Transforming a head direction signal into a goal-oriented steering command.

To navigate, we must continuously estimate the direction we are headed in, and we must correct deviations from our goal1. Direction estimation is accomplished by ring attractor networks in the head direction system2,3. However, we do not fully understand how the sense of direction is used to guide action. Drosophila connectome analyses4,5 reveal three cell populations (PFL3R, PFL3L and PFL2) that connect the head direction system to the locomotor system. Here we use imaging, electrophysiology and chemogenetic stimulation during navigation to show how these populations function. Each population receives a shifted copy of the head direction vector, such that their three reference frames are shifted approximately 120° relative to each other. Each cell type then compares its own head direction vector with a common goal vector; specifically, it evaluates the congruence of these vectors via a nonlinear transformation. The output of all three cell populations is then combined to generate locomotor commands. PFL3R cells are recruited when the fly is oriented to the left of its goal, and their activity drives rightward turning; the reverse is true for PFL3L. Meanwhile, PFL2 cells increase steering speed, and are recruited when the fly is oriented far from its goal. PFL2 cells adaptively increase the strength of steering as directional error increases, effectively managing the tradeoff between speed and accuracy. Together, our results show how a map of space in the brain can be combined with an internal goal to generate action commands, via a transformation from world-centric coordinates to body-centric coordinates.

Transforming representations of movement from body- to world-centric space.

When an animal moves through the world, its brain receives a stream of information about the body's translational velocity from motor commands and sensory feedback signals. These incoming signals are referenced to the body, but ultimately, they must be transformed into world-centric coordinates for navigation1,2. Here we show that this computation occurs in the fan-shaped body in the brain of Drosophila melanogaster. We identify two cell types, PFNd and PFNv3-5, that conjunctively encode translational velocity and heading as a fly walks. In these cells, velocity signals are acquired from locomotor brain regions6 and are multiplied with heading signals from the compass system. PFNd neurons prefer forward-ipsilateral movement, whereas PFNv neurons prefer backward-contralateral movement, and perturbing PFNd neurons disrupts idiothetic path integration in walking flies7. Downstream, PFNd and PFNv neurons converge onto hΔB neurons, with a connectivity pattern that pools together heading and translation direction combinations corresponding to the same movement in world-centric space. This network motif effectively performs a rotation of the brain's representation of body-centric translational velocity according to the current heading direction. Consistent with our predictions, we observe that hΔB neurons form a representation of translational velocity in world-centric coordinates. By integrating this representation over time, it should be possible for the brain to form a working memory of the path travelled through the environment8-10.

Sensorimotor experience remaps visual input to a heading-direction network.

In the Drosophila brain, 'compass' neurons track the orientation of the body and head (the fly's heading) during navigation 1,2. In the absence of visual cues, the compass neuron network estimates heading by integrating self-movement signals over time3,4. When a visual cue is present, the estimate of the network is more accurate1,3. Visual inputs to compass neurons are thought to originate from inhibitory neurons called R neurons (also known as ring neurons); the receptive fields of R neurons tile visual space5. The axon of each R neuron overlaps with the dendrites of every compass neuron6, raising the question of how visual cues are integrated into the compass. Here, using in vivo whole-cell recordings, we show that a visual cue can evoke synaptic inhibition in compass neurons and that R neurons mediate this inhibition. Each compass neuron is inhibited only by specific visual cue positions, indicating that many potential connections from R neurons onto compass neurons are actually weak or silent. We also show that the pattern of visually evoked inhibition can reorganize over minutes as the fly explores an altered virtual-reality environment. Using ensemble calcium imaging, we demonstrate that this reorganization causes persistent changes in the compass coordinate frame. Taken together, our data suggest a model in which correlated pre- and postsynaptic activity triggers associative long-term synaptic depression of visually evoked inhibition in compass neurons. Our findings provide evidence for the theoretical proposal that associative plasticity of sensory inputs, when combined with attractor dynamics, can reconcile self-movement information with changing external cues to generate a coherent sense of direction7-12.

