoperative investigations have enabled epilepsy specialists to better analyze the benefit of seizure reduction versus risk of functional harm. This preoperative phase and the investigative techniques used to analyze surgical candidacy will be discussed in this article., (Published by Elsevier Inc.)

Background: The most efficient approach for establishing family histories (FHs) asks informants about disorders in their relatives (a Family History Method [FHM]). However, FHMs underestimate family diagnoses. We evaluated if accuracies of young adult offspring report of their father's alcohol use disorders (AUDs) related to the age, sex, education, and/or substance-related patterns/problems of either the young adult informants or their AUD fathers., Methods: Data from the San Diego Prospective Study (SDPS), a multigenerational 35-year investigation, compared father/offspring pairs where the proband father's alcohol problems were correctly (Group 1) or incorrectly (Group 2) noted by offspring. In the key analysis, Group 1 versus 2 results were entered into bootstrapped backward logistic regression analyses predicting Group 1 membership., Results: Five proband and one offspring characteristic were associated with correct identification of their father's alcohol problems. None of these related to age, education, or sex. Characteristics associated with correct FHM diagnoses included the father's FH of AUDs, self-report of drinking despite social/interpersonal or physical/psychological alcohol-related problems, spending much time related to alcohol, and his having a religious preference. The single offspring item predicting correct identification of the father's problems was the number of DSM alcohol problems of the offspring., Conclusions: In the SDPS, FHM sensitivity was most closely related to the father's drinking characteristics, not the offspring characteristics. While unique aspects of SDPS families potentially limit generalizability of results, the data demonstrate how the FHM can offer important initial steps in the search for genetically related AUD risks in a subset of families., (© 2020 by the Research Society on Alcoholism.)

Background: Despite documented efficacy of surgical treatment in carefully selected patients, surgery is delayed and/or underutilized in both adult and children with focal onset epilepsy. The reasons for surgical delay are often assumed or theorized, and studies have predominantly targeted the adult population. To focus on a more targeted pediatric population and to determine identifiable reasons for intervention, this study aimed to investigate time to epilepsy surgery among pediatric patients with medically intractable epilepsy associated with focal cortical dysplasia and to identify sociodemographic and clinical associations in time to epilepsy surgery., Methods: We reviewed 96 consecutive pediatric patients who underwent surgery for medically intractable epilepsy with a diagnosis of focal cortical dysplasia. Descriptive statistics, univariate and multivariate analyses were conducted to study the association of sociodemographic variables of patients with focal cortical dysplasia and time to epilepsy surgery and postoperative seizure control., Results: We identified that non-white patients on average had a longer duration of epilepsy before surgery and traveled shorter distances for care. Non-white patients were more likely to have government-funded insurance. Patients who traveled the shortest distance to the surgical center underwent epilepsy surgery at an older age., Conclusions: Sociodemographic factors of travel distance, insurance, and race influenced time to epilepsy surgery for children with focal cortical dysplasia. Further research is warranted to target barriers in access to subspecialty care and develop ways to identify earlier the patients who may benefit from evaluation and deployment of surgical intervention., (Copyright © 2019. Published by Elsevier Inc.)

Background: Adequate pharmacokinetic and safety data in neonates are lacking for most antiretroviral agents. Raltegravir is a selective HIV-1 integrase strand transfer inhibitor available in a granule formulation suitable for use in neonates and young infants as prophylaxis or treatment of HIV infection., Methods: IMPAACT P1110 is a phase 1, multicenter, noncomparative dose-finding study of raltegravir in infants exposed to HIV-1 infection. A 2-cohort adaptive design was utilized where pharmacokinetic data from infants in cohort 1 who received 2 single doses of raltegravir 3 mg/kg were included in population modeling and simulations to guide selection of a daily dose for infants in cohort 2., Results: A total of 52 infants enrolled in IMPAACT 1110: cohort 1 (N = 16) and cohort 2 (N = 36). Using simulations based on population PK modeling incorporating cohort 1 data, the following daily dosing regimen was selected for study: 1.5 mg/kg daily from birth through day 7; 3 mg/kg twice daily from days 8-28 of life; and 6 mg/kg twice daily after 4 weeks of age through 6 weeks of age. The geometric mean protocol exposure targets for AUC, Ctrough, and Cmax were met or slightly exceeded in all infants. The chosen neonatal raltegravir dosing regimen was safe and well tolerated in full-term neonates during treatment over the first 6 weeks of life and follow-up to age 24 weeks., Conclusions: Raltegravir can be safely administered to full-term infants using the daily dosing regimen studied. This regimen is not recommended for use in premature infants in a new version of P1110.

