Discovery of CVN293, a Brain Permeable KCNK13 (THIK-1) Inhibitor Suitable for Clinical Assessment.

The potassium (K+) ion channel KCNK13 is specifically expressed in human microglia with elevated expression observed in post-mortem human brain tissue from patients with Alzheimer's disease. Modulation of KCNK13 activity by a small-molecule inhibitor is proposed as a potential treatment for neurodegenerative diseases. Herein, we describe the evolution of a series of KCNK13 inhibitors derived from a high-throughput screening campaign, resulting in CVN293, a potent, selective, and brain permeable clinical candidate molecule. CVN293 demonstrated a concentration-dependent inhibition of the NLRP3-inflammasome mediated production of IL-1ß from LPS-primed murine microglia. Cross-species pharmacokinetic data of CVN293 are also disclosed. These findings support the advancement of CVN293 in clinical trials.

A Novel Approach to Screen for Somatosensory Evoked Potentials in Critical Care.

BACKGROUND: Somatosensory evoked potentials (SSEPs) help prognostication, particularly in patients with diffuse brain injury. However, use of SSEP is limited in critical care. We propose a novel, low-cost approach allowing acquisition of screening SSEP using widely available intensive care unit (ICU) equipment, specifically a peripheral "train-of-four" stimulator and standard electroencephalograph. METHODS: The median nerve was stimulated using a train-of-four stimulator, and a standard 21-channel electroencephalograph was recorded to generate the screening SSEP. Generation of the SSEP was supported by visual inspection, univariate event-related potentials statistics, and a multivariate support vector machine (SVM) decoding algorithm. This approach was validated in 15 healthy volunteers and validated against standard SSEPs in 10 ICU patients. The ability of this approach to predict poor neurological outcome, defined as death, vegetative state, or severe disability at 6 months, was tested in an additional set of 39 ICU patients. RESULTS: In each of the healthy volunteers, both the univariate and the SVM methods reliably detected SSEP responses. In patients, when compared against the standard SSEP method, the univariate event-related potentials method matched in nine of ten patients (sensitivity = 94%, specificity = 100%), and the SVM had 100% sensitivity and specificity when compared with the standard method. For the 49 ICU patients, we performed both the univariate and the SVM methods: a bilateral absence of short latency responses (n = 8) predicted poor neurological outcome with 0% FPR (sensitivity = 21%, specificity = 100%). CONCLUSIONS: Somatosensory evoked potentials can reliably be recorded using the proposed approach. Given the very good but slightly lower sensitivity of absent SSEPs in the proposed screening approach, confirmation of absent SSEP responses using standard SSEP recordings is advised.

Discovery and Characterization of Novel CNS-Penetrant GPR55 Agonists.

From our NETSseq-derived human brain transcriptomics data, we identified GPR55 as a potential molecular target for the treatment of motor symptoms in patients with Parkinson's disease. From a high-throughput screen, we identified and optimized agonists with nanomolar potency against both human and rat GPR55. We discovered compounds with either strong or limited ß-arrestin signaling and receptor desensitization, indicating biased signaling. A compound that showed minimal GPR55 desensitization demonstrated a reduction in firing frequency of medium spiny neurons cultured from rat striatum but did not reverse motor deficits in a rat hypolocomotion model. Further profiling of several desensitizing and non-desensitizing lead compounds showed that they are selective over related cannabinoid receptors CB1 and CB2 and that unbound brain concentrations well above the respective GPR55 EC50 can be readily achieved following oral administration. The novel brain-penetrant GPR55 agonists disclosed can be used to probe the role of this receptor in the brain.

Discovery of CVN417, a Novel Brain-Penetrant α6-Containing Nicotinic Receptor Antagonist for the Modulation of Motor Dysfunction.

Nicotinic acetylcholine receptor (nAChR) α6 subunit RNA expression is relatively restricted to midbrain regions and is located presynaptically on dopaminergic neurons projecting to the striatum. This subunit modulates dopamine neurotransmission and may have therapeutic potential in movement disorders. We aimed to develop potent and selective α6-containing nAChR antagonists to explore modulation of dopamine release and regulation of motor function in vivo. High-throughput screening (HTS) identified novel α6-containing nAChR antagonists and led to the development of CVN417. This molecule blocks α6-containing nAChR activity in recombinant cells and reduces firing frequency of noradrenergic neurons in the rodent locus coeruleus. CVN417 modulated phasic dopaminergic neurotransmission in an impulse-dependent manner. In a rodent model of resting tremor, CVN417 attenuated this behavioral phenotype. These data suggest that selective antagonism of α6-containing nAChR, with molecules such as CVN417, may have therapeutic utility in treating the movement dysfunctions observed in conditions such as Parkinson's disease.