Direct Oral Anticoagulants Versus Warfarin in the Treatment of Cerebral Venous Thrombosis (ACTION-CVT): A Multicenter International Study.

BACKGROUND: A small randomized controlled trial suggested that dabigatran may be as effective as warfarin in the treatment of cerebral venous thrombosis (CVT). We aimed to compare direct oral anticoagulants (DOACs) to warfarin in a real-world CVT cohort. METHODS: This multicenter international retrospective study (United States, Europe, New Zealand) included consecutive patients with CVT treated with oral anticoagulation from January 2015 to December 2020. We abstracted demographics and CVT risk factors, hypercoagulable labs, baseline imaging data, and clinical and radiological outcomes from medical records. We used adjusted inverse probability of treatment weighted Cox-regression models to compare recurrent cerebral or systemic venous thrombosis, death, and major hemorrhage in patients treated with warfarin versus DOACs. We performed adjusted inverse probability of treatment weighted logistic regression to compare recanalization rates on follow-up imaging across the 2 treatments groups. RESULTS: Among 1025 CVT patients across 27 centers, 845 patients met our inclusion criteria. Mean age was 44.8 years, 64.7% were women; 33.0% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times. During a median follow-up of 345 (interquartile range, 140-720) days, there were 5.68 recurrent venous thrombosis, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years. Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization. When compared with warfarin, DOAC treatment was associated with similar risk of recurrent venous thrombosis (aHR, 0.94 [95% CI, 0.51-1.73]; P=0.84), death (aHR, 0.78 [95% CI, 0.22-2.76]; P=0.70), and rate of partial/complete recanalization (aOR, 0.92 [95% CI, 0.48-1.73]; P=0.79), but a lower risk of major hemorrhage (aHR, 0.35 [95% CI, 0.15-0.82]; P=0.02). CONCLUSIONS: In patients with CVT, treatment with DOACs was associated with similar clinical and radiographic outcomes and favorable safety profile when compared with warfarin treatment. Our findings need confirmation by large prospective or randomized studies.

Biomarkers of Coagulation and Inflammation in COVID-19-Associated Ischemic Stroke.

[Figure: see text].

Factors associated with hospitalization for ischemic stroke and TIA following an emergency department headache visit.

BACKGROUND: Misdiagnosis of cerebrovascular disease among Emergency Department (ED) patients with headache has been reported. We hypothesized that markers of substandard diagnostic processes would be associated with subsequent ischemic cerebrovascular events among patients discharged from the ED with a headache diagnosis even after adjusting for demographic variables and medical history. METHODS: We conducted a case-control study of adult ED patients diagnosed with a primary headache disorder at Montefiore Medical Center from 9/1/2013-9/1/2018. Cases were defined as patients hospitalized for an ischemic stroke or TIA within 365 days of their index ED visit. Control patients were defined as those who lacked a subsequent hospitalization for cerebrovascular disease. Pre-specified demographic, clinical, and diagnostic process factors were compared between groups; conditional logistic regression was used to assess the separate and joint influence of baseline features on risk of cerebral ischemia. RESULTS: A total of 93 consecutive headache patients with a subsequent ischemic stroke/TIA hospitalization were matched to 93 controls (n = 186). Cases were older than controls and more likely to have traditional cerebrovascular risk factors. Neurological consultation was obtained more often for cases (13% vs. 4%; P = 0.03), cases were in the ED for longer (6 vs. 5 h, P = 0.03), and more frequently received neuroimaging (80% vs. 48%; P < 0.0001). Rates of neurological examination, documented differential diagnoses, and clear discharge follow up plans were similar between cases and controls. In our conditional logistic regression model, only history of prior stroke/TIA was associated with increased odds of subsequent cerebral ischemia. CONCLUSION: Factors associated with diagnostic process failures did not increase the odds of subsequent ischemic stroke/TIA hospitalization following ED headache visit in our study.

