Search

Hemangioma is a proliferating mass of blood vessels. Its occurrence in gingiva is rare. The diagnosis and treatment of hemangioma is complex, and any attempt to carry out biopsy/surgical excision may lead to fatal consequences due to severe hemorrhage. A rare case of gingival hemangioma with port wine nevi of face is reported. The case is of periodontal interest because the lesion occurred on the gingiva, a reliable diagnostic approach (Ultrasound Spectra Doppler Flow) was used and a conservative treatment using a sclerosing agent was employed. [ABSTRACT FROM AUTHOR]

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease is a neuroinflammatory disorder (MOGAD) with heterogeneous phenotype including paroxysms of optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, brainstem demyelination, and encephalitis. Fluid-attenuated inversion recovery hyperintense cortical lesions in MOG-associated encephalitis with seizures, or FLAMES, is a manifestation of cerebral cortical encephalitis seen less frequently than other typical MOG antibody-associated disease presentations. Cases of FLAMES are rarer in children, and frequently initially misdiagnosed with infectious meningoencephalitis. Other meningocortical manifestations of MOG antibody-associated disease have been described and likely exist along a continuum. In this retrospective single-center case series, we describe the demographic, clinical, radiographic, laboratory, and electroencephalographic features of 5 children with clinicoradiographic features consistent with the spectrum of MOG-IgG-positive meningocortical syndromes., 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.

Successful surgical treatment of drug-resistant epilepsy traditionally relies on the identification of seizure onset zones (SOZs). Connectome-based analyses of electrographic data from stereo electroencephalography (SEEG) may empower improved detection of SOZs. Specifically, connectome-based analyses based on the interictal suppression hypothesis posit that when the patient is not having a seizure, SOZs are inhibited by non-SOZs through high inward connectivity and low outward connectivity. However, it is not clear whether there are other motifs that can better identify potential SOZs. Thus, we sought to use unsupervised machine learning to identify network motifs that elucidate SOZs and investigate if there is another motif that outperforms the ISH. Resting-state SEEG data from 81 patients with drug-resistant epilepsy undergoing a pre-surgical evaluation at Vanderbilt University Medical Center were collected. Directed connectivity matrices were computed using the alpha band (8-13 Hz). Principal component analysis (PCA) was performed on each patient's connectivity matrix. Each patient's components were analysed qualitatively to identify common patterns across patients. A quantitative definition was then used to identify the component that most closely matched the observed pattern in each patient. A motif characteristic of the interictal suppression hypothesis (high-inward and low-outward connectivity) was present in all individuals and found to be the most robust motif for identification of SOZs in 64/81 (79%) patients. This principal component demonstrated significant differences in SOZs compared to non-SOZs. While other motifs for identifying SOZs were present in other patients, they differed for each patient, suggesting that seizure networks are patient specific, but the ISH is present in nearly all networks. We discovered that a potentially suppressive motif based on the interictal suppression hypothesis was present in all patients, and it was the most robust motif for SOZs in 79% of patients. Each patient had additional motifs that further characterized SOZs, but these motifs were not common across all patients. This work has the potential to augment clinical identification of SOZs to improve epilepsy treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Epilepsy is a common neurological disorder affecting 1% of the global population. Loss of consciousness in focal impaired awareness seizures (FIASs) and focal-to-bilateral tonic-clonic seizures (FBTCSs) can be devastating, but the mechanisms are not well understood. Although ictal activity and interictal connectivity changes have been noted, the network states of focal aware seizures (FASs), FIASs, and FBTCSs have not been thoroughly evaluated with network measures ictally., Methods: We obtained electrographic data from 74 patients with stereoelectroencephalography (SEEG). Sliding window band power, functional connectivity, and segregation were computed on preictal, ictal, and postictal data. Five-minute epochs of wake, rapid eye movement sleep, and deep sleep were also extracted. Connectivity of subcortical arousal structures was analyzed in a cohort of patients with both SEEG and functional magnetic resonance imaging (fMRI). Given that custom neuromodulation of seizures is predicated on detection of seizure type, a convolutional neural network was used to classify seizure types., Results: We found that in the frontoparietal association cortex, an area associated with consciousness, both consciousness-impairing seizures (FIASs and FBTCSs) and deep sleep had increases in slow wave delta (1-4 Hz) band power. However, when network measures were employed, we found that only FIASs and deep sleep exhibited an increase in delta segregation and a decrease in gamma segregation. Furthermore, we found that only patients with FIASs had reduced subcortical-to-neocortical functional connectivity with fMRI versus controls. Finally, our deep learning network demonstrated an area under the curve of .75 for detecting consciousness-impairing seizures., Significance: This study provides novel insights into ictal network measures in FASs, FIASs, and FBTCSs. Importantly, although both FIASs and FBTCSs result in loss of consciousness, our results suggest that ictal network changes in FIASs uniquely resemble those that occur during deep sleep. Our results may inform novel neuromodulation strategies for preservation of consciousness in epilepsy., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objectives: The main goal of presurgical evaluation in drug-resistant focal epilepsy is to identify a seizure onset zone (SOZ). Of the noninvasive, yet resource-intensive tests available, ictal single-photon emission computed tomography (SPECT) aids SOZ localization by measuring focal increases in blood flow within the SOZ via intravenous peri-ictal radionuclide administration. Recent studies indicate that geographic and center-specific factors impact utilization of these diagnostic procedures. Our study analyzed successful ictal SPECT acquisition (defined as peri-ictal injection during inpatient admission) using surgery-related data from the Pediatric Epilepsy Research Consortium (PERC) surgery database. We hypothesized that a high seizure burden, longer duration of video EEG monitoring (VEEG), and more center-specific hours of SPECT availability would increase the likelihood of successful ictal SPECT., Methods: We identified study participants (≤18 years of age) who underwent SPECT as part of their phase 1 VEEG from January 2018 to June 2022. We assessed association between ictal SPECT outcomes (success vs. failure) and variables including patient demographics, epilepsy history, and center-specific SPECT practices., Results: Phase 1 VEEG monitoring with ictal SPECT injection was planned in 297 participants and successful in 255 participants (85.86%). On multivariable analysis, the likelihood of a successful SPECT injection was higher in patients of non-Hispanic ethnicity (p = 0.040), shorter duration VEEG (p = 0.004), and higher hours of available SPECT services (p < 0.001). Higher seizure frequency (p = 0.033) was significant only in bivariate analysis. Patients treated at centers with more operational hours were more likely to experience pre-admission protocols prior to VEEG (p = 0.002)., Significance: There is inter-center variability in protocols and SPECT acquisition capabilities. Shorter duration of EEG monitoring, non-Hispanic ethnicity (when on private insurance), extended operational hours of nuclear medicine as noted on multivariate analysis and higher seizure frequency in bivariate analysis are strongly associated with successful ictal SPECT injection., Plain Language Summary: In pediatric patients with drug-resistant epilepsy, single-photon emission computed tomography (SPECT) scans can be helpful in localizing seizure onset zone. However, due to many logistical challenges described below, which include not only the half-life of the technetium isotope used to inject intravenously during a seizure (called the ictal SPECT scan) but also available nuclear scanner time in addition to the unpredictability of seizures, obtaining an ictal SPECT during a planned elective inpatient hospital stay is not guaranteed. Thus, as healthcare costs increase, planning a prolonged hospital stay during which an ictal SPECT scan is not feasible is not optimal. We leveraged our prospective surgery database to look at center-specific factors and patient-specific factors associated with an ictal SPECT injection in the first, pediatric-focussed, large-scale, multicenter, prospective, SPECT feasibility study. We found that longer availability of the scanner is the most important center-specific factor in assuring ictal SPECT injection. Although seizure frequency is an important patient-specific factor on bivariate analysis, this factor lost statistical significance when other factors like patient insurance status and video EEG duration were also considered in our multivariable logistical model., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Competing Interests: The authors made the following disclosures: T.T.M. has served as an investigator or consultant for Abbvie, Arcutis, Acelyrin, BMS, ChemoCentryx, Eli Lilly, Galderma, Janssen, Leo Pharma, Novartis, Pfizer, and Procter and Gamble, UCB. A.S.W.O., K.Y., S.B.R., and C.A.E. declare no conflicts of interest.