Injury patterns associated with cognitive motor dissociation.

In unconscious appearing patients with acute brain injury, wilful brain activation to motor commands without behavioural signs of command following, known as cognitive motor dissociation (CMD), is associated with functional recovery. CMD can be detected by applying machine learning to EEG recorded during motor command presentation in behaviourally unresponsive patients. Identifying patients with CMD carries clinical implications for patient interactions, communication with families, and guidance of therapeutic decisions but underlying mechanisms of CMD remain unknown. By analysing structural lesion patterns and network level dysfunction we tested the hypothesis that, in cases with preserved arousal and command comprehension, a failure to integrate comprehended motor commands with motor outputs underlies CMD. Manual segmentation of T2-fluid attenuated inversion recovery and diffusion weighted imaging sequences quantifying structural injury was performed in consecutive unresponsive patients with acute brain injury (n = 107) who underwent EEG-based CMD assessments and MRI. Lesion pattern analysis was applied to identify lesion patterns common among patients with (n = 21) and without CMD (n = 86). Thalamocortical and cortico-cortical network connectivity were assessed applying ABCD classification of power spectral density plots and weighted pairwise phase consistency (WPPC) to resting EEG, respectively. Two distinct structural lesion patterns were identified on MRI for CMD and three for non-CMD patients. In non-CMD patients, injury to brainstem arousal pathways including the midbrain were seen, while no CMD patients had midbrain lesions. A group of non-CMD patients was identified with injury to the left thalamus, implicating possible language comprehension difficulties. Shared lesion patterns of globus pallidus and putamen were seen for a group of CMD patients, which have been implicated as part of the anterior forebrain mesocircuit in patients with reversible disorders of consciousness. Thalamocortical network dysfunction was less common in CMD patients [ABCD-index 2.3 (interquartile range, IQR 2.1-3.0) versus 1.4 (IQR 1.0-2.0), P < 0.0001; presence of D 36% versus 3%, P = 0.0006], but WPPC was not different. Bilateral cortical lesions were seen in patients with and without CMD. Thalamocortical disruption did not differ for those with CMD, but long-range WPPC was decreased in 1-4 Hz [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.7-0.9] and increased in 14-30 Hz frequency ranges (OR 1.2; 95% CI 1.0-1.5). These structural and functional data implicate a failure of motor command integration at the anterior forebrain mesocircuit level with preserved thalamocortical network function for CMD patients with subcortical lesions. Amongst patients with bilateral cortical lesions preserved cortico-cortical network function is associated with CMD detection. These data may allow screening for CMD based on widely available structural MRI and resting EEG.

Concordance Between Active Partial Thromboplastin Time and Anti-Factor Xa Assays in Neurocritically Ill Patients Receiving Subcutaneous Heparin Prophylaxis.

Background: Laboratory monitoring is not recommended when subcutaneous unfractionated heparin (SQ-UFH) is administered at prophylactic doses. However, aPTT prolongation and associated hemorrhage has been reported in the neurocritically ill. At our institution, Neuroscience Intensive Care Unit (Neuro-ICU) patients with prolonged aPTT are further evaluated with a follow up aPTT and anti-factor Xa. Purpose: The purpose of this study was to describe concordance between aPTT and anti-factor Xa in neurocritically ill patients receiving prophylactic SQ-UFH with evidence of aPTT prolongation. Methods: A retrospective chart review of adult patients admitted to the Neuro-ICU from June 2017 to June 2019 was performed. Patients were included if they received SQ-UFH with aPTT levels and at least one anti-factor Xa level drawn within one hour of each other. Concordance between paired aPTT and anti-factor Xa was evaluated using Cohen's weighted kappa. Results: Forty two patients with 56 paired aPTT and anti-factor Xa levels were included. The most prescribed SQ-UFH regimen was 5000 units every 8 hours (60.7%) and anti-factor Xa levels were drawn a median (IQR) of 5.7 (3.1-10.7) hours after the SQ-UFH dose. Only 16 (28.6%) pairs were in concordance. The analysis showed a weighted kappa of .09; 95% CI [-.05 to .22] indicating poor agreement. Conclusions: In neurocritically ill patients receiving prophylactic SQ-UFH with aPTT prolongation, there was poor concordance between aPTT and anti-factor Xa. This suggests that aPTT prolongation may not be solely driven by heparin activity and further evaluation of mechanistic drivers for coagulopathy in this population is necessary.

