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The subspecialty of Experimental Neurotherapeutics trains neurologists in discovering and developing new treatments for neurologic diseases. Based on development of exciting new treatments for genetic and inflammatory diseases, we predict that there will be many other breakthroughs. The job market has expanded rapidly in academia, the pharmaceutical industry, government, and not-for-profit sectors; many new opportunities can be anticipated. The burgeoning opportunities in the field mandate that training address the challenges of overcoming obstacles in therapeutic discovery, implementation science, and development of affordable and equitably available treatments. This article is protected by copyright. All rights reserved.

BACKGROUND AND OBJECTIVES: Seizures (SZs) and other SZ-like patterns of brain activity can harm the brain and contribute to in-hospital death, particularly when prolonged. However, experts qualified to interpret EEG data are scarce. Prior attempts to automate this task have been limited by small or inadequately labeled samples and have not convincingly demonstrated generalizable expert-level performance. There exists a critical unmet need for an automated method to classify SZs and other SZ-like events with expert-level reliability. This study was conducted to develop and validate a computer algorithm that matches the reliability and accuracy of experts in identifying SZs and SZ-like events, known as “ictal-interictal-injury continuum” (IIIC) patterns on EEG, including SZs, lateralized and generalized periodic discharges (LPD, GPD), and lateralized and generalized rhythmic delta activity (LRDA, GRDA), and in differentiating these patterns from non-IIIC patterns. METHODS: We used 6,095 scalp EEGs from 2,711 patients with and without IIIC events to train a deep neural network, SPaRCNet, to perform IIIC event classification. Independent training and test data sets were generated from 50,697 EEG segments, independently annotated by 20 fellowship-trained neurophysiologists. We assessed whether SPaRCNet performs at or above the sensitivity, specificity, precision, and calibration of fellowship-trained neurophysiologists for identifying IIIC events. Statistical performance was assessed by the calibration index and by the percentage of experts whose operating points were below the model's receiver operating characteristic curves (ROCs) and precision recall curves (PRCs) for the 6 pattern classes. RESULTS: SPaRCNet matches or exceeds most experts in classifying IIIC events based on both calibration and discrimination metrics. For SZ, LPD, GPD, LRDA, GRDA, and “other” classes, SPaRCNet exceeds the following percentages of 20 experts—ROC: 45%, 20%, 50%, 75%, 55%, and 40%; PRC: 50%, 35%, 50%, 90%, 70%, and 45%; and calibration: 95%, 100%, 95%, 100%, 100%, and 80%, respectively. DISCUSSION: SPaRCNet is the first algorithm to match expert performance in detecting SZs and other SZ-like events in a representative sample of EEGs. With further development, SPaRCNet may thus be a valuable tool for an expedited review of EEGs. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with epilepsy or critical illness undergoing EEG monitoring, SPaRCNet can differentiate (IIIC) patterns from non-IIIC events and expert neurophysiologists.

Temporal lobe epilepsy (TLE) is one of the most common causes of medically refractory focal epilepsy. Anterior temporal lobectomy (ATL) leads to improved seizure control in patients with medically refractory TLE. Various auras are associated with TLE; however, the relationships between aura type and outcome after ATL are poorly understood. Our objective was to investigate the associations among clinical features, aura type, and seizure outcome after ATL.The records of patients who underwent ATL between 1993 and 2016 at a single institution (N = 174) were retrospectively reviewed. Demographic and clinical variables were compared among aura types using analysis of variance and logistic regression analysis. A multiple regression analysis was conducted to determine whether aura type predicted seizure outcome after ATL.Mesial temporal sclerosis (MTS) on magnetic resonance imaging inversely correlated with cephalic auras (P = 0.0090). Affective auras (P = 0.014) and somatosensory auras (P = 0.021) were correlated with findings of MTS on pathology, whereas this finding was inversely correlated with the presence of auditory auras (P = 0.0056). On multiple regression analysis, predictors of worse seizure outcome after ATL were cephalic auras (P = 0.0048), gustatory auras (P = 0.029), visual auras (P = 0.049), and tonic-clonic seizures (P = 0.047). Fewer preoperative antiepileptic medications (P = 0.0032), and presence of multiple auras (P = 0.011) were associated with better outcome.Cephalic auras, gustatory auras, and visual auras were associated with worse seizure outcome after ATL.

A Man with Altered Mental Status and New Onset of Seizures A 38-year-old man was evaluated in the emergency department because of altered mental status and a first seizure. Examination revealed an ...

Background and ObjectivesTo explore efficacy/safety of natalizumab, a humanized monoclonal anti–α4-integrin antibody, as adjunctive therapy in adults with drug-resistant focal epilepsy.MethodsParticipants with ≥6 seizures during the 6-week baseline period were randomized 1:1 to receive natalizumab 300 mg IV or placebo every 4 weeks for 24 weeks. Primary efficacy outcome was change from baseline in log-transformed seizure frequency, with a predefined threshold for therapeutic success of 31% relative reduction in seizure frequency over the placebo group. Countable seizure types were focal aware with motor signs, focal impaired awareness, and focal to bilateral tonic-clonic. Secondary efficacy endpoints/safety were also assessed.ResultsOf 32 and 34 participants dosed in the natalizumab 300 mg and placebo groups, 30 (94%) and 31 (91%) completed the placebo-controlled treatment period, respectively (one participant was randomized to receive natalizumab but not dosed due to IV complications). Estimated relative change in seizure frequency of natalizumab over placebo was −14.4% (95% confidence interval [CI] –46.1%–36.1%; p = 0.51). The proportion of participants with ≥50% reduction from baseline in seizure frequency was 31.3% for natalizumab and 17.6% for placebo (odds ratio 2.09, 95% CI 0.64–6.85; p = 0.22). Adverse events were reported in 24 (75%) and 22 (65%) participants receiving natalizumab vs placebo.DiscussionAlthough the threshold to demonstrate efficacy was not met, there were no unexpected safety findings and further exploration of possible anti-inflammatory therapies for drug-resistant epilepsy is warranted.Trial Registration InformationThe ClinicalTrials.gov registration number is NCT03283371.Classification of EvidenceThis study provides Class I evidence that IV natalizumab every 4 weeks, compared to placebo, did not significantly change seizure frequency in adults with drug-resistant epilepsy. The study lacked the precision to exclude an important effect of natalizumab.