Neuromodulation via Responsive Neurostimulation (RNS) or Deep Brain Stimulation (DBS) is an emerging treatment strategy for pediatric drug-resistant epilepsy (DRE). Knowledge gaps exist in patient selection, surgical technique, and perioperative care. Here, we use an expert survey to clarify practices. Thirty-two members of the Pediatric Epilepsy Research Consortium were surveyed using REDCap. Respondents were from 17 pediatric epilepsy centers (missing data in one): Four centers implant RNS only while 13 implant both RNS and DBS. Thirteen RNS programs commenced in or before 2020, and 10 of 12 DBS programs began thereafter. The busiest six centers implant 6-10 new RNS devices per year; all DBS programs implant <5 annually. The youngest RNS patient was 3 years old. Most centers (11/12) utilize MP2RAGE and/or FGATIR sequences for planning. Centromedian thalamic nuclei were the unanimous target for Lennox-Gastaut syndrome. Surgeon exposure to neuromodulation occurred mostly in clinical practice (14/17). Clinically significant hemorrhage (n = 2) or infection (n = 3) were rare. Meaningful seizure reduction (>50%) was reported by 81% (13/16) of centers. RNS and DBS are rapidly evolving treatment modalities for safe and effective treatment of pediatric DRE. There is increasing interest in multicenter collaboration to gain knowledge and facilitate dialogue. PLAIN LANGUAGE SUMMARY: We surveyed 32 pediatric epilepsy centers in USA to highlight current practices of intracranial neuromodulation. Of the 17 that replied, we found that most centers are implanting thalamic targets in pediatric drug-resistant epilepsy using the RNS device. DBS device is starting to be used in pediatric epilepsy, especially after 2020. Different strategies for target identification are enumerated. This study serves as a starting point for future collaborative research., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Routine histopathological examination of hernia sac in adults remains a controversial topic. We undertook a retrospective study to assess possible clinical benefits of pathological examination of hernia sac specimens. Our pathology database between 1992 and 2020 was searched for adult specimens submitted as hernia sac. The clinical and pathological data of patients with abnormal histopathological findings were reviewed. There were 5424 hernia sac specimens (3722 inguinal, 1625 umbilical, and 77 femoral), 32/5424 (0.59%) with malignancies (28 epithelial and 4 lymphoid) and 25/32 were located in the umbilical region. Twelve out of twenty-five malignancies (48%) presented as primary clinical manifestations of the diseases (5 GI tract carcinomas, 5 gynecological tract carcinomas, and 2 lymphoid neoplasms); and 13/25 (52%) specimens were involved by previously known tumors (8 gynecological carcinomas, 3 colon carcinomas, 1 breast carcinoma, and 1 lymphoma). Among the 7 inguinal hernia sacs with malignancies, 3 (42.9%) were primary presentations of the tumors (2 prostatic carcinomas, 1 pancreatic carcinoma), and 4 (57.1%) were previously known tumors (2 ovarian carcinomas, 1 colon carcinoma, 1 lymphoid). Benign lesions were 12/5424 (0.22%), including 7 adrenal rests, 4 endometriosis, and 1 inguinal sarcoidosis. The incidence of hernia sacs with malignancies was 32/5424 (0.59%), most commonly from nearby organs in gynecological tract. However distant metastases from breast were also present. Near half of the hernia sac with malignancies (15/32, 47%) presented as the first clinical manifestation. Routine histopathological examination of hernia sac in adults is recommended, since it may provide important clinical information., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Corpus callosotomy (CC) is used to reduce seizures, primarily in patients with generalized drug-resistant epilepsy (DRE). The invasive nature of the procedure contributes to underutilization despite its potential superiority to other palliative procedures. The goal of this study was to use a multi-institutional epilepsy surgery database to characterize the use of CC across participating centers., Methods: Data were acquired from the Pediatric Epilepsy Research Consortium (PERC) Surgery Database, a prospective observational study collecting data on children 0-18 years referred for surgical evaluation of DRE across 22 U.S. pediatric epilepsy centers. Patient, epilepsy, and surgical characteristics were collected across multiple CC modalities. Outcomes and complications were recorded and analyzed statistically., Results: Eighty-three patients undergoing 85 CC procedures at 14 participating epilepsy centers met inclusion criteria. Mean age at seizure onset was 2.3 years (0-9.4); mean age for Phase I evaluation and surgical intervention were 9.45 (.1-20) and 10.46 (.2-20.6) years, respectively. Generalized seizure types were the most common (59%). Complete CC was performed in 88%. The majority of CC procedures (57%) were via open craniotomy, followed by laser interstitial thermal therapy (LiTT) (20%) and mini-craniotomy/endoscopic (mc/e) (22%). Mean operative times were significantly longer for LiTT, whereas mean estimated blood loss was greater in open cases. Complications occurred in 11 cases (13%) and differed significantly between surgical techniques (p < .001). There was no statistically significant difference in length of postoperative stay across approaches. Mean follow-up was 12.8 months (range 1-39). Favorable Engel outcomes were experienced by 37 (78.7%) of the patients who underwent craniotomy, 10 (58.8%) with LiTT, and 12 (63.2%) with mc/e; these differences were not statistically significant., Significance: CC is an effective surgical modality for children with DRE. Regardless of surgical modality, complication rates are acceptable and seizure outcomes generally favorable. Newer, less-invasive, surgical approaches may lead to increased adoption of this efficacious therapeutic option for pediatric DRE., (© 2023 International League Against Epilepsy.)

Introduction: Differences in eosinophilic esophagitis (EoE) presentation and outcomes by ethnicity or race remain understudied. We aimed to determine whether EoE patients of Hispanic/Latinx ethnicity or non-White race have differences in presentation at diagnosis or response to topical corticosteroid (tCS) treatment., Methods: This retrospective cohort study included subjects of any age with a new diagnosis of EoE and documentation of ethnicity or race. For those who had treatment with tCS and follow-up endoscopy/biopsy, we assessed histologic response (<15 eosinophils/hpf), global symptom response, and endoscopic response. Hispanic EoE patients were compared with non-Hispanics at baseline and before and after treatment. The same analyses were repeated for White vs non-Whites., Results: Of 1,026 EoE patients with ethnicity data, just 23 (2%) were Hispanic. Most clinical features at presentation were similar to non-Hispanic EoE patients but histologic response to tCS was numerically lower (38% vs 57%). Non-White EoE patients (13%) were younger at diagnosis and had less insurance, lower zip code-level income, shorter symptom duration, more vomiting, less dysphagia and food impaction, fewer typical endoscopic features, and less dilation. Of 475 patients with race data treated with tCS, non-Whites had a significantly lower histologic response rate (41% vs 59%; P = 0.01), and odds of histologic response remained lower after controlling for potential confounders (adjusted odds ratio 0.40, 95% confidence intervals: 0.19-0.87)., Discussion: Few EoE patients at our center were Hispanic, and they had similar clinical presentations as non-Hispanics. The non-White EoE group was larger, and presentation was less dysphagia-specific. Non-White patients were also less than half as likely to respond to tCS., (Copyright © 2023 by The American College of Gastroenterology.)