Visual cortex entrains to sign language.

Despite immense variability across languages, people can learn to understand any human language, spoken or signed. What neural mechanisms allow people to comprehend language across sensory modalities? When people listen to speech, electrophysiological oscillations in auditory cortex entrain to slow ([Formula: see text]8 Hz) fluctuations in the acoustic envelope. Entrainment to the speech envelope may reflect mechanisms specialized for auditory perception. Alternatively, flexible entrainment may be a general-purpose cortical mechanism that optimizes sensitivity to rhythmic information regardless of modality. Here, we test these proposals by examining cortical coherence to visual information in sign language. First, we develop a metric to quantify visual change over time. We find quasiperiodic fluctuations in sign language, characterized by lower frequencies than fluctuations in speech. Next, we test for entrainment of neural oscillations to visual change in sign language, using electroencephalography (EEG) in fluent speakers of American Sign Language (ASL) as they watch videos in ASL. We find significant cortical entrainment to visual oscillations in sign language <5 Hz, peaking at [Formula: see text]1 Hz. Coherence to sign is strongest over occipital and parietal cortex, in contrast to speech, where coherence is strongest over the auditory cortex. Nonsigners also show coherence to sign language, but entrainment at frontal sites is reduced relative to fluent signers. These results demonstrate that flexible cortical entrainment to language does not depend on neural processes that are specific to auditory speech perception. Low-frequency oscillatory entrainment may reflect a general cortical mechanism that maximizes sensitivity to informational peaks in time-varying signals.

Mapping language to the world: the role of iconicity in the sign language input.

Most research on the mechanisms underlying referential mapping has assumed that learning occurs in ostensive contexts, where label and referent co-occur, and that form and meaning are linked by arbitrary convention alone. In the present study, we focus on iconicity in language, that is, resemblance relationships between form and meaning, and on non-ostensive contexts, where label and referent do not co-occur. We approach the question of language learning from the perspective of the language input. Specifically, we look at child-directed language (CDL) in British Sign Language (BSL), a language rich in iconicity due to the affordances of the visual modality. We ask whether child-directed signing exploits iconicity in the language by highlighting the similarity mapping between form and referent. We find that CDL modifications occur more often with iconic signs than with non-iconic signs. Crucially, for iconic signs, modifications are more frequent in non-ostensive contexts than in ostensive contexts. Furthermore, we find that pointing dominates in ostensive contexts, and suggest that caregivers adjust the semiotic resources recruited in CDL to context. These findings offer first evidence for a role of iconicity in the language input and suggest that iconicity may be involved in referential mapping and language learning, particularly in non-ostensive contexts.

Mapping DNA polymerase errors by single-molecule sequencing.

Genomic integrity is compromised by DNA polymerase replication errors, which occur in a sequence-dependent manner across the genome. Accurate and complete quantification of a DNA polymerase's error spectrum is challenging because errors are rare and difficult to detect. We report a high-throughput sequencing assay to map in vitro DNA replication errors at the single-molecule level. Unlike previous methods, our assay is able to rapidly detect a large number of polymerase errors at base resolution over any template substrate without quantification bias. To overcome the high error rate of high-throughput sequencing, our assay uses a barcoding strategy in which each replication product is tagged with a unique nucleotide sequence before amplification. This allows multiple sequencing reads of the same product to be compared so that sequencing errors can be found and removed. We demonstrate the ability of our assay to characterize the average error rate, error hotspots and lesion bypass fidelity of several DNA polymerases.

Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism.