Pilot Study of a Wearable Hydration Monitor in Haemodialysis Patients: Haemodialysis Outcomes & Patient Empowerment Study 02.

Introduction: We aimed to assess the validity and reproducibility of a wearable hydration device in a cohort of maintenance dialysis patients. Methods: We conducted a prospective, single-arm observational study on 20 haemodialysis patients between January and June 2021 in a single centre. A prototype wearable infrared spectroscopy device, termed the Sixty device, was worn on the forearm during dialysis sessions and nocturnally. Bioimpedance measurements were performed 4 times using the body composition monitor (BCM) over 3 weeks. Measurements from the Sixty device were compared with the BCM overhydration index (litres) pre- and post-dialysis and with standard haemodialysis parameters. Results: 12 out of 20 patients had useable data. Mean age was 52 ± 12.4 years. The overall accuracy for predicting pre-dialysis categories of fluid status using Sixty device was 0.55 [K = 0.00; 95% CI: -0.39-0.42]. The accuracy for the prediction of post-dialysis categories of volume status was low [accuracy = 0.34, K = 0.08; 95% CI: -0.13-0.3]. Sixty outputs at the start and end of dialysis were weakly correlated with pre- and post-dialysis weights (r = 0.27 and r = 0.27, respectively), as well as weight loss during dialysis (r = 0.31), but not ultrafiltration volume (r = 0.12). There was no difference between the change in Sixty readings overnight and the change in Sixty readings during dialysis (mean difference 0.09 ± 1.5 kg), [t(39) = 0.38, p = 0.71]. Conclusion: A prototype wearable infrared spectroscopy device was unable to accurately assess changes in fluid status during or between dialysis sessions. In the future, hardware development and advances in photonics may enable the tracking of interdialytic fluid status.

Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR7 Allosteric Agonist.

The low affinity metabotropic glutamate receptor mGluR7 has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR7 agonists. Of particular interest is the chromane CVN636, a potent (EC50 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR7 compared to not only other mGluRs, but also a broad range of targets. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. CVN636 thus has potential to progress as a drug candidate in CNS disorders involving mGluR7 and glutamatergic dysfunction.

Characterisation of C101248: A novel selective THIK-1 channel inhibitor for the modulation of microglial NLRP3-inflammasome.

Neuroinflammation, specifically the NLRP3 inflammasome cascade, is a common underlying pathological feature of many neurodegenerative diseases. Evidence suggests that NLRP3 activation involves changes in intracellular K+. Nuclear Enriched Transcript Sort Sequencing (NETSseq), which allows for deep sequencing of purified cell types from human post-mortem brain tissue, demonstrated a highly specific expression of the tandem pore domain halothane-inhibited K+ channel 1 (THIK-1) in microglia compared to other glial and neuronal cell types in the human brain. NETSseq also showed a significant increase of THIK-1 in microglia isolated from cortical regions of brains with Alzheimer's disease (AD) relative to control donors. Herein, we report the discovery and pharmacological characterisation of C101248, the first selective small-molecule inhibitor of THIK-1. C101248 showed a concentration-dependent inhibition of both mouse and human THIK-1 (IC50: ∼50 nM) and was inactive against K2P family members TREK-1 and TWIK-2, and Kv2.1. Whole-cell patch-clamp recordings of microglia from mouse hippocampal slices showed that C101248 potently blocked both tonic and ATP-evoked THIK-1 K+ currents. Notably, C101248 had no effect on other constitutively active resting conductance in slices from THIK-1-depleted mice. In isolated microglia, C101248 prevented NLRP3-dependent release of IL-1ß, an effect not seen in THIK-1-depleted microglia. In conclusion, we demonstrated that inhibiting THIK-1 (a microglia specific gene that is upregulated in brains from donors with AD) using a novel selective modulator attenuates the NLRP3-dependent release of IL-1ß from microglia, which suggests that this channel may be a potential therapeutic target for the modulation of neuroinflammation in AD.