We investigated multiple signaling pathways activated by CYP11A1-derived vitamin D3 hydroxymetabolites in human skin fibroblasts by assessing the actions of these molecules on their cognate receptors and by investigating the role of CYP27B1 in their biological activities. The actions of 20(OH)D3, 20,23(OH) 2 D3, 1,20(OH) 2 D3 and 1,20,23(OH) 3 D3 were compared to those of classical 1,25(OH) 2 D3. This was undertaken using wild type (WT) fibroblasts, as well as cells with VDR , RORs , or CYP27B1 genes knocked down with siRNA. Vitamin D3 hydroxymetabolites had an inhibitory effect on the proliferation of WT cells, but this effect was abrogated in cells with silenced VDR or RORs. The collagen expression by WT cells was reduced upon secosteroid treatment. This effect was reversed in cells where VDR or RORs were knocked down where the inhibition of collagen production and the expression of anti-fibrotic genes in response to the hydroxymetabolites was abrogated, along with ablation of their anti-inflammatory action. The knockdown of CYP27B 1 did not change the effect of either 20(OH)D3 or 20,23(OH) 2 D3, indicating that their actions are independent of 1α-hydroxylation. In conclusion, the expression of the VDR and/or RORα/γ receptors in fibroblasts is necessary for the inhibition of both the proliferation and fibrogenic activity of hydroxymetabolites of vitamin D3, while CYP27B1 is not required.

Background and Objectives: In the United States, many child neurologists (CNs) and neurodevelopmental disability (NDD) specialists who read EEGs in clinical practice had no additional EEG training other than what was received during residency. This practice highlights the importance of ensuring that CN/NDD residents achieve EEG competence before graduation. However, prior survey-based evidence showed that roughly a third of graduating CN residents in the United States do not feel confident interpreting EEGs independently. As part of a needs assessment, we conducted a descriptive study characterizing EEG practices in CN and NDD residency programs in the United States and Canada., Methods: A 30-question e-survey focused on characteristics of residency programs and their EEG teaching practices was sent to all 88 CN and NDD residency program directors listed in the Accreditation Council for Graduate Medical Education, Child Neurology Society, and Canadian Residency Matching Service websites., Results: Twenty-nine (n = 29/88; 33%) residency programs completed the survey, most of which were CN (90%), academic (90%), and located in the United States (83%). The mean number of weeks dedicated to EEG training required to graduate was 7.3 ± 4 (mean ± SD). EEG rotations involved the clinic/outpatient setting (83%), epilepsy monitoring unit (EMU) (76%), and inpatient setting (excluding EMU) (72%). During a 4-week EEG rotation, residents typically read 16-45 EEGs (62%). The most common methods of EEG teaching in CN/NDD programs were teaching during EEG rotation and yearly didactics. The mean number of EEGs read per rotation had a significant positive correlation with the average percentage of residents who reportedly achieve EEG competence by graduation (coefficient 0.461; p = 0.007). Barriers to EEG education were reported by 28% of the programs; the most common barrier identified was insufficient EEG exposure. Possible solutions were primarily related to increasing quality and quantity of EEG exposure. Almost two-thirds of programs reported not using objective measures to assess EEG competence., Discussion: Our results characterize resident EEG education in a third of CN/NDD residency programs in the United States and Canada. We suggest that residency leaderships consider standardization of EEG learning along with establishment and implementation of objective measures in training requirements and competence assessment., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NE for full disclosures., (© 2024 American Academy of Neurology.)

Since 2003, we have seen the emergence of novel viruses, such as SARS-CoV-1, MERS, ZIKA, swine flu virus H1N1, Marburg, Monkeypox, Ebola, and SARS-CoV-2, but none of them gained pandemic proportions similar to SARS-CoV-2. This could be attributed to unique viral traits, allowing its rapid global dissemination following its emergence in October 2019 in Wuhan, China, which appears to be primarily driven by the emergence of highly transmissible and virulent variants that also associate, in some cases, with severe disease and considerable mortality caused by fatal pneumonia, acute respiratory distress syndrome (ARDS) in infected individuals. Mechanistically, several factors are involved in viral pathogenesis, and epigenetic alterations take the front seat in host-virus interactions. The molecular basis of all viral infections, including SARS-CoV-2, tightly hinges on the transitory silencing of the host gene machinery via epigenetic modulation. SARS-CoV-2 also hijacks and subdues the host gene machinery, leading to epigenetic modulation of the critical host elements responsible for antiviral immunity. Epigenomics is a powerful, unexplored avenue that can provide a profound understanding of virus-host interactions and lead to the development of epigenome-based therapies and vaccines to counter viruses. This review discusses current developments in SARS-CoV-2 variation and its role in epigenetic modulation in infected hosts. This review provides an overview, especially in the context of emerging viral strains, their recombinants, and their possible roles in the epigenetic exploitation of host defense and viral pathogenesis. It provides insights into host-virus interactions at the molecular, genomic, and immunological levels and sheds light on the future of epigenomics-based therapies for SARS-CoV-2 infection., Competing Interests: Declaration of competing interest We declare that there is no conflict of interest, and all authors have approved the content and authorships., (Copyright © 2023. Published by Elsevier B.V.)