Single gene disorders of the autophagy pathway are an emerging, novel and diverse group of multisystem diseases in children. Clinically, these disorders prominently affect the central nervous system at various stages of development, leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others. Frequent early and severe involvement of the central nervous system puts the paediatric neurologist, neurogeneticist, and neurometabolic specialist at the forefront of recognizing and treating these rare conditions. On a molecular level, mutations in key autophagy genes map to different stages of this highly conserved pathway and thus lead to impairment in isolation membrane (or phagophore) and autophagosome formation, maturation, or autophagosome-lysosome fusion. Here we discuss 'congenital disorders of autophagy' as an emerging subclass of inborn errors of metabolism by using the examples of six recently identified monogenic diseases: EPG5-related Vici syndrome, beta-propeller protein-associated neurodegeneration due to mutations in WDR45, SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome, and three forms of hereditary spastic paraplegia, SPG11, SPG15 and SPG49 caused by SPG11, ZFYVE26 and TECPR2 mutations, respectively. We also highlight associations between defective autophagy and other inborn errors of metabolism such as lysosomal storage diseases and neurodevelopmental diseases associated with the mTOR pathway, which may be included in the wider spectrum of autophagy-related diseases from a pathobiological point of view. By exploring these emerging themes in disease pathogenesis and underlying pathophysiological mechanisms, we discuss how congenital disorders of autophagy inform our understanding of the importance of this fascinating cellular pathway for central nervous system biology and disease. Finally, we review the concept of modulating autophagy as a therapeutic target and argue that congenital disorders of autophagy provide a unique genetic perspective on the possibilities and challenges of pathway-specific drug development.

The association of hemodialysis and survival in intubated salicylate-poisoned patients.

INTRODUCTION: Salicylate poisonings are common due to their multiple uses and wide availability. The variation of presenting symptoms contributes to inconsistent treatments in the emergency department. Patients with severe salicylate overdose require a high minute ventilation. Early in the course of an overdose, a patient will require hyperventilation. If they become too fatigued to compensate, mechanical ventilation may be needed. It can be impossible to recreate such a high minute ventilation with mechanical ventilation. This places patients at a high risk for decompensation and death. Hemodialysis is an effective elimination technique for salicylate overdose and should be considered early. METHODS: All salicylate cases reported to the Illinois Poison Center were reviewed from 2003-2014. All intubated patients with a salicylate level >50mg/dl were included for analysis. Survival was compared to measured serum salicylate level and the administration of hemodialysis. RESULTS: 56 Cases were identified with an overall survival rate of 73.2% in patients with a serum salicylate level >50mg/dl. When patients did not receive hemodialysis, a peak salicylate level >50mg/dl had a 56% survival rate and 0% survival when the level was >80mg/dl. In the patients who received hemodialysis, a peak salicylate level >50mg/dl had a 83.9% survival rate and 83.3% survival when the level was >80mg/dl. CONCLUSION: Survival was decreased in these patients if hemodialysis was not performed. Mortality increases with the measured serum salicylate level. Timely hemodialysis for intubated salicylate overdose patients decreases mortality.

The impact of input quality on early sign development in native and non-native language learners.

There is debate about how input variation influences child language. Most deaf children are exposed to a sign language from their non-fluent hearing parents and experience a delay in exposure to accessible language. A small number of children receive language input from their deaf parents who are fluent signers. Thus it is possible to document the impact of quality of input on early sign acquisition. The current study explores the outcomes of differential input in two groups of children aged two to five years: deaf children of hearing parents (DCHP) and deaf children of deaf parents (DCDP). Analysis of child sign language revealed DCDP had a more developed vocabulary and more phonological handshape types compared with DCHP. In naturalistic conversations deaf parents used more sign tokens and more phonological types than hearing parents. Results are discussed in terms of the effects of early input on subsequent language abilities.

Examining the role of mood in pain-limited treadmill walking duration in young healthy individuals.