This study was undertaken to determine the dose-response relation between epileptiform activity burden and outcomes in acutely ill patients.A single center retrospective analysis was made of 1,967 neurologic, medical, and surgical patients who underwent16 hours of continuous electroencephalography (EEG) between 2011 and 2017. We developed an artificial intelligence algorithm to annotate 11.02 terabytes of EEG and quantify epileptiform activity burden within 72 hours of recording. We evaluated burden (1) in the first 24 hours of recording, (2) in the 12-hours epoch with highest burden (peak burden), and (3) cumulatively through the first 72 hours of monitoring. Machine learning was applied to estimate the effect of epileptiform burden on outcome. Outcome measure was discharge modified Rankin Scale, dichotomized as good (0-4) versus poor (5-6).Peak epileptiform burden was independently associated with poor outcomes (p 0.0001). Other independent associations included age, Acute Physiology and Chronic Health Evaluation II score, seizure on presentation, and diagnosis of hypoxic-ischemic encephalopathy. Model calibration error was calculated across 3 strata based on the time interval between last EEG measurement (up to 72 hours of monitoring) and discharge: (1) 5 days between last measurement and discharge, 0.0941 (95% confidence interval [CI] = 0.0706-0.1191); 5 to 10 days between last measurement and discharge, 0.0946 (95% CI = 0.0631-0.1290);10 days between last measurement and discharge, 0.0998 (95% CI = 0.0698-0.1335). After adjusting for covariates, increase in peak epileptiform activity burden from 0 to 100% increased the probability of poor outcome by 35%.Automated measurement of peak epileptiform activity burden affords a convenient, consistent, and quantifiable target for future multicenter randomized trials investigating whether suppressing epileptiform activity improves outcomes. ANN NEUROL 2021;90:300-311.

No clear evidence‐based treatment paradigm currently exists for refractory and super‐refractory status epilepticus, which can result in significant mortality and morbidity. While patients are typically treated with antiepileptic drugs and anesthetics, neurosurgical neuromodulation techniques can also be considered. We present a novel case in which responsive neurostimulation was used to effectively treat a patient who had developed super‐refractory status epilepticus, later consistent with epilepsia partialis continua, that was refractory to antiepileptic drugs, immunomodulatory therapies, and transcranial magnetic stimulation. This case demonstrates how regional therapy provided by responsive neurostimulation can be effective in treating super‐refractory status epilepticus through neuromodulation of seizure networks.

BACKGROUND AND OBJECTIVES: The validity of brain monitoring using electroencephalography (EEG), particularly to guide care in patients with acute or critical illness, requires that experts can reliably identify seizures and other potentially harmful rhythmic and periodic brain activity, collectively referred to as “ictal-interictal-injury continuum” (IIIC). Previous interrater reliability (IRR) studies are limited by small samples and selection bias. This study was conducted to assess the reliability of experts in identifying IIIC. METHODS: This prospective analysis included 30 experts with subspecialty clinical neurophysiology training from 18 institutions. Experts independently scored varying numbers of ten-second EEG segments as “seizure (SZ),” “lateralized periodic discharges (LPDs),” “generalized periodic discharges (GPDs),” “lateralized rhythmic delta activity (LRDA),” “generalized rhythmic delta activity (GRDA),” or “other.” EEGs were performed for clinical indications at Massachusetts General Hospital between 2006 and 2020. Primary outcome measures were pairwise IRR (average percent agreement [PA] between pairs of experts) and majority IRR (average PA with group consensus) for each class and beyond chance agreement (κ). Secondary outcomes were calibration of expert scoring to group consensus, and latent trait analysis to investigate contributions of bias and noise to scoring variability. RESULTS: Among 2,711 EEGs, 49% were from women, and the median (IQR) age was 55 (41) years. In total, experts scored 50,697 EEG segments; the median [range] number scored by each expert was 6,287.5 [1,002, 45,267]. Overall pairwise IRR was moderate (PA 52%, κ 42%), and majority IRR was substantial (PA 65%, κ 61%). Noise-bias analysis demonstrated that a single underlying receiver operating curve can account for most variation in experts' false-positive vs true-positive characteristics (median [range] of variance explained ([Image: see text]): 95 [93, 98]%) and for most variation in experts' precision vs sensitivity characteristics ([Image: see text]: 75 [59, 89]%). Thus, variation between experts is mostly attributable not to differences in expertise but rather to variation in decision thresholds. DISCUSSION: Our results provide precise estimates of expert reliability from a large and diverse sample and a parsimonious theory to explain the origin of disagreements between experts. The results also establish a standard for how well an automated IIIC classifier must perform to match experts. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that an independent expert review reliably identifies ictal-interictal injury continuum patterns on EEG compared with expert consensus.

We sought to investigate electroencephalographers’ real-world behaviors and opinions concerning reading routine EEG (rEEG) with or without clinical information. An eight-question, anonymous, online survey targeted at electroencephalographers was disseminated on social media from the authors’ personal accounts and emailed to authors’ select colleagues. A total of 389 responses were included. Most respondents reported examining clinical information before describing rEEG findings. Nonetheless, only a minority of respondents believe that EEG analysis/description should be influenced by clinical information. We recommend reviewing clinical data only after an unbiased EEG read to prevent history bias and ensure generation of reliable electrodiagnostic information.