Objective: This study assesses current practices and outcomes of epilepsy surgery in children with a genetic etiology. It explores the pre-surgical workup, types of surgeries, and post-surgical outcomes in a broad array of disorders., Methods: Patients ≤18 years who completed epilepsy surgery and had a known genetic etiology prior to surgical intervention were extrapolated from the Pediatric Epilepsy Research Consortium (PERC) surgery database, across 18 US centers. Data were assessed univariably by neuroimaging and EEG results, genetic group (structural gene, other gene, chromosomal), and curative intent. Outcomes were based on a modified International League Against Epilepsy (ILAE) outcome score., Results: Of 81 children with genetic epilepsy, 72 % had daily seizures when referred for surgery evaluation, which occurred a median of 2.2 years (IQR 0.3, 5.2) after developing drug resistance. Following surgery, 68 % of subjects had >50 % seizure reduction, with 33 % achieving seizure freedom [median follow-up 11 months (IQR 6, 17). Seizure freedom was most common in the monogenic structural group, but significant palliation was present across all groups. Presence of a single EEG focus was associated with a greater likelihood of seizure freedom (p=0.02)., Significance: There are meaningful seizure reductions following epilepsy surgery in the majority of children with a genetic etiology, even in the absence of a single structural lesion and across a broad spectrum of genetic causes. These findings highlight the need for expedited referral for epilepsy surgery and support of a broadened view of which children may benefit from epilepsy surgery, even when the intent is palliative., Competing Interests: Declaration of Competing Interest Allyson Alexander, MD is a consultant for NuXceland. All additional authors report no declarations of interest., (Copyright © 2023 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background Guided bone regeneration (GBR) is an often-used technique to aid the successful placement of dental implants in sites with deficient bone. The search for the ideal GBR membrane with bioactive components improving the regenerative outcomes is still on. In this study, a novel composite GBR membrane was developed using selenium-doped bio-glass, collagen, and gelatin. It was further characterized for surface, chemical, biocompatibility, and antibacterial properties. Methodology Selenium-doped bio-glass was prepared using the sol-gel method. The membrane was fabricated using an equal ratio of collagen and gelatin mixed with 1% selenium-doped bio-glass. The solution was poured to obtain a thin layer of the material which was lyophilized to obtain the final GBR membrane. The membrane was analyzed with scanning electron microscopy, energy dispersive X-ray (EDX) analysis, attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), zebrafish cytotoxicity test, and antibacterial assay. Results The membrane revealed good surface roughness with lamellar and fibrillar arrangement with a minute granular surface ideal for cell attachment and proliferation. The EDX analysis revealed the presence of carbon, oxygen, and nitrogen as predominant components with trace amounts of calcium, phosphorus, silica, and selenium. Fourier transform infrared spectroscopy analysis also proved the presence of collagen, gelatin, and bio-glass. The membrane revealed excellent biocompatibility with zebrafish growth at a normal rate with 90% viability maintained at 48, 72, and 96 hours and 95% viability at 120 hours. It also exhibited excellent antibacterial activity against Staphylococcus aureus and Escherichia coli with minimal growth of bacterial colonies. Conclusion The developed novel selenium bio-glass collagen and gelatin composite scaffold has a good surface and antibacterial properties along with excellent biocompatibility. Further cell line and in vivo studies should be conducted to explore its role in bone regeneration., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Reddy et al.)

Several independent lines of evidence suggest that megakaryocytes are dysfunctional in severe COVID-19. Herein, we characterized peripheral circulating megakaryocytes in a large cohort of inpatients with COVID-19 and correlated the subpopulation frequencies with clinical outcomes. Using peripheral blood, we show that megakaryocytes are increased in the systemic circulation in COVID-19, and we identify and validate S100A8/A9 as a defining marker of megakaryocyte dysfunction. We further reveal a subpopulation of S100A8/A9+ megakaryocytes that contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein and RNA. Using flow cytometry of peripheral blood and in vitro studies on SARS-CoV-2-infected primary human megakaryocytes, we demonstrate that megakaryocytes can transfer viral antigens to emerging platelets. Mechanistically, we show that SARS-CoV-2-containing megakaryocytes are nuclear factor κB (NF-κB)-activated, via p65 and p52; express the NF-κB-mediated cytokines interleukin-6 (IL-6) and IL-1β; and display high surface expression of Toll-like receptor 2 (TLR2) and TLR4, canonical drivers of NF-κB. In a cohort of 218 inpatients with COVID-19, we correlate frequencies of megakaryocyte subpopulations with clinical outcomes and show that SARS-CoV-2-containing megakaryocytes are a strong risk factor for mortality and multiorgan injury, including respiratory failure, mechanical ventilation, acute kidney injury, thrombotic events, and intensive care unit admission. Furthermore, we show that SARS-CoV-2+ megakaryocytes are present in lung and brain autopsy tissues from deceased donors who had COVID-19. To our knowledge, this study offers the first evidence implicating SARS-CoV-2+ peripheral megakaryocytes in severe disease and suggests that circulating megakaryocytes warrant investigation in inflammatory disorders beyond COVID-19., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The Accreditation Council for Graduate Medical Education (ACGME) milestones state that neurology residents should be able to "interpret common EEG abnormalities, recognize normal EEG variants, and create a report." Yet, recent studies have shown that only 43% of neurology residents express confidence in interpreting EEG without supervision and can recognize less than half of normal and abnormal EEG patterns. Our objective was to create a curriculum to improve both confidence and competence in reading EEGs., Methods: At Vanderbilt University Medical Center (VUMC), adult and pediatric neurology residents have required EEG rotations in their first and second years of neurology residency and can choose an EEG elective in their third year. A curriculum consisting of specific learning objectives, self-directed modules, EEG lectures, epilepsy-related conferences, supplemental educational material, and tests was created for each of the three years of training., Results: Since the implementation of an EEG curriculum at VUMC from September 2019 until November 2022, 12 adult and 21 pediatric neurology residents completed pre- and post-rotation tests. Among the 33 residents, there was a statistically significant improvement in post-rotation test scores, with a mean score improvement of 17% (60.0 ± 12.9 to 77.9 ± 11.8, n = 33, p < 0.0001). When differentiated by training, the mean improvement of 18.8% in the adult cohort was slightly higher than in the pediatric cohort, 17.3%, though it was not significantly different. Overall improvement was significantly increased in the junior resident cohort with a 22.6% improvement in contrast to 11.5% in the senior resident cohort (p = 0.0097 by Student's t-test, n = 14 junior residents and 15 senior residents)., Discussion: With the creation of an EEG curriculum specific to each year of neurology residency, adult and pediatric neurology residents demonstrated a statistically significant mean improvement between pre- and post-rotation test scores. The improvement was significantly higher in junior residents in contrast to senior residents. Our structured and comprehensive EEG curriculum objectively improved EEG knowledge in all neurology residents at our institution. The findings may suggest a model which other neurology training programs may consider for the implementation of a similar curriculum to both standardize and address gaps in resident EEG education., 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 Elsevier Inc. All rights reserved.)

