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Objective: This study was undertaken to estimate incidence of rare epilepsies and compare with literature. Methods: We used electronic health record text search to identify children with 28 rare epilepsies in New York City (2010–2014). We estimated cumulative incidence and compared with literature. Results: Eight of 28 rare epilepsies had five or more prior estimates, and our measurements were within the published range for all. The most common were infantile epileptic spasms syndrome (1 in 2920 live births), Lennox–Gastaut syndrome (1 in 9690), and seizures associated with tuberous sclerosis complex (1 in 14 300). Fifteen of 28 had fewer than five prior estimates, and of these, we provided additional estimates for early infantile developmental and epileptic encephalopathy (1 in 32 700), epilepsy with myoclonic–atonic seizures (1 in 34 100), Sturge–Weber syndrome plus seizures/epilepsy (1 in 40 900), epilepsy in infancy with migrating focal seizures (1 in 54 500), Aicardi syndrome plus seizures/epilepsy (1 in 71 600), hypothalamic hamartoma with seizures (1 in 225 000), and Rasmussen syndrome (1 in 450 000). Five of 28 rare epilepsies had no prior estimates, and of these, we provided a new estimate for developmental/epileptic encephalopathy with spike‐and‐wave activation in sleep and/or continuous spikes and waves during sleep (1 in 34 100). Data were limited for the remaining 12 rare epilepsies, which were all genetic epilepsies, including PCDH19, CDKL5, Alpers disease, SCN8A, KCNQ2, SCN2A, GLUT1 deficiency, Phelan‐McDermid syndrome, myoclonic epilepsy with ragged‐red fibers, dup15q syndrome, ring chromosome 14, and ring chromosome 20. Significance: We estimated the incidence of rare epilepsies using population‐based electronic health record data and literature review. More research is needed to better estimate the incidence of genetic epilepsies with nonspecific clinical features. Electronic health records may be a valuable data source for studying rare epilepsies and other rare diseases, particularly as genetic testing becomes more widely adopted. [ABSTRACT FROM AUTHOR]

The escalating use of digital technologies has spotlighted the crucial role of cybersecurity in safeguarding sensitive information within companies. This study explores the relationship between a firm's major customers and its cybersecurity awareness. Drawing on SEC‐mandated disclosures, we employ four proxies to measure changes in customer‐supplier relationships. Our findings reveal that customers increase their purchases from suppliers whose cybersecurity awareness scores improve. Additionally, we examine the interplay between customers and suppliers more susceptible to nonpublic adverse news, particularly during cyber events. The study emphasizes the importance of cybersecurity disclosure for regulators, supply chain partners, and corporate management. It also contributes to the literature on factors influencing the duration of customer‐supplier relationships and underscores the significance of supplier characteristics. "Understanding and disclosing cybersecurity risks are" paramount in an increasingly digital business landscape. [ABSTRACT FROM AUTHOR]

Background: Intravenous dihydroergotamine (DHE) has well‐established efficacy for the acute treatment of migraine, but its use is limited by the need for in‐hospital administration and the nausea/vomiting associated with a high maximum plasma concentration (Cmax). Inhalation is an alternative to intravenous dosing. The surface area of the lung allows for rapid absorption of a self‐administered dose. Objective: This study evaluated the safety, tolerability, and systemic pharmacokinetics (PK) of a dry powder formulation (PUR3100) DHE when delivered via inhalation compared to intravenous delivery. Method s : In this double‐blind, double‐dummy Phase 1 study, healthy volunteers (N = 26) were randomized (1:1:1:1) to one of four groups: orally inhaled placebo plus intravenous DHE 1.0 mg or orally inhaled PUR3100 (0.5, 1.0, or 1.5 mg) plus intravenous placebo. Blood samples were drawn pre‐dose and at time points post‐dose over 48 h. Standard PK and safety parameters were assessed and values for Cmax and area under plasma concentration time curve (AUC) were used to assess comparative exposures of PUR3100 versus intravenous DHE. Results: All doses of PUR3100 were associated with a lower incidence of nausea (21% vs. 86%), vomiting (0% vs. 29%), and headache (16% vs. 57%) compared to intravenous DHE. The PK profile of PUR3100 versus intravenous DHE was characterized by a similar mean time to Cmax (5 vs. 5.5 min), with reduced AUC0–2h (1120–4320 vs. 6340), and a lower Cmax (3620–14,400 vs. 45,000). Compared to intravenous DHE 1.0 mg, the highest nominal PUR3100 dose (1.5 mg), which delivers a fine‐particle dose of approximately 0.9 mg to the lungs, had a geometric mean ratio percentage (90% confidence interval [CI]) for Cmax of 32% [17.2, 59.6] and AUC0–inf of 93% (62.9, 138.5), the latter of which was not significantly different. Conclusions: Inhaled PUR3100 is associated with rapid systemic PK within the therapeutic window and an improved safety profile relative to intravenous DHE. Plain Language Summary: Intravenous dihydroergotamine (DHE) works for the acute treatment of migraine; however, it must be given in a hospital or clinic and has side‐effects including nausea and vomiting. A dry powder formulation of DHE (PUR3100) delivered by oral inhalation had fewer side‐effects than intravenous DHE in healthy volunteers. The pharmacokinetics (the amount of the study drug in blood) showed that inhaled PUR3100 was associated with rapid absorption of DHE into the blood within the desired range associated with pain relief. [ABSTRACT FROM AUTHOR]