ObjectiveTo examine the relationship between scalp EEG biomarkers of hyperexcitability in Alzheimer disease (AD) and to determine how these electric biomarkers relate to the clinical expression of seizures in AD.MethodsIn this cross-sectional study, we performed 24-hour ambulatory scalp EEGs on 43 cognitively normal elderly healthy controls (HC), 41 participants with early-stage AD with no history or risk factors for epilepsy (AD-NoEp), and 15 participants with early-stage AD with late-onset epilepsy related to AD (AD-Ep). Two epileptologists blinded to diagnosis visually reviewed all EEGs and annotated all potential epileptiform abnormalities. A panel of 9 epileptologists blinded to diagnosis was then surveyed to generate a consensus interpretation of epileptiform abnormalities in each EEG.ResultsEpileptiform abnormalities were seen in 53% of AD-Ep, 22% of AD-NoEp, and 4.7% of HC. Specific features of epileptiform discharges, including high frequency, robust morphology, right temporal location, and occurrence during wakefulness and REM, were associated with clinical seizures in AD. Multiple EEG biomarkers concordantly demonstrated a pattern of left temporal lobe hyperexcitability in early stages of AD, whereas clinical seizures in AD were often associated with bitemporal hyperexcitability. Frequent small sharp spikes were specifically associated with epileptiform EEGs and thus identified as a potential biomarker of hyperexcitability in AD.ConclusionEpileptiform abnormalities are common in AD but not all equivalent. Specific features of epileptiform discharges are associated with clinical seizures in AD. Given the difficulty recognizing clinical seizures in AD, these EEG features could provide guidance on which patients with AD are at high risk for clinical seizures.

Algal bioremediation can significantly improve the quality of wastewater by assimilating nutrients. However, the efficiency and stability of this approach depends on identifying suitable algae based on their biomass productivity and ability to outcompete less desirable algae. Here, we compare the productivity and competitive ability of three taxa of filamentous macroalgae under the seasonal light and temperature conditions experienced in temperate environments, including extremes of heat and cold. Specific growth rate was greatest for the tropical isolate of Oedogonium under summer conditions (36–40%; P 90% for both) and, in its absence, Hyalotheca also dominate over Oedogonium. Our results suggest that rather than finding an optimal taxon for all four seasons, the best decision for maximising stable biomass production will require either seasonal rotation of algae, or bi-cultures of the most dominant ones. Further, prioritising competition over production when selecting freshwater algae for wastewater bioremediation is likely to prove the most successful strategy.

Background Uncertain validity of epilepsy diagnoses within health insurance claims and other large datasets have hindered efforts to study and monitor care at the population level. Objectives To develop and validate prediction models using longitudinal Medicare administrative data to identify patients with actual epilepsy among those with the diagnosis. Research design, subjects, measures We used linked electronic health records and Medicare administrative data including claims to predict epilepsy status. A neurologist reviewed electronic health record data to assess epilepsy status in a stratified random sample of Medicare beneficiaries aged 65+ years between January 2012 and December 2014. We then reconstructed the full sample using inverse probability sampling weights. We developed prediction models using longitudinal Medicare data, then in a separate sample evaluated the predictive performance of each model, for example, area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity. Results Of 20,945 patients in the reconstructed sample, 2.1% had confirmed epilepsy. The best-performing prediction model to identify prevalent epilepsy required epilepsy diagnoses with multiple claims at least 60 days apart, and epilepsy-specific drug claims: AUROC=0.93 [95% confidence interval (CI), 0.90-0.96], and with an 80% diagnostic threshold, sensitivity=87.8% (95% CI, 80.4%-93.2%), specificity=98.4% (95% CI, 98.2%-98.5%). A similar model also performed well in predicting incident epilepsy (k=0.79; 95% CI, 0.66-0.92). Conclusions Prediction models using longitudinal Medicare data perform well in predicting incident and prevalent epilepsy status accurately.

Greenhouse gas emissions are a global problem facing the dairy/beef industry. Novel feed additives consisting of seaweeds and hemp containing bioactive compounds are theorized to reduce enteric methane emissions. In this study we aimed to investigate the metabolic profiles of brown, red and green seaweeds and hemp using gas chromatography and liquid chromatography mass spectrometry. We used targeted and untargeted approaches, quantifying known halomethanes and phenolics, as well as identifying potentially novel bioactive compounds with anti-methanogenic properties. The main findings were: (a) Asparagopsis taxiformis contained halomethanes, with high concentrations of bromoform (4200 µg/g DW), six volatile halocarbons were tentatively identified; (b) no halomethanes were detected in the other studied seaweeds nor in hemp; (c) high concentrations of lignans were measured in hemp; (d) a high numbers of sulfated phenolic acids and unidentified sulfuric acid-containing compounds were detected in all seaweeds; (e) flavonoid glucosides and glucuronides were mainly identified in hemp; and (f) the condensed tannin gallocatechin was tentatively identified in Fucus sp. Using the combined metabolomics approach, an overview and in-depth information on secondary metabolites were provided. Halomethanes of Asparagopsis sp. have already been shown to be anti-methanogenic; however, metabolic profiles of seaweeds such as Dictyota and Sargassum have also been shown to contain compounds that may have anti-methanogenic potential.

The relationship between COVID-19 severity and viral load is unknown. Our objective was to assess the association between viral load and disease severity in COVID-19. In this single center observational study of adults with laboratory confirmed SARS-CoV-2, the first positive in-hospital nasopharyngeal swab was used to calculate the log10 copies/ml [log10 copy number (CN)] of SARS-CoV-2. Four categories based on level of care and modified sequential organ failure assessment score (mSOFA) at time of swab were determined. Median log10CN was compared between different levels of care and mSOFA quartiles. Median log10CN was compared in patients who did and did not receive influenza vaccine, and the correlation between log10CN and D-dimer was examined. We found that of 396 patients, 54.3% were male, and 25% had no major comorbidity. Hospital mortality was 15.7%. Median mSOFA was 2 (IQR 0–3). Median log10CN was 5.5 (IQR 3.3–8.0). Median log10CN was highest in non-intubated ICU patients [6.4 (IQR 4.4–8.1)] and lowest in intubated ICU patients [3.6 (IQR 2.6–6.9)] (p value