Background: Population modeling and simulations can be used to facilitate the conduct of phase I studies to develop safe and effective dosing regimens in neonates., Setting: P1110 is an international, multicenter trial to determine safe and effective raltegravir doses in neonates at risk for HIV infection., Methods: P1110 used a 2-cohort adaptive design incorporating population pharmacokinetic modeling and simulations. An initial cohort of neonates received 2 single oral doses of raltegravir with standard-of-care therapy for prevention of perinatal transmission-one within 48 hours of birth and a second at 7-10 days of life. Raltegravir concentration data after administration of these doses were combined with data from a previous study of infants aged 4 weeks to 2 years. The combined database was used for population pharmacokinetic modeling and simulations to select a daily dosing regimen for investigation in a second cohort of neonates., Results: Raltegravir concentration data from 6 neonates were combined with data from infants aged 4 weeks to 2 years receiving raltegravir twice daily. The combined data set allowed for successful development of a population pharmacokinetic model with reasonable precision of parameter estimates. Monte Carlo simulations were run to evaluate potential daily dosing regimens from birth to 6 weeks of age, allowing for selection of a regimen to be evaluated in a subsequent cohort of neonates receiving chronic raltegravir dosing., Conclusions: An adaptive design incorporating population pharmacokinetic modeling and simulations was used to select a developmentally appropriate neonatal raltegravir dosing regimen in the first 6 weeks of life.

Background: Various studies suggest that the insular cortex may play an underappreciated role in pediatric frontotemporal/parietal epilepsy. Here, we report on the postsurgical outcomes in 26 pediatric patients with confirmed insular involvement by depth electrode monitoring., Objective: To describe one of the largest series of pediatric patients with medically refractory epilepsy undergoing laser interstitial thermal therapy (LITT) or surgical resection of at least some portion of the insular cortex., Methods: Pediatric patients in whom invasive insular sampling confirmed insular involvement and who subsequently underwent a second stage surgery (LITT or open resection) were included. Complications and Engel Class outcomes at least 1 yr postsurgery were compiled as well as pathology results in the open surgical cases., Results: The average age in our cohort was 10.3 yr, 58% were male, and the average length of follow-up was 2.43 ± 0.20 (SEM) yr. A total of 14 patients underwent LITT, whereas 12 patients underwent open resection. Complications in patients undergoing either LITT or open resection were mostly minimal and generally transient. Forty-three percent of patients who underwent LITT were Engel Class I, compared to 50% of patients who underwent open insular resection., Conclusion: Both surgical resection and LITT are valid management options in the treatment of medically refractory insular/opercular epilepsy in children. Although LITT may be a less invasive alternative to craniotomy, further studies are needed to determine its noninferiority in terms of complication rates and seizure freedom, especially in cases of cortical dysplasia that may involve extensive regions of the brain., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Intractable epilepsy may have a more severe effect on children in comparison to adults because the motor, sensorial, and cognitive functions of children are still undergoing development. For this same reason, however, children maintain a greater potential for recovery from intractable epilepsy because of the remaining cerebral plasticity. Thus, after 2 unsuccessful antiepileptic medications, surgical intervention is recommended. Pre-surgical localization of the epileptogenic zone increases seizure-freedom post-surgery by 200% to 300%. Single-photon emission computed tomography (SPECT) is commonly used, with magneto-encephalography (MEG) and electroencephalography (EEG), to localize the epileptogenic zone, because it localizes cerebral blood flow. There is limited research in the efficacy of SPECT localization in pediatric pharmacoresistant epilepsy. Therefore, the objective of this study was to determine the efficacy of SPECT in it's ability to localize the epileptogenic zone in laser ablation cases of pediatric pharmacoresistant epilepsy. Out of 122 SPECTs conducted at Dell Children's Medical Center from July 2010 to January 2015, 12 underwent laser ablation. In the 12 cases of laser ablation, SPECT displayed more sensitivity and specificity than EEG and more specificity than MEG when held against the laser ablation outcomes. This study further proves that SPECT is efficacious in epileptogenic zone localization of pediatric pharmacoresistant epilepsy.