Why are people with focal epilepsy not continuously having seizures? Previous neuronal signalling work has implicated gamma-aminobutyric acid balance as integral to seizure generation and termination, but is a high-level distributed brain network involved in suppressing seizures? Recent intracranial electrographic evidence has suggested that seizure-onset zones have increased inward connectivity that could be associated with interictal suppression of seizure activity. Accordingly, we hypothesize that seizure-onset zones are actively suppressed by the rest of the brain network during interictal states. Full testing of this hypothesis would require collaboration across multiple domains of neuroscience. We focused on partially testing this hypothesis at the electrographic network level within 81 individuals with drug-resistant focal epilepsy undergoing presurgical evaluation. We used intracranial electrographic resting-state and neurostimulation recordings to evaluate the network connectivity of seizure onset, early propagation and non-involved zones. We then used diffusion imaging to acquire estimates of white-matter connectivity to evaluate structure-function coupling effects on connectivity findings. Finally, we generated a resting-state classification model to assist clinicians in detecting seizure-onset and propagation zones without the need for multiple ictal recordings. Our findings indicate that seizure onset and early propagation zones demonstrate markedly increased inwards connectivity and decreased outwards connectivity using both resting-state (one-way ANOVA, P-value = 3.13 × 10-13) and neurostimulation analyses to evaluate evoked responses (one-way ANOVA, P-value = 2.5 × 10-3). When controlling for the distance between regions, the difference between inwards and outwards connectivity remained stable up to 80 mm between brain connections (two-way repeated measures ANOVA, group effect P-value of 2.6 × 10-12). Structure-function coupling analyses revealed that seizure-onset zones exhibit abnormally enhanced coupling (hypercoupling) of surrounding regions compared to presumably healthy tissue (two-way repeated measures ANOVA, interaction effect P-value of 9.76 × 10-21). Using these observations, our support vector classification models achieved a maximum held-out testing set accuracy of 92.0 ± 2.2% to classify early propagation and seizure-onset zones. These results suggest that seizure-onset zones are actively segregated and suppressed by a widespread brain network. Furthermore, this electrographically observed functional suppression is disproportionate to any observed structural connectivity alterations of the seizure-onset zones. These findings have implications for the identification of seizure-onset zones using only brief electrographic recordings to reduce patient morbidity and augment the presurgical evaluation of drug-resistant epilepsy. Further testing of the interictal suppression hypothesis can provide insight into potential new resective, ablative and neuromodulation approaches to improve surgical success rates in those suffering from drug-resistant focal epilepsy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Patients with eosinophilic esophagitis (EoE) typically have concomitant atopic conditions, but whether there are differences in presentation or treatment response by the number of atopic diseases is unknown., Objective: To determine whether patients with EoE having multiple atopic conditions have differences in presentation or response to topical corticosteroid (TCS) treatment., Methods: We performed a retrospective cohort study of adults and children with newly diagnosed EoE. The total number of atopic comorbidities (allergic rhinitis, asthma, eczema, food allergy) was calculated. Patients with at least 2 atopic conditions other than allergic rhinitis were defined as having multiple atopic conditions and their baseline characteristics were compared with those with less than 2 atopic conditions. Histologic, symptom, and endoscopic responses to TCS treatment were also compared with bivariable and multivariable analyses., Results: Of the 1020 patients with EoE having atopic disease information, 235 (23%) had 1 atopic comorbidity, 211 (21%) had 2, 113 (11%) had 3, and 34 (3%) had 4. At baseline, the 180 (18%) patients with 2 or more atopic diseases were younger and had more vomiting, less abdominal pain, more exudates and edema on endoscopy, and higher peak eosinophil counts. Among those treated with TCS, there was a trend toward better global symptom response in patients with less than 2 atopic conditions, but there was no difference in histologic or endoscopic response compared with those with 2 or more atopic conditions., Conclusion: There were differences in the initial presentation of EoE between those with and without multiple atopic conditions, but there were no major differences in histologic treatment response to corticosteroids by atopic status., (Copyright © 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Responsive neurostimulation (RNS), a closed-loop intracranial electrical stimulation system, is a palliative surgical option for patients with drug-resistant epilepsy (DRE). RNS is approved by the US Food and Drug Administration for patients aged ≥18 years with pharmacoresistant partial seizures. The published experience of RNS in children is limited., Methods: This is a combined prospective and retrospective study of patients aged ≤18 years undergoing RNS placement. Patients were identified from the multicenter Pediatric Epilepsy Research Consortium Surgery Registry from January 2018 to December 2021, and additional data relevant to this study were retrospectively collected and analyzed., Results: Fifty-six patients received RNS during the study period. The mean age at implantation was 14.9 years; the mean duration of epilepsy, 8.1 years; and the mean number of previously trialed antiseizure medications, 4.2. Five patients (9%) previously trialed dietary therapy, and 19 patients (34%) underwent prior surgery. Most patients (70%) underwent invasive electroencephalography evaluation before RNS implantation. Complications occurred in three patients (5.3%) including malpositioned leads or transient weakness. Follow-up (mean 11.7 months) was available for 55 patients (one lost), and four were seizure-free with RNS off. Outcome analysis of stimulation efficacy was available for 51 patients: 33 patients (65%) were responders (≥50% reduction in seizure frequency), including five patients (10%) who were seizure free at follow-up., Conclusions: For young patients with focal DRE who are not candidates for surgical resection, neuromodulation should be considered. Although RNS is off-label for patients aged <18 years, this multicenter study suggests that it is a safe and effective palliative option for children with focal DRE., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: There is conflicting evidence about the association between eosinophilic esophagitis (EoE) and esophageal motility disorders. The aim of this study was to evaluate esophageal manometry findings in EoE., Methods: We conducted a systematic review using PubMed, EMBASE, and Web of Science. All articles from 1990 to 2021 with EoE patients who underwent esophageal manometry were eligible. We also included pertinent abstracts from national conferences from 2015 to 2020. The primary outcomes were the prevalence of specific Chicago 3 Classification (CCv3) diagnoses in EoE, as well as broader categories of non-relaxing lower esophageal sphincter, and major and minor peristaltic disorders. When multiple studies reported a specific outcome, we performed random effects meta-analysis to obtain pooled prevalence of each outcome. To reduce heterogeneity, we restricted meta-analysis to high-resolution manometry (HRM) studies only., Key Results: Of 763 publications identified, 27 original studies met criteria for inclusion, encompassing 706 EoE patients; 14 studies (425 patients) had HRM and underwent meta-analysis. The pooled prevalence of any motility abnormality was 53% (95% CI: 43%-63%), largely comprised of minor motility disorders such as ineffective esophageal motility and fragmented peristalsis. Major motility disorders, classified by CCv3, were less common in EoE, with pooled prevalence of 2% (0%-7%), 10% (5%-16%), and 1% (0%-3%), for achalasia, esophagogastric-junction outflow obstruction, and hypercontractile disorders, respectively., Conclusion and Inferences: Non-specific motility disorders were common in patients with EoE, but major motility disorders were rare. Further studies are needed to determine the relationship between eosinophilic infiltration and the clinical relevance of abnormal esophageal motility findings in this population., (© 2022 John Wiley & Sons Ltd.)

Introduction: Recognizing and sampling intramammary lymph nodes (IMLNs) is important in the clinical management of patients with breast carcinomas. We undertook a retrospective study to evaluate the clinical utility of fine-needle aspiration (FNA) in assessing IMLNs., Materials and Methods: Our pathology database was searched for all IMLN FNA cytology cases from January 2005 to December 2021. The cytologic findings, radiographic features, and clinical data were reviewed., Results: A total of 149 cases were identified. Eighteen of 149 (12%) patients had synchronous breast tumors, including 13 invasive ductal carcinomas (IDCs), 1 ductal carcinoma in situ (DCIS), and 4 fibroadenomas. Among patients with synchronous IDCs, FNA of IMLNs was positive for metastatic carcinoma in 4 of 13 (30.7%) cases. The 4 patients with positive IMLNs all received mastectomies. Fifteen of 149 (10.7%) patients had a prior history of breast tumors, including 9 IDCs, 4 DCISs, 1 lobular carcinoma in situ (LCIS), and 1 fibroadenoma. Two of 149 (1.3%) patients had a prior history of lymphoma. In the patients with prior history of IDC, DCIS, LCIS, lymphomas and fibroadenomas, IMLN FNAs were all negative for malignancy. Two of 149 cases (1.3%) showed granulomatous lymphadenitis. The remaining 112 cases had negative IMLN FNAs and no significant clinical or pathological findings., Conclusions: Our study showed that IMLNs are commonly associated with synchronous/metachronous breast tumors (33 of 149, 22.1%). The incidence of positive IMLN FNA in patients with synchronous invasive breast carcinoma was 30.7% (4 of 13). FNA of IMLNs in conjunction with clinical presentation and radiologic findings allows triage of patients for appropriate clinical management and avoids additional unnecessary surgical procedures., (Copyright © 2022 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Purpose: To ascertain the rates of 30-day readmissions and emergency department presentations among pediatric patients with an index admission for functional seizures., Method: A retrospective chart review of pediatric patients with an index discharge from the pediatric epilepsy monitoring unit (EMU) or general neurology service for functional seizures. Data collected included demographics, comorbidities, risk factors, and treatment during the index admission., Results: A total of one hundred and two patients were included, of which nearly one in five had a 30-day readmission or emergency department presentation. Index admission to the general neurology service was independently associated with more re-presentations to the hospital (t = 3.26, p < 0.0015). The univariate analysis indicated that cognitive impairment and autism were associated with a lower likelihood of readmission, while a neurology referral and being started on an anti-seizure medication were associated with a greater likelihood of readmission., Conclusion: A substantial proportion of pediatric patients with FS return to the hospital within 30 days of discharge. Our data suggest that patients admitted to the EMU service have a lower likelihood of readmission. We speculate that this may be due to differences in patient clinical characteristics as well as the comprehensiveness of the diagnostic evaluation and management in the EMU compared to the general neurology service., 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.)