© 2019 The Authors Approximately 70% of the aquatic-based production of animals is fed aquaculture, whereby animals are provided with high-protein aquafeeds. Currently, aquafeeds are reliant on fish meal and fish oil sourced from wild-captured forage fish. However, increasing use of forage fish is unsustainable and, because an additional 37.4 million tons of aquafeeds will be required by 2025, alternative protein sources are needed. Beyond plant-based ingredients, fishery and aquaculture byproducts and insect meals have the greatest potential to supply the protein required by aquafeeds over the next 10–20 years. Food waste also has potential through the biotransformation and/or bioconversion of raw waste materials, whereas microbial and macroalgal biomass have limitations regarding their scalability and protein content, respectively. In this review, we describe the considerable scope for improved efficiency in fed aquaculture and discuss the development and optimization of alternative protein sources for aquafeeds to ensure a socially and environmentally sustainable future for the aquaculture industry.

INTRODUCTION: Vitamin C deficiency has been described in patients with sepsis. The post-cardiac arrest syndrome shares similarities to sepsis, however vitamin C levels in post-arrest patients have been incompletely characterized. We assessed vitamin C levels in a post-arrest population. METHODS: This was a retrospective observational study at a tertiary care center. A convenience sample of post-arrest, sepsis, and healthy control patients was selected from prior studies. Vitamin C levels were measured from samples obtained within 6-hours of emergency department admission. A subset of cardiac arrest patients had vitamin C levels additionally measured at 24-hours later. RESULTS: A total of 84 patients (34 healthy controls, 25 post-arrest, and 25 septic patients) were included. The median baseline vitamin C level in cardiac arrest patients was 0.33 mg/dL (0.05–0.83), as compared to 0.91mg/dL (0.69–1.48) in the healthy control group (p

Algae-based products have applications in the food and pharmaceutical industries, bioremediation of waste streams and biofuel production. Drying has been recognised to constitute the largest energy cost in algae processing, yet there is limited data or modelling characterising the drying kinetics of macroalgae. This research modelled the equilibrium moisture content of two macroalgae species, Ulva ohnoi, a saltwater alga and Oedogonium intermedium, a freshwater alga. The Guggenheim&ndash, Anderson&ndash, de Boer model was found to best represent experimental equilibrium moisture contents. Drying rate curves obtained under both convective and radiative conditions were fitted to an analytical solution of Fick&rsquo, s second law, including the modelled equilibrium moisture values. Effective diffusivity values for the two species are presented.

BACKGROUND: Burst suppression in mechanically ventilated intensive care unit (ICU) patients is associated with increased mortality. However, the relative contributions of propofol use and critical illness itself to burst suppression; of burst suppression, propofol, and critical illness to mortality; and whether preventing burst suppression might reduce mortality, have not been quantified. METHODS: The dataset contains 471 adults from seven ICUs, after excluding anoxic encephalopathy due to cardiac arrest or intentional burst suppression for therapeutic reasons. We used multiple prediction and causal inference methods to estimate the effects connecting burst suppression, propofol, critical illness, and in-hospital mortality in an observational retrospective study. We also estimated the effects mediated by burst suppression. Sensitivity analysis was used to assess for unmeasured confounding. RESULTS: The expected outcomes in a “counterfactual” Randomized Controlled Trial (cRCT) that assigned patients to mild vs. severe illness is expected to show a difference in burst suppression burden of 39%, 95% CI [8–66]%, and in mortality of 35% [29–41]%. Assigning patients to maximal (100%) burst suppression burden is expected to increase mortality by 12% [7–17]% compared to 0% burden. Burst suppression mediates 10% [2–21]% of the effect of critical illness on mortality. A high cumulative propofol dose (1316 mg/kg) is expected to increase burst suppression burden by 6% [0.8–12]% compared to a low dose (284 mg/kg). Propofol exposure has no significant direct effect on mortality; its effect is entirely mediated through burst suppression. CONCLUSIONS: Our analysis clarifies how important factors contribute to mortality in ICU patients. Burst suppression appears to contribute to mortality but is primarily an effect of critical illness rather than iatrogenic use of propofol.

We present nonlinear resistive MHD simulations of the response of a rotating plasma to an error field when the plasma has weakly damped linear tearing modes (TM's), stabilized by pressure gradient and favorable curvature. Favorable curvature leads to the Glasser effect: the occurrence of real frequencies and stabilization with positive stability index $\Delta'$. A cylinder with hollow pressure is used to model the toroidal favorable curvature. Linear simulations with rotation and an error field $\tilde{\psi}_w$ show, in agreement with analytic results, that the peak reconnected flux occurs for a rotation rate near the TM phase velocity. Nonlinear simulations with small $\tilde{\psi}_w$ show that the real frequency and stabilization by favorable average curvature are masked by a nonlinear effect that occurs for very thin islands: flattening of the pressure across the island, mainly due to sound wave propagation. This flattening causes the disappearance of real frequencies destabilization of the mode, allowing it to grow to large amplitude similar to a $\beta=0$ unstable TM. The flattening of the current for larger islands saturates the mode nonlinearly. In the post-saturation phase, the interaction of the error field with the destabilized spontaneous tearing mode, which rotates with the plasma, leads to oscillations in the Maxwell torque and therefore modulations in the plasma rotation. The islands also rotate with modulated phase velocity, undergoing small-amplitude oscillations due to these modulations. We also present a quasilinear model with an unstable spontaneous TM and error fields, showing that the superposition of these fields results in similar oscillations., Comment: 13 pages, 10 figures