Purpose of Review: Efforts to improve epilepsy care outcomes in low- and middle-income countries (LMICs) are occurring through global health work. Despite an increase in these efforts, several barriers exist and a significant epilepsy treatment gap remains. This paper will review barriers to epilepsy care in LMICs and summarize recent published and unpublished data about global health projects which aimed to improve epilepsy care in these regions, focusing on work in the past 5 years., Recent Findings: There are multiple recent and ongoing projects including clinical, research, education, and advocacy programs. We conclude that collaborative efforts are necessary in order to develop long-term and sustainable projects. The creation of a database and a formal method of communication between stakeholders can contribute to improving the efficiency and impact of global health efforts in epilepsy.

We use annotated genomes of 14 Drosophila species covering diverse host use phenotypes to test whether 4 gene families that often have detoxification functions are associated with host shifts among species. Bark, slime flux, flower, and generalist necrotic fruit-feeding species all have similar numbers of carboxyl/cholinesterase, glutathione S-transferase, cytochrome P450, and UDP-glucuronosyltransferase genes. However, species feeding on toxic Morinda citrifolia fruit and the fresh fruit-feeding Drosophila suzukii have about 30 and 60 more, respectively. ABC transporters show a different pattern, with the flower-feeding D. elegans and the generalist necrotic fruit and cactus feeder D. hydei having about 20 and >100 more than the other species, respectively. Surprisingly, despite the complex secondary chemistry we find that 3 cactophilic specialists in the mojavensis species cluster have variably fewer genes than any of the other species across all 4 families. We also find 82 positive selection events across the 4 families, with the terminal D. suzukii and M. citrifolia-feeding D. sechellia branches again having the highest number of such events in proportion to their respective branch lengths. Many of the genes involved in these host-use-specific gene number differences or positive selection events lie in specific clades of the gene families that have been recurrently associated with detoxification. Several genes are also found to be involved in multiple duplication and/or positive selection events across the species studied regardless of their host use phenotypes; the most frequently involved are the ABC transporter CG1718, which is not in a specific clade associated with detoxification, and the α-esterase gene cluster, which is.

Objectives: The objective of the study is to investigate the association between insurance transitions and healthcare utilization among children with refractory epilepsy., Methods: We applied published algorithms to identify the study cohort of children with a diagnosis of refractory epilepsy who were treated between 10/1/2013 and 9/30/2014 at 36 children's hospitals in the United States. Insurance transition was defined as having any change in the type of primary payer from the first date of diagnosis to the date of the last visit at the same hospital. Univariate and multilevel multivariable analytical methods were used in the study., Results: Among 3488 children hospitalized with refractory epilepsy, rates of insurance transitions at 1, 2, and 5 years of refractory epilepsy diagnosis were 8.1%, 14%, and 29.9%, respectively. Patients whose primary payer at diagnosis was Private or Others were more likely to experience insurance transitions than patients whose primary payer was Medicaid. Younger children were associated with a higher risk of insurance transitions than older children. The high intensity of insurance transitions was associated with a higher number of emergency department and inpatient visits., Conclusions: Insurance transitions interrupted the continuity of medical care for children with refractory epilepsy and were associated with more frequent hospitalizations and emergency department visits, which then translated to higher healthcare costs. Medicaid provided stable insurance coverage and is critically important for these patients and should be the main focus for policies aiming to minimize insurance transitions and optimize healthcare delivery., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: It has been increasingly recognized that the insular cortex plays an important role in frontotemporal-parietal epilepsy in children. The insula, however, cannot be properly interrogated with conventional subdural grids, and its anatomy makes it difficult to implicate the insula with semiology or noninvasive modalities. Frame-based, stereotactic placement of insular depth electrodes for direct extraoperative monitoring is a relatively low-risk maneuver that allows for conclusive interrogation of this region, and, in select cases, can easily be replaced with a laser applicator for minimally invasive treatment via thermoablation., Objective: To describe the largest reported series of pediatric patients with refractory epilepsy undergoing insular depth electrode placement., Methods: We used current procedural terminology billing records to identify cases of depth electrode insertion performed at our institution. Clinical information from patients undergoing invasive insular sampling was then retrospectively collected., Results: Seventy-four insular depth electrodes were placed in 49 patients for extraoperative, inpatient monitoring. The decision to place insular depth electrodes was determined by a multidisciplinary epilepsy team. In 65.3% of cases, direct invasive sampling implicated the insula in seizure onset and prompted either thermoablation or surgical resection of some portion of the insula. There were no serious adverse effects or complications associated with the placement of insular depth electrodes., Conclusion: Given the low morbidity of insular depth electrode insertion and the high proportion of patients who exhibited insular involvement, it is worth considering whether insular depth electrodes should be part of the standard presurgical evaluation in children with treatment-refractory frontotemporal-parietal epilepsy.