There is increasing interest in asking patients questions before their visits to elicit goals and concerns, which is part of the move to support the concept of coproducing care. The phrasing and delivery of such questions differs across settings and is likely to influence responses. This report describes a study that (i) used a three-level model to categorize the goals and concerns elicited by two different pre-visit questions, and (ii) describes associations between responses elicited and the phrasing and delivery of the two questions. The questions were administered to patients with rheumatic disease, and patients with inflammatory bowel disease (IBD). Paper-based responses from 150 patients with rheumatic disease and 338 patients with IBD were analyzed (163 paper, 175 electronic). The goals and concerns elicited were primarily disease or symptom-specific. The specific goal and concern examples featured in one pre-visit question were more commonly reported in responses to that question, compared to the question without examples. Questions completed electronically before the visit were associated with longer responses than those completed on paper in the waiting room. In conclusion, how and when patients' goals and concerns are elicited appears to have an impact on responses and warrants further investigation.

Mutations in GABA A receptor subunit genes ( GABRs ) are a major etiology for developmental and epileptic encephalopathies (DEEs). This article reports a case of a genetic abnormality in GABRG2 and updates the pathophysiology and treatment development for mutations in DEEs based on recent advances. Mutations in GABRs , especially in GABRA1 , GABRB2 , GABRB3 , and GABRG2 , impair GABAergic signaling and are frequently associated with DEEs such as Dravet syndrome and Lennox-Gastaut syndrome, as GABAergic signaling is critical for early brain development. We here present a novel association of a microdeletion of GABRG2 with a diagnosed DEE phenotype. We characterized the clinical phenotype and underlying mechanisms, including molecular genetics, EEGs, and MRI. We then compiled an update of molecular mechanisms of GABR mutations, especially the mutations in GABRB3 and GABRG2 attributed to DEEs. Genetic therapy is also discussed as a new avenue for treatment of DEEs through employing antisense oligonucleotide techniques. There is an urgent need to define treatment targets and explore new treatment paradigms for the DEEs, as early deployment could alleviate long-term disabilities and improve quality of life for patients. This study highlights biomolecular targets for future therapeutic interventions, including via both pharmacological and genetic approaches.

Endolymphatic sac tumors are extremely rare, locally aggressive neoplasms that arise from the endolymphatic sac or duct, primarily in the intraosseous portion. These neoplasms show diverse histomorphological architectures and despite a bland cytologic appearance, can locally recur. Although the clinicopathological and radiological features of this entity are well characterized, the literature on cytological features is extremely sparse. Herein, we describe the cytological features of the endolymphatic sac tumors and discuss the relevant differential diagnoses., (© 2022 Wiley Periodicals LLC.)

CYP11A1 and CYP27A1 hydroxylate tachysterol 3 , a photoproduct of previtamin D 3 , producing 20S-hydroxytachysterol 3 [20S(OH)T 3 ] and 25(OH)T 3 , respectively. Both metabolites were detected in the human epidermis and serum. Tachysterol 3 was also detected in human serum at a concentration of 7.3 ± 2.5 ng/ml. 20S(OH)T 3 and 25(OH)T 3 inhibited the proliferation of epidermal keratinocytes and dermal fibroblasts and stimulated the expression of differentiation and anti-oxidative genes in keratinocytes in a similar manner to 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ]. They acted on the vitamin D receptor (VDR) as demonstrated by image flow cytometry and the translocation of VDR coupled GFP from the cytoplasm to the nucleus of melanoma cells, as well as by the stimulation of CYP24A1 expression. Functional studies using a human aryl hydrocarbon receptor (AhR) reporter assay system revealed marked activation of AhR by 20S(OH)T 3 , a smaller effect by 25(OH)T 3 , and a minimal effect for their precursor, tachysterol 3 . Tachysterol 3 hydroxyderivatives showed high-affinity binding to the ligan-binding domain (LBD) of the liver X receptor (LXR) α and β, and the peroxisome proliferator-activated receptor γ (PPARγ) in LanthaScreen TR-FRET coactivator assays. Molecular docking using crystal structures of the LBDs of VDR, AhR, LXRs, and PPARγ revealed high docking scores for 20S(OH)T 3 and 25(OH)T 3 , comparable to their natural ligands. The scores for the non-genomic-binding site of the VDR were very low indicating a lack of interaction with tachysterol 3 ligands. Our identification of endogenous production of 20S(OH)T 3 and 25(OH)T 3 that are biologically active and interact with VDR, AhR, LXRs, and PPARγ, provides a new understanding of the biological function of tachysterol 3 ., (© 2022 Federation of American Societies for Experimental Biology.)

The benefits of continuous electroencephalography (cEEG) monitoring in the intensive care unit (ICU) are increasingly appreciated, though expanding indications for cEEG may strain resources. The current standard of care in babies with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH) includes cEEG monitoring throughout the entire TH and rewarming process (at least 72 h). Recent cEEG data demonstrate that most seizures occur within the first 24 h of monitoring. We hypothesized that abnormal head imaging and EEG background could stratify seizure risk in babies with HIE undergoing TH to identify candidates for early cEEG discontinuation. In this retrospective review of 126 neonates undergoing TH and cEEG, we identified seizures in 38 (30%) neonates, 33 (87%) of whom seized within the first 24 h of cEEG monitoring. EEG background was graded and demonstrated that 90% of neonates with seizures had a moderately/markedly abnormal background versus 33% of neonates who did not seize (p < 0.0001). Additionally, while head ultrasound (HUS) obtained before EEG did not stratify seizure risk alone, no neonates with both a normal/mildly abnormal EEG background and a normal HUS (0/25) experienced seizures in contrast to 60% (24/40) neonates with both an abnormal EEG background and an abnormal HUS (p < 0.0001). Our data suggest that neonates with abnormal EEG backgrounds and abnormal HUS should be monitored for seizures throughout TH and rewarming, while neonates with normal/mildly abnormal EEG backgrounds and normal HUS are at low risk of seizures after 24 h of monitoring, and thus would be candidates for early cEEG discontinuation., 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: Epilepsy with myoclonic absences is a rare epilepsy syndrome with distinct features and high rates of drug resistance. Identifying this syndrome may help guide treatment decisions. We highlight clinical heterogeneity in this case series and two cases in which corpus callosotomy was performed., Methods: Medical records were reviewed between 2017 and 2021 to identify demographics, comorbidities, age at onset, EEG findings, diagnostic evaluations, seizure semiologies, seizure frequency, anti-seizure medications, diet therapy and surgical treatments in patients with myoclonic absences., Results: Ten patients were identified including twins with myoclonic absence status epilepticus. Forty percent had an atonic component, 20% presented with myoclonic absence status epilepticus and 60% had incomplete control of seizures at last follow-up visit. Two patients with epilepsy with myoclonic absences with atonia underwent corpus callosotomy; one patient was seizurefree eight months after surgery and the other had greater than 50% seizure reduction over a five-month period., Significance: Phenotypic heterogeneity was evident based on seizure semiologies, comorbidities, seizure frequency and response to anti-seizure medications and non-medication treatments. Of patients with an atonic component, 75% did not achieve seizure freedom with medication alone. Corpus callosotomy was performed in two of these patients with encouraging seizure response thus far, however, the efficacy of this treatment should be further evaluated in a larger study.