BACKGROUND: Although most patients with medically refractory temporal lobe epilepsy (TLE) experience seizure freedom after anterior temporal lobectomy, approximately 40% may continue to have seizures. Functional network integration, as measured with preoperative resting-state functional MRI, may help stratify patients who are more likely to experience postoperative seizure freedom. PURPOSE: To relate preoperative resting-state functional MRI and surgical outcome in patients with medically refractory TLE. MATERIALS AND METHODS: Data from patients with medically intractable TLE were retrospectively analyzed. Patients underwent preoperative resting-state functional MRI between March 2010 and April 2013 and subsequent unilateral anterior temporal lobectomy. Postoperative seizure-free status was categorized using the Engel Epilepsy Surgery Outcome Scale. Global and regional resting-state functional MRI network properties on preoperative functional MRI scans related to integration were calculated and statistically compared between patients who experienced complete postoperative seizure freedom (Engel class IA) and all others (Engel class IB to class IV) using t tests and multiple logistic regression. RESULTS: Forty patients (mean age, 34 years ± 15 [standard deviation]; 21 female) were evaluated. Preoperative global network integration was different (P = .01) between patients who experienced seizure freedom after surgery and all other patients, with 9% lower leaf fraction and 10% lower tree hierarchy in patients with ongoing seizures. Preoperative regional network integration in the contralateral temporoinsular region was different (P = .04) between patients in these two groups. Specifically, the group-level leaf proportion was 59% lower in the entorhinal cortex, 73% lower in the inferior temporal gyrus, 43% lower in the temporal pole, and 69% lower in the insula in patients with ongoing seizures after surgery. When using multivariate regression, contralateral temporoinsular leaf proportion (P = .002) and epilepsy duration (P = .04) were predictive of postoperative seizure freedom, while age (P > .70) and age at seizure onset (P > .50) were not. CONCLUSION: Lower network integration globally and involving the contralateral temporoinsular cortex on preoperative resting-state functional MRI scans is associated with ongoing postoperative seizures in patients with temporal lobe epilepsy. © RSNA, 2020

The successful implementation of the intensive cultivation of freshwater macroalgae for bioremediation purposes relies on the consistent year-round uptake of nutrients, which is closely linked to the amount of biomass produced. This study examined how light and temperature influence the biomass productivity and photosynthetic efficiency of a tropical strain of the freshwater macroalga Oedogonium intermedium (Wittrock ex Hirn). We subsequently use this information to identify, at a coarse level, the locations within Australia that can provide a thermal and light environment that is conducive to the intensive year-round, production of this species. The optimal temperature range to cultivate O. intermedium is between 20 and 35 °C, and in general productivity increased with increasing photon flux within this temperature range. At temperatures outside of this optimal range O. intermedium still had positive growth when cultured at a constant temperature of as low as 15 °C and as high as 40 °C, but productivity was impaired, and these temperatures represent the minimum and maximum temperature thresholds for chronic exposure. At low temperatures, higher photon flux rates increased productivity, however, at higher temperatures (>35 °C) a higher photon flux decreased productivity. These experimental insights have enabled us to identify, at a coarse level, locations within Australia that provide a suitable thermal and light environment for the year-round cultivation of O. intermedium. In general, latitudes of ≤25° provide a thermal and light environment that can maintain a high rate of biomass productivity year-round. In contrast, most locations at latitudes higher than 25° provide a suitable environment only during the summer months. During winter the combination of low temperatures and low solar irradiances will prevent the successful cultivation of this tropical strain. In these cooler locations alternative species of locally adapted, freshwater macroalgae should be identified and domesticated to ensure bioremediation outcomes are maintained at these lower latitudes.

We hypothesize that epileptiform abnormalities (EAs) in the electroencephalogram (EEG) during the acute period following traumatic brain injury (TBI) independently predict first-year post-traumatic epilepsy (PTE1 ). We analyze PTE1 risk factors in two cohorts matched for TBI severity and age (n = 50). EAs independently predict risk for PTE1 (odds ratio [OR], 3.16 [0.99, 11.68]); subdural hematoma is another independent risk factor (OR, 4.13 [1.18, 39.33]). Differences in EA rates are apparent within 5 days following TBI. Our results suggest that increased EA prevalence identifies patients at increased risk for PTE1 , and that EAs acutely post-TBI can identify patients most likely to benefit from antiepileptogenesis drug trials. Ann Neurol 2018;83:858-862.

Extracts produced from marine macroalgal biomass promote plant growth, improve yield, and increase the tolerance of plants to physiological stressors. Most of these extracts are produced with dried macroalgal biomass as their stock material, and use processing techniques that cause considerable modification to the original biomass and require a substantial investment in energy and equipment. As such, the aim of this study was to determine whether the freshwater macroalga Oedogonium intermedium could be successfully fermented using freshly harvested biomass, such that this biomass was transformed into a stable, non-offensive product that had plant growth-promoting properties. This was demonstrated by manipulating the starting conditions (presence or absence of salinity, molasses, and microbes) of the fermentations. The liquid extracts had a positive effect on the growth of mung bean plants compared with the positive controls – a soluble plant fertiliser and a commercially available fermented seaweed product. The most effective extract (Oedo 4), which was fermented in 20 ppt saltwater with the addition of molasses, demonstrated a 28.9–48.6% larger total plant dry weight than the commercial controls, respectively. Notably, extracts fermented in 20 ppt saltwater resulted in larger quantities of N, P, K, Ca, and Fe than those fermented in freshwater, while extracts fermented with molasses had the lowest final pH (

OBJECTIVES: An increasing body of evidence supports a significant contributory role for pancreatic α-cell dysfunction in the pathophysiology of diabetic ketoacidosis (DKA). In normal physiology, high glucose levels stimulate insulin and inhibit glucagon secretion, while low glucose stimulates glucagon but inhibits insulin release. This regulatory mechanism is progressively lost in diabetes mellitus (DM), where diminished insulin levels are accompanied by hyperglucagonemia leading to the further aggravation of hyperglycemia caused by insulin deficiency. Glucagon is produced via the posttranslational modification of proglucagon in a process that also produces other proglucagon molecules including major proglucagon fragment (MPGF) and glucagon like peptide-1 (GLP-1). Here we hypothesized that DKA is associated with α-cell dysfunction leading to elevated levels of proglucagon molecules. METHODS: We measured levels of glucagon, GLP-1 and MPGF as indices of glucagon synthesis/α-cell function in the plasma of patients with DKA and in healthy controls. The inclusion criteria for DKA patients were glucose > 250 mg/dL, pH