Long-Term Outcomes of Patients with Stroke Predicted by Clinicians to have no Chance of Meaningful Recovery: A Japanese Cohort Study.

BACKGROUND: Little is known about the natural history of comatose patients with brain injury, as in many countries most of these patients die in the context of withdrawal of life-sustaining therapies (WLSTs). The accuracy of predicting recovery that is used to guide goals-of-care decisions is uncertain. We examined long-term outcomes of patients with ischemic or hemorrhagic stroke predicted by experienced clinicians to have no chance of meaningful recovery in Japan, where WLST in patients with isolated neurological disease is uncommon. METHODS: We retrospectively reviewed the medical records of all patients admitted with acute ischemic stroke, intracerebral hemorrhage, or nontraumatic subarachnoid hemorrhage between January 2018 and December 2020 to a neurocritical care unit at Toda Medical Group Asaka Medical Center in Saitama, Japan. We screened for patients who were predicted by the attending physician on postinjury day 1-4 to have no chance of meaningful recovery. Primary outcome measures were disposition at hospital discharge and the ability to follow commands and functional outcomes measured by the Glasgow Outcome Scale-Extended (GOS-E), which was assessed 6 months after injury. RESULTS: From 860 screened patients, we identified 40 patients (14 with acute ischemic stroke, 19 with intracerebral hemorrhage, and 7 with subarachnoid hemorrhage) who were predicted to have no chance of meaningful recovery. Median age was 77 years (interquartile range 64-85), 53% (n = 21) were women, and 80% (n = 32) had no functional deficits prior to hospitalization. Six months after injury, 17 patients were dead, 14 lived in a long-term care hospital, 3 lived at home, 2 lived in a rehabilitation center, and 2 lived in a nursing home. Three patients reliably followed commands, two were in a vegetative state (GOS-E 2), four fully depended on others and required constant assistance (GOS-E 3), one could be left alone independently for 8 h per day but remained dependent (GOS-E 4), and one was independent and able to return to work-like activities (GOS-E 5). CONCLUSIONS: In the absence of WLST, almost half of the patients predicted shortly after the injury to have no chance of meaningful recovery were dead 6 months after the injury. A small minority of patients had good functional recovery, highlighting the need for more accurate neurological prognostication.

A first look at perceived stress in southeastern university students during the COVID-19 pandemic.

Objective: Shelter-in-place and social distancing reduce the risk of infection spread, but evidence is appearing to support an unintentional spread of negative mental health effects. The aim of this study was to assess perceived stress in a sample of undergraduate students reflecting upon Spring 2020. Participants and methods: Undergraduate students (N = 312, 75% female, 88% white) completed an online survey assessing demographic information and stress assessed via Cohen's Perceived Stress Scale. Results: Student respondents averaged PSS scores of 21.31(7.54) with 82% of students classified as having moderate or high perceived stress. Females reported higher perceived stress scores compared to males (Z = 4.89, p < 0.01). Conclusions: With concerns about enrollment and financial viability of universities, funneling limited funds to student mental health services could be a utilization of universities' limited funds during Fall 2020.

Classification of Level of Consciousness in a Neurological ICU Using Physiological Data.