The learning speed of feed-forward neural networks is notoriously slow and has presented a bottleneck in deep learning applications for several decades. For instance, gradient-based learning algorithms, which are used extensively to train neural networks, tend to work slowly when all of the network parameters must be iteratively tuned. To counter this, both researchers and practitioners have tried introducing randomness to reduce the learning requirement. Based on the original construction of Igelnik and Pao, single layer neural-networks with random input-to-hidden layer weights and biases have seen success in practice, but the necessary theoretical justification is lacking. In this study, we begin to fill this theoretical gap. We then extend this result to the non-asymptotic setting using a concentration inequality for Monte-Carlo integral approximations. We provide a (corrected) rigorous proof that the Igelnik and Pao construction is a universal approximator for continuous functions on compact domains, with approximation error squared decaying asymptotically like O(1/n) for the number n of network nodes. We then extend this result to the non-asymptotic setting, proving that one can achieve any desired approximation error with high probability provided n is sufficiently large. We further adapt this randomized neural network architecture to approximate functions on smooth, compact submanifolds of Euclidean space, providing theoretical guarantees in both the asymptotic and non-asymptotic forms. Finally, we illustrate our results on manifolds with numerical experiments. [ABSTRACT FROM AUTHOR]

Objective: Absence seizures result from aberrant thalamocortical processing that confers synchronous, bilateral spike-and-wave discharges (SWDs) and behavioral arrest. Previous work has demonstrated that SWDs can result from enhanced thalamic tonic inhibition, consistent with the mechanism of first-line antiabsence drugs that target thalamic low-voltage-activated calcium channels. However, nearly half of patients with absence epilepsy are unresponsive to first-line medications. In this study we evaluated the role of cortical tonic inhibition and its manipulation on absence seizure expression. Methods: We used video-electroencephalogram (EEG) monitoring to show that mice with a γ-aminobutyric acid type A (GABAA) receptor mutation (γ2R43Q) display absence seizures. Voltage-clamp recordings in brain slices from wild type and γ2R43Q mice were used to evaluate the amount of tonic inhibition and its selective pharmacological modulation. Finally, we determined whether modulating tonic inhibition controls seizure expression. Results: γ2R43Q mice completely lack tonic inhibition in principal neurons of both layer 2/3 cortex and ventrobasal thalamus. Blocking cortical tonic inhibition in wild type mice is sufficient to elicit SWDs. Tonic inhibition in slices from γ2R43Q mice could be rescued in a dose-dependent fashion by the synthetic neurosteroid ganaxolone. Low-dose ganaxolone suppressed seizures in γ2R43Q mice. Conclusions: Our data suggest that reduced cortical tonic inhibition promotes absence seizures and that normal function can be restored via selective pharmacological rescue. These results, together with previous findings, suggest that deviations of tonic inhibition either above or below an optimal set point can contribute to absence epilepsy. Returning the thalamocortical system to this set point may provide a novel treatment for refractory absence epilepsy. [ABSTRACT FROM AUTHOR]