Freshwater macroalgae are an attractive treatment option for waste streams that have very high concentrations of nutrients. However, the long water residence times required in these scenarios will result in carbon becoming a limiting nutrient that negatively impacts the rate of biomass productivity and, subsequently, the potential for nutrient uptake. This study examined how the rate of carbon supplementation influenced the biomass productivity of Oedogonium intermedium, during both winter and summer periods in high rate algal ponds (HRAPs) maintained under batch conditions. We also examined the novel use of molasses as a source of carbon for intensive algal cultures and compared its effect on biomass productivity to that of CO2 gas. Oedogonium intermedium responded positively to carbon supplementation from both molasses and CO2 gas, with biomass productivity increasing as the rate of carbon supplementation increased. In cultures with no carbon supplementation, the average productivity of O. intermedium was 2.2 (± 0.8) g m− 2 day− 1, and a maximum of 17.3 g m− 2 day− 1 and 20.8 g m− 2 day− 1 during summer when carbon was supplemented through the addition of molasses and CO2, respectively. The optimal rate of carbon supplementation was 0.06 g of carbon per liter (g (C) L− 1) in winter and 0.08 g (C) L− 1 during summer. The addition of an exogenous source of carbon resulted in a decline in the culture pH and increased the availability of the dissolved inorganic carbon (DIC) pool and subsequently, carbon uptake by the algae. This study has identified a novel method to supplement carbon to algal cultures, where the waste residue from the sugar industry can be used as viable source of inorganic carbon. Importantly, we have demonstrated that O. intermedium can be cultivated in HRAPs without requiring a high rate of water exchange, providing that its requirements of DIC are satisfied.

The macroalga Oedogonium intermedium has a diverse elemental profile, high energy potential, high lipid content, a high proportion of essential amino acids and a total concentration of protein with the potential to meet the nutritional requirements of herbivorous fishes. The aim of this study was to assess growth, condition, colouration and reproductive output in an herbivorous ornamental fish. The catfish Ancistrus cirrhosus was fed one of three pelletised experimental feeds, Oedogonium, a formulated commercial feed and a 50:50 mix of the two, over a 10 month trial. After 10 months, fish that were fed exclusively on Oedogonium had equivalent growth rates, body condition, colouration, fecundity and fertilisation rates compared to those fed the commercial and mixed feeds. The absence of any major differences of these characteristics between feeds, especially between Oedogonium and the commercial feed, demonstrates the viability of Oedogonium as a feed, or significant feed ingredient, for this herbivorous fish. As such, linking the cultivation of Oedogonium with the production of herbivorous fish may provide an ideal application for Oedogonium.

Objective In mesial temporal lobe (mTL) epilepsy, seizure onset can precede the appearance of a scalp EEG ictal pattern by many seconds. The ability to identify this early, occult mTL seizure activity could improve lateralization and localization of mTL seizures on scalp EEG. Methods Using scalp EEG spectral features and machine learning approaches on a dataset of combined scalp EEG and foramen ovale electrode recordings in patients with mTL epilepsy, we developed an algorithm, SCOPE-mTL, to detect and lateralize early, occult mTL seizure activity, prior to the appearance of a scalp EEG ictal pattern. Results Using SCOPE-mTL, 73% of seizures with occult mTL onset were identified as such, and no seizures that lacked an occult mTL onset were identified as having one. Predicted mTL seizure onset times were highly correlated with actual mTL seizure onset times (r = 0.69). 50% of seizures with early mTL onset were lateralizable prior to scalp ictal onset, with 94% accuracy. Conclusions SCOPE-mTL can identify and lateralize mTL seizures prior to scalp EEG ictal onset, with high sensitivity, specificity, and accuracy. Significance Quantitative analysis of scalp EEG can provide important information about mTL seizures, even in the absence of a visible scalp EEG ictal correlate.

Industrial ecology is focused on recognising the inherent value in waste streams and developing techniques that can efficiently recover this value. Freshwater macroalgae can become a foundation of this concept as they can be cultured in a range of waste streams where they can effectively remove excess nutrients, metals and metalloids, providing both a bioremediation service and a biomass resource. The cultured algal biomass can then be used as a product in animal feeds, biochar, biosorbents or as a feedstock biomass for the production of bioenergy. Freshwater macroalgae provide a unique opportunity to transform a range of industries through the utilisation of wastewater to produce biomass that can be converted into valuable bioproducts.

Super‐refractory status epilepticus (SRSE) is associated with high morbidity and mortality. Treatment of SRSE is complicated by progressive cortical hyperexcitability believed to result in part from synaptic GABA receptor internalization and desensitization. Allopregnanolone, a neurosteroid that positively modulates synaptic and extrasynaptic GABAA receptors, has been proposed as a novel treatment. We describe the first two patients with SRSE who were each successfully treated with a 120‐h continuous infusion of allopregnanolone. Both patients recovered from prolonged SRSE with good cognitive outcomes.