BACKGROUND: Impaired consciousness is common in intensive care unit (ICU) patients, and an individual's degree of consciousness is crucial to determining their care and prognosis. However, there are no methods that continuously monitor consciousness and alert clinicians to changes. We investigated the use of physiological signals collected in the ICU to classify levels of consciousness in critically ill patients. METHODS: We studied 61 patients with subarachnoid hemorrhage (SAH) and 178 patients with intracerebral hemorrhage (ICH) from the neurological ICU at Columbia University Medical Center in a retrospective observational study of prospectively collected data. The level of consciousness was determined on the basis of neurological examination and mapped to comatose, vegetative state or unresponsive wakefulness syndrome (VS/UWS), minimally conscious minus state (MCS-), and command following. For each physiological signal, we extracted time-series features and performed classification using extreme gradient boosting on multiple clinically relevant tasks across subsets of physiological signals. We applied this approach independently on both SAH and ICH patient groups for three sets of variables: (1) a minimal set common to most hospital patients (e.g., heart rate), (2) variables available in most ICUs (e.g., body temperature), and (3) an extended set recorded mainly in neurological ICUs (absent for the ICH patient group; e.g., brain temperature). RESULTS: On the commonly performed classification task of VS/UWS versus MCS-, we achieved an area under the receiver operating characteristic curve (AUROC) in the SAH patient group of 0.72 (sensitivity 82%, specificity 57%; 95% confidence interval [CI] 0.63-0.81) using the extended set, 0.69 (sensitivity 83%, specificity 51%; 95% CI 0.59-0.78) on the variable set available in most ICUs, and 0.69 (sensitivity 56%, specificity 78%; 95% CI 0.60-0.78) on the minimal set. In the ICH patient group, AUROC was 0.64 (sensitivity 56%, specificity 65%; 95% CI 0.55-0.74) using the minimal set and 0.61 (sensitivity 50%, specificity 80%; 95% CI 0.51-0.71) using the variables available in most ICUs. CONCLUSIONS: We find that physiological signals can be used to classify states of consciousness for patients in the ICU. Building on this with intraday assessments and increasing sensitivity and specificity may enable alarm systems that alert physicians to changes in consciousness and frequent monitoring of consciousness throughout the day, both of which may improve patient care and outcomes.

Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction.

Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRNVglut3) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRNVglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRNVglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRNVglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders.

Management of Refractory Status Epilepticus: An International Cohort Study (MORSE CODe) Analysis of Patients Managed in the ICU.

BACKGROUND AND OBJECTIVES: Status epilepticus that continues after the initial benzodiazepine and a second anticonvulsant medication is known as refractory status epilepticus (RSE). Management is highly variable because adequately powered clinical trials are missing. We aimed to determine whether propofol and midazolam were equally effective in controlling RSE in the intensive care unit, focusing on management in resource-limited settings. METHODS: Patients with RSE treated with midazolam or propofol between January 2015 and December 2018 were retrospectively identified among 9 centers across 4 continents from upper-middle-income economies in Latin America and high-income economies in North America, Europe, and Asia. Demographics, Status Epilepticus Severity Score, etiology, treatment details, and discharge modified Rankin Scale (mRS) were collected. The primary outcome measure was good functional outcome defined as a mRS score of 0-2 at hospital discharge. RESULTS: Three hundred eighty-seven episodes of RSE (386 patients) were included, with 162 (42%) from upper-middle-income and 225 (58%) from high-income economies. Three hundred six (79%) had acute and 79 (21%) remote etiologies. Initial RSE management included midazolam in 266 (69%) and propofol in 121 episodes (31%). Seventy episodes (26%) that were initially treated with midazolam and 42 (35%) with propofol required the addition of a second anesthetic to treat RSE. Baseline characteristics and outcomes of patients treated with midazolam or propofol were similar. Breakthrough (odds ratio [OR] 1.6, 95% CI 1.3-2.0) and withdrawal seizures (OR 2.0, 95% CI 1.7-2.5) were associated with an increased number of days requiring continuous intravenous anticonvulsant medications (cIV-ACMs). Prolonged EEG monitoring was associated with fewer days of cIV-ACMs (1-24 hours OR 0.5, 95% CI 0.2-0.9, and >24 hours OR 0.7, 95% CI 0.5-1.0; reference EEG <1 hour). This association was seen in both, high-income and upper-middle-income economies, but was particularly prominent in high-income countries. One hundred ten patients (28%) were dead, and 80 (21%) had good functional outcomes at hospital discharge. DISCUSSION: Outcomes of patients with RSE managed in the intensive care unit with propofol or midazolam infusions are comparable. Prolonged EEG monitoring may allow physicians to decrease the duration of anesthetic infusions safely, but this will depend on the implementation of RSE management protocols. Goal-directed management approaches including EEG targets may hold promise for patients with RSE. CLASSIFICATION OF EVIDENCE: This study provides Class III data that propofol and midazolam are equivalently efficacious for RSE.

Cognitive-motor dissociation and time to functional recovery in patients with acute brain injury in the USA: a prospective observational cohort study.