Objective: Administrative codes to identify people with rare epilepsies in electronic health records are limited. The current study evaluated the use of keyword search as an alternative method for rare epilepsy cohort creation using electronic health records data. Methods: Data included clinical notes from encounters with International Classification of Diseases, Ninth Revision (ICD‐9) codes for seizures, epilepsy, and/or convulsions during 2010–2014, across six health care systems in New York City. We identified cases with rare epilepsies by searching clinical notes for keywords associated with 33 rare epilepsies. We validated cases via manual chart review. We compared the performance of keyword search to manual chart review using positive predictive value (PPV), sensitivity, and F‐score. We selected an initial combination of keywords using the highest F‐scores. Results: Data included clinical notes from 77 924 cases with ICD‐9 codes for seizures, epilepsy, and/or convulsions. The all‐keyword search method identified 6095 candidates, and manual chart review confirmed that 2068 (34%) had a rare epilepsy. The initial combination method identified 1862 cases with a rare epilepsy, and this method performed as follows: PPV median =.64 (interquartile range [IQR] =.50–.81, range =.20–1.00), sensitivity median =.93 (IQR =.76–1.00, range =.10–1.00), and F‐score median =.71 (IQR =.63–.85, range =.18–1.00). Using this method, we identified four cohorts of rare epilepsies with over 100 individuals, including infantile spasms, Lennox–Gastaut syndrome, Rett syndrome, and tuberous sclerosis complex. We identified over 50 individuals with two rare epilepsies that do not have specific ICD‐10 codes for cohort creation (epilepsy with myoclonic atonic seizures, Sturge–Weber syndrome). Significance: Keyword search is an effective method for cohort creation. These findings can improve identification and surveillance of individuals with rare epilepsies and promote their referral to specialty clinics, clinical research, and support groups. [ABSTRACT FROM AUTHOR]

A recent report postulated that the mast cell population is a significant reservoir for persistent HIV infection. Our study attempted to validate this hypothesis by quantitatively comparing the distribution of mast cells and cells expressing the HIV protein p24 in HIV infected patients. Consecutive sections of paraffin-embedded human tissues from various tissue sites were subjected to immunohistochemistry with monoclonal antibodies to mast cell tryptase, viral protein p24, and other molecules. The sub-cellular distribution of these molecules was examined, to determine whether immunoreactivities to these molecules would be co-localized within the same cells. Our study revealed that, in two immediate adjacent sections immunostained for mast cell tryptase and p24, respectively, all or nearly all tryptase and p24 expressing cells were distributed at different areas. In the single section double immunostained for mast cell tryptase and p24, 5 (1.1%) of 460 large p24 expressing cell clusters encountered showed a single or few mast cells within or adjacent to p24 expressing cell clusters, but no distinct co-localization of these two proteins was observed. Similarly, no distinct co-localization was observed in any of over 500 isolated individual mast cells and p24 expressing cells. In contrast, macrophages were consistently intermixed with or adjacent to p24 expressing cells, and p24 immunostaining were seen in the cytoplasm of a subset of macrophages. These findings suggest that tissue mast cells do not show evidence for active virus replication by the techniques employed.

The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries., Introduction The mature CNS is among tissues most refractory to healing after injury. In contrast to neuronal genesis in the fetal CNS, regeneration of axons in the adult brain and [...]

Medulloblastoma is a cerebellar tumor that can arise through aberrant activation of Sonic hedgehog (Shh) signaling, which normally regulates cerebellar granule cell proliferation. Mutations of the Shh receptor PATCHED (PTCH) are associated with medulloblastomas, which have not been found to have loss of PTCH heterozygosity. We address whether patched (Ptc) heterozygosity fundamentally alters granule cell differentiation and contributes to tumorigenesis by increasing proliferation and/or decreasing apoptosis in Ptc mice. Our data show that postnatal Ptc mouse granule cell precursor growth is not globally altered. However, many older Ptc mice display abnormal cerebellar regions containing persistently proliferating granule cell precursors. Since fewer Ptc mice form medulloblastomas, these granule cell rests represent a developmentally disrupted, but uncommitted stage of tumorigenesis. Although Ptc mouse medulloblastomas express neurodevelopmental genes, they diverge from granule cell differentiation in their discordant coexpression of postmitotic markers despite their ongoing growth. Like human medulloblastomas, mouse tumors with reduced levels of the neurotrophin-3 receptor, trkC/Ntrk3, display decreased apoptosis in vivo, illustrating the role of TrkC in regulating tumor cell survival. These results indicate that Ptc heterozygosity contributes to tumorigenesis by predisposing a subset of granule cell precursors to the formation of proliferative rests and subsequent dysregulation of developmental gene expression. Keywords: Apoptosis; Cerebellum; Granule cell; Medulloblastoma; Mouse; patched; Proliferation; trkC