SummaryObjective Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. Methods Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. Results There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. Significance Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

SummaryObjective To evaluate published algorithms for the identification of epilepsy cases in medical claims data using a unique linked dataset with both clinical and claims data. Methods Using data from a large, regional health delivery system, we identified all patients contributing biologic samples to the health system's Biobank (n = 36K). We identified all subjects with at least one diagnosis potentially consistent with epilepsy, for example, epilepsy, convulsions, syncope, or collapse, between 2014 and 2015, or who were seen at the epilepsy clinic (n = 1,217), plus a random sample of subjects with neither claims nor clinic visits (n = 435); we then performed a medical chart review in a random subsample of 1,377 to assess the epilepsy diagnosis status. Using the chart review as the reference standard, we evaluated the test characteristics of six published algorithms. Results The best-performing algorithm used diagnostic and prescription drug data (sensitivity = 70%, 95% confidence interval [CI] 66–73%; specificity = 77%, 95% CI 73–81%; and area under the curve [AUC] = 0.73, 95%CI 0.71–0.76) when applied to patients age 18 years or older. Restricting the sample to adults aged 18–64 years resulted in a mild improvement in accuracy (AUC = 0.75,95%CI 0.73–0.78). Adding information about current antiepileptic drug use to the algorithm increased test performance (AUC = 0.78, 95%CI 0.76–0.80). Other algorithms varied in their included data types and performed worse. Significance Current approaches for identifying patients with epilepsy in insurance claims have important limitations when applied to the general population. Approaches incorporating a range of information, for example, diagnoses, treatments, and site of care/specialty of physician, improve the performance of identification and could be useful in epilepsy studies using large datasets.

Municipal wastewater treatment plants discharge large quantities of treated water that, in many regions, is not productively used and is instead released directly into the environment. In this study we examine the use of freshwater macroalgae as an in-line tertiary treatment process for existing municipal treatment plants. We examine the suitability of using the treated discharge water from a 29,000 m3.day− 1 municipal wastewater treatment plant as the sole source of water and nutrients for the intensive cultivation of the freshwater macroalga Oedogonium intermedium. A monoculture of algae was initially cultivated for a 3 month period in which water quality and biomass productivity were quantified and the composition of the biomass characterized. These cultures were then maintained for a further 9 months to determine the average monthly biomass productivity, and seasonal variation, over a 12 month period. The cultivation of Oedogonium significantly improved the quality of the discharged water with a 36% reduction in total nitrogen and a 65% reduction in total phosphorous. The average monthly biomass productivity of Oedogonium ranged between a minimum of 8.9 g DW·m− 2·day− 1 in June (austral winter – dry season) and a maximum of 15.8 g DW·m− 2·day− 1 in January (austral summer – wet season) with an average annual rate of 12.5 g DW·m− 2·day− 1. The biomass produced was of a high quality with a total protein content of 23 g·100 g− 1 and a total lipid content of 10 g·100 g− 1. Both the protein (10 g·100 g− 1 of essential amino acids) and lipid (4.5 g·100 g− 1 of polyunsaturated fatty acids) provide product opportunities for animal nutrition. This study demonstrates that the production of algae integrated with the operation of conventional wastewater treatment can complement and add value to existing processes by recovering residual nutrients and metals and, at the same time, create a high-quality biomass resource for product development.

Three strains of coxsackievirus B3 (CVB3) differ by single mutations in capsid protein VP1 or VP3 and also differ in stability at 37°C in tissue culture medium. Among these strains, the CVB3/28 parent strain has been found to be uniquely sensitive to a component in fetal bovine serum (FBS) identified as serum albumin. In cell culture medium, serum increased the rate of CVB3/28 conversion to noninfectious particles at least 2-fold. The effect showed a saturable dose response. Rates of conversion to noninfectious virus with high concentrations of soluble coxsackievirus and adenovirus receptor (sCAR) were similar with and without FBS, but FBS amplified the catalytic effect of 100 nM sCAR nearly 3-fold. Such effects in other systems are due to nonessential activating cofactors. IMPORTANCE A factor other than the virus receptor expressed by target cells has been found to accelerate the loss of an enterovirus (CVB3/28) infectious titer, with little effect on nearly identical mutant strains. The destabilizing factor in fetal bovine serum, identified as albumin, does not interfere with the catalytic activity of soluble receptor at saturating receptor concentrations and amplifies the catalytic activity of the soluble receptor at a concentration that otherwise produces about one-third the saturated receptor-catalyzed rate of virus decay. This finding evidences the possibility that other virus-“priming” ligands may also be nonessential activating cofactors that serve to accelerate receptor-catalyzed viral eclipse.

Importance Interictal epileptiform discharges (IEDs) in electroencephalograms (EEGs) are a biomarker of epilepsy, seizure risk, and clinical decline. However, there is a scarcity of experts qualified to interpret EEG results. Prior attempts to automate IED detection have been limited by small samples and have not demonstrated expert-level performance. There is a need for a validated automated method to detect IEDs with expert-level reliability. Objective To develop and validate a computer algorithm with the ability to identify IEDs as reliably as experts and classify an EEG recording as containing IEDs vs no IEDs. Design, Setting, and Participants A total of 9571 scalp EEG records with and without IEDs were used to train a deep neural network (SpikeNet) to perform IED detection. Independent training and testing data sets were generated from 13 262 IED candidates, independently annotated by 8 fellowship-trained clinical neurophysiologists, and 8520 EEG records containing no IEDs based on clinical EEG reports. Using the estimated spike probability, a classifier designating the whole EEG recording as positive or negative was also built. Main Outcomes and Measures SpikeNet accuracy, sensitivity, and specificity compared with fellowship-trained neurophysiology experts for identifying IEDs and classifying EEGs as positive or negative or negative for IEDs. Statistical performance was assessed via calibration error and area under the receiver operating characteristic curve (AUC). All performance statistics were estimated using 10-fold cross-validation. Results SpikeNet surpassed both expert interpretation and an industry standard commercial IED detector, based on calibration error (SpikeNet, 0.041; 95% CI, 0.033-0.049; vs industry standard, 0.066; 95% CI, 0.060-0.078; vs experts, mean, 0.183; range, 0.081-0.364) and binary classification performance based on AUC (SpikeNet, 0.980; 95% CI, 0.977-0.984; vs industry standard, 0.882; 95% CI, 0.872-0.893). Whole EEG classification had a mean calibration error of 0.126 (range, 0.109-0.1444) vs experts (mean, 0.197; range, 0.099-0.372) and AUC of 0.847 (95% CI, 0.830-0.865). Conclusions and Relevance In this study, SpikeNet automatically detected IEDs and classified whole EEGs as IED-positive or IED-negative. This may be the first time an algorithm has been shown to exceed expert performance for IED detection in a representative sample of EEGs and may thus be a valuable tool for expedited review of EEGs.