BACKGROUND: Recovery trajectories of clinically unresponsive patients with acute brain injury are largely uncertain. Brain activation in the absence of a behavioural response to spoken motor commands can be detected by EEG, also known as cognitive-motor dissociation. We aimed to explore the role of cognitive-motor dissociation in predicting time to recovery in patients with acute brain injury. METHODS: In this observational cohort study, we prospectively studied two independent cohorts of clinically unresponsive patients (aged ≥18 years) with acute brain injury. Machine learning was applied to EEG recordings to diagnose cognitive-motor dissociation by detecting brain activation in response to verbal commands. Survival statistics and shift analyses were applied to the data to identify an association between cognitive-motor dissociation and time to and magnitude of recovery. The prediction accuracy of the model that was built using the derivation cohort was assessed using the validation cohort. Functional outcomes of all patients were assessed with the Glasgow Outcome Scale-Extended (GOS-E) at hospital discharge and at 3, 6, and 12 months after injury. Patients who underwent withdrawal of life-sustaining therapies were censored, and death was treated as a competing risk. FINDINGS: Between July 1, 2014, and Sept 30, 2021, we screened 598 patients with acute brain injury and included 193 (32%) patients, of whom 100 were in the derivation cohort and 93 were in the validation cohort. At 12 months, 28 (15%) of 193 unresponsive patients had a GOS-E score of 4 or above. Cognitive-motor dissociation was seen in 27 (14%) patients and was an independent predictor of shorter time to good recovery (hazard ratio 5·6 [95% CI 2·5-12·5]), as was underlying traumatic brain injury or subdural haematoma (4·4 [1·4-14·0]), a Glasgow Coma Scale score on admission of greater than or equal to 8 (2·2 [1·0-4·7]), and younger age (1·0 [1·0-1·1]). Among patients discharged home or to a rehabilitation setting, those diagnosed with cognitive-motor dissociation consistently had higher scores on GOS-E indicating better functional recovery compared with those without cognitive-motor dissociation, which was seen as early as 3 months after the injury (odds ratio 4·5 [95% CI 2·0-33·6]). INTERPRETATION: Recovery trajectories of clinically unresponsive patients diagnosed with cognitive-motor dissociation early after brain injury are distinctly different from those without cognitive-motor dissociation. A diagnosis of cognitive-motor dissociation could inform the counselling of families of clinically unresponsive patients, and it could help clinicians to identify patients who will benefit from rehabilitation. FUNDING: US National Institutes of Health.

Gender differences in stress, resilience, and physical activity during the COVID-19 pandemic.

Objective: To evaluate gender differences in physical activity (PA), stress and resiliency during the COVID-19 pandemic. Participants: Students (n = 300) at a southeastern US university. Methods: Perceived Stress (PSS), Resiliency (BRS), Life Events (LEI), and PA were recorded via online survey in Summer 2020. PSS, BRS, LEI, and PA were compared between males and females. Two-way ANOVAs examined gender and frequency effects on PSS and BRS. Results: Females had lower BRS and higher PSS and LEI scores than males (all p < .001). PSS/BRS scores were more strongly correlated with PA in males. Significant gender × frequency interactions were found for PSS (vigorous, p = .03) and for BRS (moderate, p = .049). There was a significant main effect of frequency for PSS with strength training (p < .001). Conclusions: Results suggest that interventions may be particularly needed for females and those with low PA levels.

Prolonged Unconsciousness is Common in COVID-19 and Associated with Hypoxemia.

OBJECTIVE: The purpose of this study was to estimate the time to recovery of command-following and associations between hypoxemia with time to recovery of command-following. METHODS: In this multicenter, retrospective, cohort study during the initial surge of the United States' pandemic (March-July 2020) we estimate the time from intubation to recovery of command-following, using Kaplan Meier cumulative-incidence curves and Cox proportional hazard models. Patients were included if they were admitted to 1 of 3 hospitals because of severe coronavirus disease 2019 (COVID-19), required endotracheal intubation for at least 7 days, and experienced impairment of consciousness (Glasgow Coma Scale motor score <6). RESULTS: Five hundred seventy-one patients of the 795 patients recovered command-following. The median time to recovery of command-following was 30 days (95% confidence interval [CI] = 27-32 days). Median time to recovery of command-following increased by 16 days for patients with at least one episode of an arterial partial pressure of oxygen (PaO2 ) value ≤55 mmHg (p < 0.001), and 25% recovered ≥10 days after cessation of mechanical ventilation. The time to recovery of command-following  was associated with hypoxemia (PaO2 ≤55 mmHg hazard ratio [HR] = 0.56, 95% CI = 0.46-0.68; PaO2 ≤70 HR = 0.88, 95% CI = 0.85-0.91), and each additional day of hypoxemia decreased the likelihood of recovery, accounting for confounders including sedation. These findings were confirmed among patients without any imagining evidence of structural brain injury (n = 199), and in a non-overlapping second surge cohort (N = 427, October 2020 to April 2021). INTERPRETATION: Survivors of severe COVID-19 commonly recover consciousness weeks after cessation of mechanical ventilation. Long recovery periods are associated with more severe hypoxemia. This relationship is not explained by sedation or brain injury identified on clinical imaging and should inform decisions about life-sustaining therapies. ANN NEUROL 2022;91:740-755.