We performed an in vitro evaluation of the effect of maraviroc or dolutegravir on bilirubin to albumin binding. At typical treatment and low albumin concentrations, maraviroc had no impact, while dolutegravir affected bilirubin to albumin binding to an equivalent extent as sulfisoxazole. However in vivo, neither is likely to significantly impact bilirubin to albumin binding because of their low concentrations relative to albumin.

Introduction: Antiretroviral drugs are used in neonates for prevention and treatment of HIV infection. Use of antiretrovirals to prevent perinatal HIV transmission is well established. Early identification of neonates infected with HIV and rapid initiation of combination antiretroviral treatment during the neonatal period is now recommended by WHO and DHHS. However, few antiretrovirals are available in formulations suitable for neonates and there are limited safety and pharmacokinetic data for most antiretrovirals in neonates. Areas covered: We summarize existing neonatal antiretroviral safety and pharmacokinetic information and discuss implementation considerations for programs providing antiretrovirals to neonates and young infants. Expert commentary: Antiretrovirals currently recommended by WHO for use in neonates are zidovudine, lamivudine, lopinavir/ritonavir, nevirapine, and raltegravir. Significant implementation challenges exist to the widespread use of these antiretrovirals in neonates. Optimal, feasible treatment of HIV-exposed and HIV-infected newborns will require development of practical neonatal dosage forms and their study in neonates for a wide range of antiretrovirals.

OBJECTIVE Seizure onset within the insula is increasingly recognized as a cause of intractable epilepsy. Surgery within the insula is difficult, with considerable risks, given the rich vascular supply and location near critical cortex. MRI-guided laser interstitial thermal therapy (LiTT) provides an attractive treatment option for insular epilepsy, allowing direct ablation of abnormal tissue while sparing nearby normal cortex. Herein, the authors describe their experience using this technique in a large cohort of children undergoing treatment of intractable localization-related epilepsy of insular onset. METHODS The combined epilepsy surgery database of Cook Children's Medical Center and Dell Children's Hospital was queried for all cases of insular onset epilepsy treated with LiTT. Patients without at least 6 months of follow-up data and cases preoperatively designated as palliative were excluded. Patient demographics, presurgical evaluation, surgical plan, and outcome were collected from patient charts and described. RESULTS Twenty patients (mean age 12.8 years, range 6.1-18.6 years) underwent a total of 24 LiTT procedures; 70% of these patients had normal findings on MRI. Patients underwent a mean follow-up of 20.4 months after their last surgery (range 7-39 months), with 10 (50%) in Engel Class I, 1 (5%) in Engel Class II, 5 (25%) in Engel Class III, and 4 (20%) in Engel Class IV at last follow-up. Patients were discharged within 24 hours of the procedure in 15 (63%) cases, in 48 hours in 6 (24%) cases, and in more than 48 hours in the remaining cases. Adverse functional effects were experienced following 7 (29%) of the procedures: mild hemiparesis after 6 procedures (all patients experienced complete resolution or had minimal residual dysfunction by 6 months), and expressive language dysfunction after 1 procedure (resolved by 3 months). CONCLUSIONS To their knowledge, the authors present the largest cohort of pediatric patients undergoing insular surgery for treatment of intractable epilepsy. The patient outcomes suggest that LiTT can successfully treat intractable seizures originating within the insula and offers an attractive alternative to open resection. This is the first description of LiTT applied to insular epilepsy and represents one of only a few series describing the use of LiTT in children. The results indicate that seizure reduction after LiTT compares favorably to that after conventional open surgical techniques.