1. Evidence suggests that the restoration of plant diversity in grasslands not only brings benefits for biodiversity conservation, but also the delivery of ecosystem services. While biodiversity- function experiments show that greater plant diversity increases resistance of plant productivity to climate extremes, it is not known whether real-world management options for grassland restoration likewise stabilise ecosystem responses to extreme climate events.2. We used a long-term (23 year) field experiment in northern England to test the hypothesis that management aimed at biodiversity restoration increases the resistance and recovery of ecosystem carbon (C) fluxes to short-term summer drought. This was tested by measuring plant, soil and microbial responses to a simulated drought in experimental grassland plots where fertiliser application and seed addition have been managed to enhance plant species diversity.3. The cessation of fertiliser application brought about small increases in plant species richness. Additionally, cessation of fertiliser application reduced overall plant productivity and promoted hemi-parasitic plants at the expense of grasses and forbs.4. Resistance of CO2 fluxes to drought, measured as ecosystem respiration, was greater in non-fertilised plots, as lower plant biomass reduced water demand, likely aided by proportionally more hemi-parasitic plants further reducing plant biomass. Additionally, legumes increased under drought thereby contributing to overall resistance of plant productivity.5. Recovery of soil microbial C and nitrogen was more rapid after rewetting than soil microbial community composition, irrespective of restoration treatment, suggesting high resilience of soil microbial communities to drought.6. Synthesis and applications. This study shows that while grassland diversity restoration management increases the resistance of C fluxes to drought, it also reduces agricultural yields, revealing a trade-off for land managers. Furthermore legumes, promoted through long-term restoration treatments, can help to maintain plant community productivity under drought by increasing their biomass. As such, grassland management strategies not only have consequences for ecosystem processes, but also the capacity to withstand extreme weather events.

Purpose Stereotactic radiosurgery (SRS) may be an alternative to anterior temporal lobectomy (ATL) for mesial temporal lobe epilepsy (MTLE). Visual field defects (VFD) occur in 9–100% of patients following open surgery for MTLE. Postoperative VFD after minimally invasive versus open surgery may differ. Methods This prospective trial randomized patients with unilateral hippocampal sclerosis and concordant video-EEG findings to SRS versus ATL. Humphries perimetry was obtained at 24 m after surgery. VFD ratios (VFDR = proportion of missing homonymous hemifield with 0 = no VFD, 0.5 = complete superior quadrantanopsia) quantified VFD. Regressions of VFDR were evaluated against treatment arm and covariates. MRI evaluated effects of volume changes on VFDR. The relationships of VFDR with seizure remission and driving status 3 years after surgery were evaluated. Results No patients reported visual changes or had abnormal bedside examinations, but 49 of 54 (91%) of patients experienced VFD on formal perimetry. Neither incidence nor severity of VFDR differed significantly by treatment arm. VFDR severity was not associated with seizure remission or driving status. Conclusion The nature of VFD was consistent with lesions of the optic radiations. Effective surgery (defined by seizure remission) of the mesial temporal lobe results in about a 90% incidence of typical VFD regardless of method.

A 64-year-old right-handed man presented to the emergency department with a 4-week history of bilateral blurred and distorted vision. He reported that objects in his central visual field appeared to change shape and were disproportionately large or small. He also reported intermittent flashes of light with altered color perception. His medical history was notable for prostate cancer treated with prostatectomy, Bell palsy at age 25, gastroesophageal reflux disease, and bilateral refractive errors. His family had also noted intermittent episodes of confusion and anger over the preceding weeks along with difficulty recognizing family members. He endorsed minimal right-sided periorbital headache but reported no diplopia, weakness, paresthesiae, numbness, speech changes, or history of similar symptoms. He had no recent history of fever, illness, or infectious exposures. He had no history of seizures or migraine. He was taking omeprazole and did not smoke or use alcohol or illicit drugs.

Lidia M V R Moura,1 Thiago S Carneiro,1 Andrew J Cole,1 John Hsu,2,3 Barbara G Vickrey,4 Daniel B Hoch1 1Department of Neurology, 2Mongan Institute for Health Policy, Department of Medicine, Massachusetts General Hospital, 3Department of Health Care Policy, Harvard Medical School, Boston, MA, 4Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Background and aim: Adherence to treatment is a critical component of epilepsy management. This study examines whether addressing antiepileptic drug (AED) side effects at every visit is associated with increased patient-reported medication adherence.Patients and methods: This study identified 243 adults with epilepsy who were seen at two academic outpatient neurology settings and had at least two visits over a 3-year period. Demographic and clinical characteristics were abstracted. Evidence that AED side effects were addressed was measured through 1) phone interview (patient-reported) and 2) medical records abstraction (physician-documented). Medication adherence was assessed using the validated Morisky Medication Adherence Scale-4. Complete adherence was determined as answering “no” to all questions.Results: Sixty-two (25%) patients completed the interviews. Participants and nonparticipants were comparable with respect to demographic and clinical characteristics; however, a smaller proportion of participants had a history of drug-resistant epilepsy than nonparticipants (17.7% vs 30.9%, P=0.04). Among the participants, evidence that AED side effects were addressed was present in 48 (77%) medical records and reported by 51 (82%) patients. Twenty-eight (45%) patients reported complete medication adherence. The most common reason for incomplete adherence was missed medication due to forgetfulness (n=31, 91%). There was no association between addressing AED side effects (neither physician-documented nor patient-reported) and complete medication adherence (P=0.22 and 0.20).Discussion and conclusion: Among patients with epilepsy, addressing medication side effects at every visit does not appear to increase patient-reported medication adherence. Keywords: epilepsy, antiepileptic drug side effects, medication adherence&nbsp