Disorders of Consciousness in Hospitalized Patients with COVID-19: The Role of the Systemic Inflammatory Response Syndrome.

BACKGROUND: Prevalence and etiology of unconsciousness are uncertain in hospitalized patients with coronavirus disease 2019 (COVID-19). We tested the hypothesis that increased inflammation in COVID-19 precedes coma, independent of medications, hypotension, and hypoxia. METHODS: We retrospectively assessed 3203 hospitalized patients with COVID-19 from March 2 through July 30, 2020, in New York City with the Glasgow Coma Scale and systemic inflammatory response syndrome (SIRS) scores. We applied hazard ratio (HR) modeling and mediation analysis to determine the risk of SIRS score elevation to precede coma, accounting for confounders. RESULTS: We obtained behavioral assessments in 3203 of 10,797 patients admitted to the hospital who tested positive for SARS-CoV-2. Of those patients, 1054 (32.9%) were comatose, which first developed on median hospital day 2 (interquartile range [IQR] 1-9). During their hospital stay, 1538 (48%) had a SIRS score of 2 or above at least once, and the median maximum SIRS score was 2 (IQR 1-2). A fivefold increased risk of coma (HR 5.05, 95% confidence interval 4.27-5.98) was seen for each day that patients with COVID-19 had elevated SIRS scores, independent of medication effects, hypotension, and hypoxia. The overall mortality in this population was 13.8% (n = 441). Coma was associated with death (odds ratio 7.77, 95% confidence interval 6.29-9.65) and increased length of stay (13 days [IQR 11.9-14.1] vs. 11 [IQR 9.6-12.4]), accounting for demographics. CONCLUSIONS: Disorders of consciousness are common in hospitalized patients with severe COVID-19 and are associated with increased mortality and length of hospitalization. The underlying etiology of disorders of consciousness in this population is uncertain but, in addition to medication effects, may in part be linked to systemic inflammation.

Identification of Endotypes of Hospitalized COVID-19 Patients.

Background: Characterization of coronavirus disease 2019 (COVID-19) endotypes may help explain variable clinical presentations and response to treatments. While risk factors for COVID-19 have been described, COVID-19 endotypes have not been elucidated. Objectives: We sought to identify and describe COVID-19 endotypes of hospitalized patients. Methods: Consensus clustering (using the ensemble method) of patient age and laboratory values during admission identified endotypes. We analyzed data from 528 patients with COVID-19 who were admitted to telemetry capable beds at Columbia University Irving Medical Center and discharged between March 12 to July 15, 2020. Results: Four unique endotypes were identified and described by laboratory values, demographics, outcomes, and treatments. Endotypes 1 and 2 were comprised of low numbers of intubated patients (1 and 6%) and exhibited low mortality (1 and 6%), whereas endotypes 3 and 4 included high numbers of intubated patients (72 and 85%) with elevated mortality (21 and 43%). Endotypes 2 and 4 had the most comorbidities. Endotype 1 patients had low levels of inflammatory markers (ferritin, IL-6, CRP, LDH), low infectious markers (WBC, procalcitonin), and low degree of coagulopathy (PTT, PT), while endotype 4 had higher levels of those markers. Conclusions: Four unique endotypes of hospitalized patients with COVID-19 were identified, which segregated patients based on inflammatory markers, infectious markers, evidence of end-organ dysfunction, comorbidities, and outcomes. High comorbidities did not associate with poor outcome endotypes. Further work is needed to validate these endotypes in other cohorts and to study endotype differences to treatment responses.