Background and Objectives: Functional connectivity (FC) measures can be used to differentiate epileptogenic zones (EZs) from non-EZs in patients with medically refractory epilepsy. Little work has been done to evaluate the stability of stereo-EEG (SEEG) FC measures over time and their relationship with antiseizure medication (ASM) use, a critical confounder in epilepsy FC studies. We aimed to answer the following questions: Are SEEG FC measures stable over time? Are they influenced by ASMs? Are they affected by patient data collection state?, Methods: In 32 patients with medically refractory focal epilepsy, we collected a single 2-minute prospective SEEG resting-state (awake, eyes closed) data set and consecutive 2-minute retrospective pseudo-rest (awake, eyes open) data sets for days 1-7 postimplantation. ASM dosages were recorded for days 1-7 postimplantation and drug load score (DLS) per day was calculated to standardize and compare across patients. FC was evaluated using directed and nondirected measures. Standard clinical interpretation of ictal SEEG was used to classify brain regions as EZs and non-EZs., Results: Over 7 days, presumed EZs consistently had higher FC than non-EZs when using between imaginary coherence (ImCoh) and partial directed coherence (PDC) inward strength, without accounting for DLS. These measures were demonstrated to be stable over a short-term period of 3 consecutive days with the same DLS. Between ImCoh FC differences between EZs and non-EZs were reduced with DLS decreases, whereas other measures were not affected by DLS. FC differences between EZs and non-EZs were seen during both resting-state and pseudo-rest conditions; ImCoh values were strongly correlated between the 2 conditions, whereas PDC values were not., Discussion: Inward and nondirected SEEG FC is higher in presumed EZs vs non-EZs and measures are stable over time. However, certain measures may be affected by ASM dose, as between ImCoh differences between EZs and non-EZs are less pronounced with lower doses, and other measures such as PDC are poorly correlated across recording conditions. These findings allow novel insight into how SEEG FC measures may aid surgical localization and how they are influenced by ASMs and other factors., (© 2022 American Academy of Neurology.)

New and more efficient routes of chemical synthesis of vitamin D 3 (D 3 ) hydroxy (OH) metabolites, including 20S(OH)D 3 , 20S,23S(OH) 2 D 3 and 20S,25(OH) 2 D 3 , that are endogenously produced in the human body by CYP11A1, and of 20S,23R(OH) 2 D 3 were established. The biological evaluation showed that these compounds exhibited similar properties to each other regarding inhibition of cell proliferation and induction of cell differentiation but with subtle and quantitative differences. They showed both overlapping and differential effects on T-cell immune activity. They also showed similar interactions with nuclear receptors with all secosteroids activating vitamin D, liver X, retinoic acid orphan and aryl hydrocarbon receptors in functional assays and also as indicated by molecular modeling. They functioned as substrates for CYP27B1 with enzymatic activity being the highest towards 20S,25(OH) 2 D 3 and the lowest towards 20S(OH)D 3 . In conclusion, defining new routes for large scale synthesis of endogenously produced D 3 -hydroxy derivatives by pathways initiated by CYP11A1 opens an exciting era to analyze their common and differential activities in vivo, particularly on the immune system and inflammatory diseases., (Copyright © 2022. Published by Elsevier Inc.)

"Guitar pick sign," also referred to as posterior globe tenting, is a radiological surrogate marker of tense orbit and profound vision loss. It is seen commonly in traumatic retrobulbar hemorrhage and carotico-cavernous fistula and less frequently in orbital cellulitis, subperiosteal abscess, and invasive fungal infections. We report a case series of Coronavirus disease-19-associated rhino-orbito-cerebral mucormycosis with guitar pick sign, of which none survived, and discuss the causative pathomechanisms, severity grade, and the clinical relevance of this unique radiological finding., Competing Interests: None

Objective: Drug-resistant epilepsy (DRE) occurs at higher rates in children <3 years old. Epilepsy surgery is effective, but rarely utilized in young children despite developmental benefits of early seizure freedom. The present study aims to identify unique patient characteristics and evaluation strategies in children <3 years old who undergo epilepsy surgery evaluation as a means to assess contributors and potential solutions to health care disparities in this group., Methods: The Pediatric Epilepsy Research Consortium Epilepsy Surgery Database, a multicentered, cross-sectional collaboration of 21 US pediatric epilepsy centers, collects prospective data on children <18 years of age referred for epilepsy surgery evaluation. We compared patient characteristics, diagnostic utilization, and surgical treatment between children <3 years old and those older undergoing initial presurgical evaluation. We evaluated patient characteristics leading to delayed referral (>1 year) after DRE diagnosis in the very young., Results: The cohort included 437 children, of whom 71 (16%) were <3 years of age at referral. Children evaluated before the age of 3 years more commonly had abnormal neurological examinations (p = .002) and daily seizures (p = .001). At least one ancillary test was used in 44% of evaluations. Fifty-nine percent were seizure-free following surgery (n = 34), with 35% undergoing limited focal resections. Children with delayed referrals more often had focal aware (p < .001) seizures and recommendation for palliative surgeries (p < .001)., Significance: There are relatively few studies of epilepsy surgery in the very young. Surgery is effective, but may be disproportionally offered to those with severe presentations. Relatively low utilization of ancillary testing may contribute to reduced surgical therapy for those without evident lesions on magnetic resonance imaging. Despite this, a sizeable portion of patients have favorable outcome after focal epilepsy surgery resections., (© 2021 International League Against Epilepsy.)

Background: The Caprini risk assessment model (RAM) stratifies surgical patients for prescription of post-discharge extended heparin prophylaxis to reduce post-operative venous thromboembolism (VTE) events. The average cost for treatment of a VTE event is $15,123. The 30-day post-operative VTE rate after benign esophageal procedures is < 0.8% per the Society of Thoracic Surgeons database. We hypothesized that the financial cost of selective extended prophylaxis in patients undergoing surgery for benign esophageal disease would exceed the cost of treating these rare events and therefore use of risk stratification for extended prophylaxis would not be beneficial., Methods: All patients undergoing operations for benign esophageal pathology from July 2014 to May 2019 were reviewed. Patients designated as moderate or high risk for VTE were prescribed a 10- or 30-day post-operative course of extended prophylaxis with low-molecular weight heparin (LMWH). VTE and adverse bleeding events were recorded for the 60-day post-operative period. The cost of LMWH was provided by the institution pharmacy., Results: Records from 154 patients were eligible for review. Caprini RAM was used for all patients with the following distribution of risk categories: low = 64.9% (100/154); moderate = 31.8% (49/154); and high = 3.2% (5/154). The average cost of extended prophylaxis at discharge for the moderate-risk group was $121.23, while the high-risk group was $446.46. There were no 60-day VTE or adverse bleeding events recorded., Conclusions: The majority of patients undergoing surgical therapy were at low risk of post-operative VTE event, with only 35% requiring extended VTE prophylaxis at time of discharge. When compared with the average cost of treatment for a VTE event, the cost of extended prophylaxis per patient in moderate or high-risk groups is substantially lower. In the era of cost-containment, risk stratification and extended prophylaxis may reduce healthcare costs and warrant future investigations., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