PURPOSE: The purpose of the study was to examine the effects of acute mood modulation on treadmill walking duration during experimental pain application. METHODS: This was a repeated measure, within-subject study design. 30 healthy individuals (Males: Females 16:14; age 22.9 ± 2.5 years; height 170.9 ± 9.5 cm; body mass 68.4 ± 14.6 kg) attended a familiarization session and three experimental sessions, whereby they simultaneously viewed emotionally evoking stimulus from the International Affective Picture System (IAPS) and performed two treadmill walking tests (maximum 10 min duration) with a fixed nociceptive input applied to the thigh (pressure cuff). The primary outcome was treadmill walking duration during pain application to achieve a fixed pain score. During walking, mood (Self-Assessment Manikin: SAM 0-9) and pain (numerical rating scale: NRS 0-10) were measured. RESULTS: Mood valence scores were significantly different in all conditions (p < 0.001), negative (2.4 ± 0.3), neutral (4.9 ± 0.6) and positive (6.6 ± 0.3). There was a significant difference (p = 0.04) in the treadmill walking duration for different mood states. For the primary outcome, post hoc analysis found differences between the negative and positive mood conditions for the treadmill walking durations to reach pain scores of 3 (negative: 224 ± 49 s; positive: 259 ± 60s, effect size [ES]: 0.80), 4 (negative: 262 ± 59 s; positive: 326 ± 90s, ES: 0.92), 5 (negative: 313 ± 86 s; positive: 385 ± 113 s, ES: 0.90), 6 (negative: 367 ± 106 s; positive: 447 ± 113 s, ES: 1.04) and 7 (negative: 423 ± 114 s; positive: 521 ± 110 s, ES: 1.02). There was no significant difference in the treadmill walking duration between the neutral vs negative mood and neutral vs positive mood conditions. CONCLUSION: These results highlight the potential psychophysiological impacts on the pain experience in healthy individuals and encourages pursuit in strategies to minimize pain-limited exercise, a highly prevalent issue in the chronic pain population. SIGNIFICANCE: Walking-based rehabilitation, designed to improve physical activity, has been shown to improve pain and disability. However active participation and adherence in walking-based rehabilitation has shown to be jeopardized by pain and pain-related cognitive and behavioural adaptations. This study examined the effect of a shift in mood on pain perception and treadmill walking tolerance. We found that with a worse mood, individuals were less tolerant of pain and walked on the treadmill for a shorter duration. These results suggest that factors which improve mood should be combined with walking-based training to improve tolerance.

GQ-16, a novel peroxisome proliferator-activated receptor γ (PPARγ) ligand, promotes insulin sensitization without weight gain.

The recent discovery that peroxisome proliferator-activated receptor γ (PPARγ) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPARγ activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPARγ. The structure of GQ-16 bound to PPARγ demonstrates that the compound utilizes a binding mode distinct from other reported PPARγ ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the ß-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby "ideal" PPARγ-based therapeutics stabilize the ß-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPARγ modulators that retain antidiabetic actions while minimizing untoward effects.

Metabolism-guided discovery of a potent and orally bioavailable urea-based calcimimetic for the treatment of secondary hyperparathyroidism.

A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics.

AIBP regulates TRPV1 activation in chemotherapy-induced peripheral neuropathy by controlling lipid raft dynamics and proximity to TLR4 in dorsal root ganglion neurons.

ABSTRACT: Nociceptive afferent signaling evoked by inflammation and nerve injury is mediated by the opening of ligand-gated and voltage-gated receptors or channels localized to cholesterol-rich lipid raft membrane domains. Dorsal root ganglion (DRG) nociceptors express high levels of toll-like receptor 4 (TLR4), which also localize to lipid rafts. Genetic deletion or pharmacologic blocking of TLR4 diminishes pain associated with chemotherapy-induced peripheral neuropathy (CIPN). In DRGs of mice with paclitaxel-induced CIPN, we analyzed DRG neuronal lipid rafts, expression of TLR4, activation of transient receptor potential cation channel subfamily V member 1 (TRPV1), and TLR4-TRPV1 interaction. Using proximity ligation assay, flow cytometry, and whole-mount DRG microscopy, we found that CIPN increased DRG neuronal lipid rafts and TLR4 expression. These effects were reversed by intrathecal injection of apolipoprotein A-I binding protein (AIBP), a protein that binds to TLR4 and specifically targets cholesterol depletion from TLR4-expressing cells. Chemotherapy-induced peripheral neuropathy increased TRPV1 phosphorylation, localization to neuronal lipid rafts, and proximity to TLR4. These effects were also reversed by AIBP treatment. Regulation of TRPV1-TLR4 interactions and their associated lipid rafts by AIBP covaried with the enduring reversal of mechanical allodynia otherwise observed in CIPN. In addition, AIBP reduced intracellular calcium in response to the TRPV1 agonist capsaicin, which was increased in DRG neurons from paclitaxel-treated mice and in the naïve mouse DRG neurons incubated in vitro with paclitaxel. Together, these results suggest that the assembly of nociceptive and inflammatory receptors in the environment of lipid rafts regulates nociceptive signaling in DRG neurons and that AIBP can control lipid raft-associated nociceptive processing.