Background: Helicoverpa armigera and Helicoverpa zea are major caterpillar pests of Old and New World agriculture, respectively. Both, particularly H. armigera, are extremely polyphagous, and H. armigera has developed resistance to many insecticides. Here we use comparative genomics, transcriptomics and resequencing to elucidate the genetic basis for their properties as pests., Results: We find that, prior to their divergence about 1.5 Mya, the H. armigera/H. zea lineage had accumulated up to more than 100 more members of specific detoxification and digestion gene families and more than 100 extra gustatory receptor genes, compared to other lepidopterans with narrower host ranges. The two genomes remain very similar in gene content and order, but H. armigera is more polymorphic overall, and H. zea has lost several detoxification genes, as well as about 50 gustatory receptor genes. It also lacks certain genes and alleles conferring insecticide resistance found in H. armigera. Non-synonymous sites in the expanded gene families above are rapidly diverging, both between paralogues and between orthologues in the two species. Whole genome transcriptomic analyses of H. armigera larvae show widely divergent responses to different host plants, including responses among many of the duplicated detoxification and digestion genes., Conclusions: The extreme polyphagy of the two heliothines is associated with extensive amplification and neofunctionalisation of genes involved in host finding and use, coupled with versatile transcriptional responses on different hosts. H. armigera's invasion of the Americas in recent years means that hybridisation could generate populations that are both locally adapted and insecticide resistant.

Background: Symptomatic intracranial hemorrhage is a rare complication of laser interstitial thermal therapy (LITT)., Objectives: To present a unique case of delayed symptomatic intracranial hemorrhage occurring after a LITT procedure for epilepsy in a high-volume center (68 LITT procedures for pediatric epilepsy have been performed)., Methods: An 18-year-old male with epilepsy underwent LITT to an area of heterotopia near the right lateral ventricle. He did well initially and was discharged home on postoperative day 1 but returned on postoperative day 9 with headache and left hemiparesis. He was found to have intraparenchymal and intraventricular hemorrhage in the region of the LITT catheter tract., Results: CT angiography on admission revealed a small vascular abnormality near the focus of hemorrhage suspicious for pseudoaneurysm, although conventional angiography was negative. The patient declined neurologically and underwent craniotomy and hemorrhage evacuation. He eventually convalesced and was discharged to inpatient rehabilitation with persistent left hemiparesis. He has been seizure free since the intervention but remains on antiepileptic drugs., Conclusions: Evidence from the literature suggests that the pathophysiology of symptomatic hemorrhage after LITT may be related to vascular injury and pseudoaneurysm formation from LITT catheter placement and/or thermal injury from the ablation itself., (© 2017 S. Karger AG, Basel.)

We report our experience with 2 infants with in utero HIV-1 infection who began very early combination antiretroviral therapy within 4 hours of birth. Further neonatal studies of antiretroviral pharmacokinetics (PKs), safety, efficacy and treatment strategies are critically needed for the development of more potent regimens for use in HIV-infected infants.

Manduca sexta, known as the tobacco hornworm or Carolina sphinx moth, is a lepidopteran insect that is used extensively as a model system for research in insect biochemistry, physiology, neurobiology, development, and immunity. One important benefit of this species as an experimental model is its extremely large size, reaching more than 10 g in the larval stage. M. sexta larvae feed on solanaceous plants and thus must tolerate a substantial challenge from plant allelochemicals, including nicotine. We report the sequence and annotation of the M. sexta genome, and a survey of gene expression in various tissues and developmental stages. The Msex&#95;1.0 genome assembly resulted in a total genome size of 419.4 Mbp. Repetitive sequences accounted for 25.8% of the assembled genome. The official gene set is comprised of 15,451 protein-coding genes, of which 2498 were manually curated. Extensive RNA-seq data from many tissues and developmental stages were used to improve gene models and for insights into gene expression patterns. Genome wide synteny analysis indicated a high level of macrosynteny in the Lepidoptera. Annotation and analyses were carried out for gene families involved in a wide spectrum of biological processes, including apoptosis, vacuole sorting, growth and development, structures of exoskeleton, egg shells, and muscle, vision, chemosensation, ion channels, signal transduction, neuropeptide signaling, neurotransmitter synthesis and transport, nicotine tolerance, lipid metabolism, and immunity. This genome sequence, annotation, and analysis provide an important new resource from a well-studied model insect species and will facilitate further biochemical and mechanistic experimental studies of many biological systems in insects., (Copyright © 2016 Elsevier Ltd. All rights reserved.)