As awareness of pediatric epilepsy increases, accompanied by advancements in technology and research, it is important to identify certain types of patients that are overlooked for surgical management of epilepsy. Identifying these populations will allow us to study and elucidate the factors contributing to the underutilization and/or delayed application of surgical interventions. Demographically, African-American and Hispanic patients, as well as patients of certain Asian ethnicities, have relatively lower rates of undergoing epilepsy surgery than non-Hispanic and white patients. Among patients with epilepsy, those with higher odds of seizure-freedom following surgery are more likely to be referred for surgical evaluation by their neurologists, with the most common diagnosis being lesional focal epilepsy. However, patients with multifocal or generalized epilepsy, genetic etiologies, or normal (non-lesional) brain magnetic resonance imaging (MRI) are less likely be to referred for evaluation for resective surgery. With an increasing number of high-quality imaging modalities to help localize the epileptogenic zone as well as new techniques for both curative and palliative epilepsy surgery, there are very few populations of patients and/or types of epilepsy that should be precluded from evaluation to determine the suitability of epilepsy surgery. Ultimately, a clearer understanding of the populations who are underrepresented among those considered for epilepsy surgery, coupled with further study of the underlying reasons for this trend, will lead to less disparity in access to this critical treatment among patients with epilepsy., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Plasmodium falciparum parasites cause malaria and co-exist in humans together with B-cells for long periods of time. Immunity is only achieved after repeated exposure. There has been a lack of methods to mimic the in vivo co-occurrence, where cells and parasites can be grown together for many days, and it has been difficult with long time in vitro studies., Methods and Results: A new method for growing P. falciparum in 5% CO 2 with a specially formulated culture medium is described. This knowledge was used to establish the co-culture of live P. falciparum together with human B-cells in vitro for 10 days. The presence of B-cells clearly enhanced parasite growth, but less so when Transwell inserts were used (not allowing passage of cells or merozoites), showing that direct contact is advantageous. B-cells also proliferated more in presence of parasites. Symbiotic parasitic growth was verified using CESS cell-line and it showed similar results, indicating that B-cells are indeed the cells responsible for the effect. In malaria endemic areas, people often have increased levels of atypical memory B-cells in the blood, and in this assay it was demonstrated that when parasites were present there was an increase in the proportion of CD19 + CD20 + CD27 - FCRL4 + B-cells, and a contraction of classical memory B-cells. This effect was most clearly seen when direct contact between B-cells and parasites was allowed., Conclusions: These results demonstrate that P. falciparum and B-cells undoubtedly can affect each other when allowed to multiply together, which is valuable information for future vaccine studies.

Background: A standardized treatment algorithm for sternoclavicular joint infection management is lacking in the literature. While major risk factors for sternoclavicular joint infection, including immunosuppression, rheumatoid arthritis, type 2 diabetes, indwelling catheters, and intravenous drug use have been identified, clear association with treatment outcome has not been established. As our safety net hospital treats a patient population with high incidence of intravenous drug use, we sought to identify risk factors associated with failure of non-operative management of sternoclavicular joint infection., Methods: We conducted a retrospective cohort study, reviewing charts of patients diagnosed with sternoclavicular joint infection between January 2001 and December 2017 to collect demographic information as well as clinical risk factors and treatment patterns. A chi-square test was performed to determine any association between clinical variables and management, as well as relation to treatment outcome., Results: The study cohort consisted of 35 patients with diagnosis of sternoclavicular joint infection and complete follow-up. Intravenous drug use was prevalent, seen in 45.6% (16/35) of subjects, though there was no association with failure of non-operative management (P=0.50). Operative management was the initial treatment for 25.7% (9/35) of subjects and was associated with abscess on presentation (P=0.03). Failure of non-operative management was seen in 26.9% (7/26). Type 2 diabetes was associated with failed initial non-operative management, present in 42.9% (3/7) of patients (P=0.03) experiencing failure., Conclusions: This study constitutes the largest series of sternoclavicular joint infection with intravenous drug use. While intravenous drug use was not associated with failure of non-operative management, we observed that type 2 diabetes is associated with failure of non-operative management and could be considered in determining management of sternoclavicular joint infection patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-1897). The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Merkel cell carcinoma (MCC) is a rare aggressive form of skin cancer originating in neuroendocrine cells. The antiprogrammed death ligand 1 (PD-L1) monoclonal antibody (mAb) avelumab has been approved for treatment of MCC, but options are limited, should it be ineffective as a monotherapy. Combined therapy with low/moderate dose nab-paclitaxel and an interleukin 15 (IL-15)-based therapeutic such as the IL-15 'superagonist' N-803 may increase response by activation of the immune system. The case of a 71-year-old man diagnosed with MCC who achieved and maintained a complete response (CR) by treatment with the anti-PD-L1 mAb avelumab in combination with IL-15 superagonist N-803 and nab-paclitaxel (Abraxane) is presented. Avelumab treatment alone resulted in a response in a para-aortic lesion, but not the other tumor masses. N-803 was added, followed by nab-paclitaxel; CT showed a decrease in the size of the abdominal mass at 1 month, near resolution at 3 months and CR at 5 months. Abraxane was discontinued after the first CR on CT, and the patient continues on avelumab/N-803 treatment and maintains a CR. Combination of avelumab with low/moderate-dose chemotherapy and an immune enhancer such as N-803 may offer a viable treatment option for MCC patients for whom avelumab therapy alone was not effective., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: More than 2 months separated the initial description of SARS-CoV-2 and discovery of its widespread dissemination in the United States. Despite this lengthy interval, implementation of specific quantitative reverse transcription (qRT)-PCR-based SARS-CoV-2 tests in the US has been slow, and testing is still not widely available. Metagenomic sequencing offers the promise of unbiased detection of emerging pathogens, without requiring prior knowledge of the identity of the responsible agent or its genomic sequence., Methods: To evaluate metagenomic approaches in the context of the current SARS-CoV-2 epidemic, laboratory-confirmed positive and negative samples from Seattle, WA were evaluated by metagenomic sequencing, with comparison to a 2019 reference genomic database created before the emergence of SARS-CoV-2., Results: Within 36 h our results showed clear identification of a novel human Betacoronavirus, closely related to known Betacoronaviruses of bats, in laboratory-proven cases of SARS-CoV-2. A subset of samples also showed superinfection or colonization with human parainfluenza virus 3 or Moraxella species, highlighting the need to test directly for SARS-CoV-2 as opposed to ruling out an infection using a viral respiratory panel. Samples negative for SARS-CoV-2 by RT-PCR were also negative by metagenomic analysis, and positive for Rhinovirus A and C. Unlike targeted SARS-CoV-2 qRT-PCR testing, metagenomic analysis of these SARS-CoV-2 negative samples identified candidate etiological agents for the patients' respiratory symptoms., Conclusion: Taken together, these results demonstrate the value of metagenomic analysis in the monitoring and response to this and future viral pandemics., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)