AMG 837: a potent, orally bioavailable GPR40 agonist.

The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of ß-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4'-(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of insulin secretion in rodents.

Variability in hyperbaric oxygen treatment for acute carbon monoxide poisoning.

CONTEXT: In patients with acute carbon monoxide (CO) poisoning, we have noted wide clinical variability in both criteria for hyperbaric oxygen (HBO2) treatment as well as HBO2 treatment regimens. Our aim was to survey Midwest hyperbaric centers for insight into specific criteria and protocols for treating acute CO toxicity with HBO2. METHODS: Hyperbaric centers were identified from the published list of the Undersea and Hyperbaric Medical Society. Ninety-three centers from nine Midwestern states were contacted via telephone. A standard script was used to minimize surveyor bias. RESULTS: Thirty centers that treat CO poisonings were identified. One did not participate in the study. Nineteen reported a specific level of carboxyhemoglobin (COHb) that served as an independent indication for initiation of HBO2 treatment. Four centers used the COHb level as the exclusive indication for HBO2 treatment. Ten centers relied solely on reported symptoms, while the remaining centers used a combination of symptoms plus COHb levels. There were 19 separate treatment protocols. CONCLUSION: No uniform practice for either the initiation or implementation of HBO2 therapy for CO poisoning exists among U.S. Midwest hyperbaric centers responding to a survey. We see opportunity for specific targeted educational programs as well as further study.

Altered mental status in COVID-19.

BACKGROUND: Altered mental status (AMS) is a common neurological manifestation of COVID-19 infection in hospitalized patients. The principal causes of AMS have yet to be determined. We aimed to identify the common causes of AMS in patients with COVID-19 presenting to the emergency department with AMS on arrival. METHODS: We conducted a retrospective observational study of patients presenting with AMS to three New York hospitals, from March 1 to April 16, 2020. Underlying causes of AMS on arrival to the emergency department (ED) were categorized as (1) neurological causes (stroke, seizure, encephalitis); (2) metabolic encephalopathy; (3) indeterminant. Multivariable analysis was used to assess independent predictors. RESULTS: Overall, 166 patients presented to the ED with AMS. Metabolic encephalopathy was diagnosed as the cause in 154 (92.8%), with 118 (71.1%) categorized as multifactorial ME and 36 (21.7%) with single-cause ME. Hypoxia 103 (62.0%) and renal failure 75 (45.2%) were the most common underlying mechanisms. Neurological causes of AMS occurred in a total 20 patients (12%) and as the sole factor in 5 (3.0%); 10 (6.0%) cases were seizure related and 10 (6.0%) were cerebrovascular events. Of the 7 patients with indeterminant causes, only 1 was suspicious for encephalitis (0.6%). Age, pre-existing dementia and cerebrovascular disease, and impaired renal function were independent predictors of AMS. CONCLUSION: In patients with COVID-19, AMS on presentation to the ED is most frequently caused by metabolic encephalopathy (delirium). Seizures and cerebrovascular events contribute to a lesser degree; encephalitis appears rare.