Faculty Bibliography

Importance/UNASSIGNED:Clinical evidence of the potential treatment benefit of mechanical thrombectomy for posterior circulation distal, medium vessel occlusion (DMVO) is sparse. Objective/UNASSIGNED:To investigate the frequency as well as the clinical and safety outcomes of mechanical thrombectomy for isolated posterior circulation DMVO stroke and to compare them with the outcomes of standard medical treatment with or without intravenous thrombolysis (IVT) in daily clinical practice. Design, Setting, and Participants/UNASSIGNED:This multicenter case-control study analyzed patients who were treated for primary distal occlusion of the posterior cerebral artery (PCA) of the P2 or P3 segment. These patients received mechanical thrombectomy or standard medical treatment (with or without IVT) at 1 of 23 comprehensive stroke centers in Europe, the United States, and Asia between January 1, 2010, and June 30, 2020. All patients who met the inclusion criteria were matched using 1:1 propensity score matching. Interventions/UNASSIGNED:Mechanical thrombectomy or standard medical treatment with or without IVT. Main Outcomes and Measures/UNASSIGNED:Clinical end point was the improvement of National Institutes of Health Stroke Scale (NIHSS) scores at discharge from baseline. Safety end point was the occurrence of symptomatic intracranial hemorrhage and hemorrhagic complications were classified based on the Second European-Australasian Acute Stroke Study (ECASSII). Functional outcome was evaluated with the modified Rankin Scale (mRS) score at 90-day follow-up. Results/UNASSIGNED:Of 243 patients from all participating centers who met the inclusion criteria, 184 patients were matched. Among these patients, the median (interquartile range [IQR]) age was 74 (62-81) years and 95 (51.6%) were female individuals. Posterior circulation DMVOs were located in the P2 segment of the PCA in 149 patients (81.0%) and in the P3 segment in 35 patients (19.0%). At discharge, the mean NIHSS score decrease was -2.4 points (95% CI, -3.2 to -1.6) in the standard medical treatment cohort and -3.9 points (95% CI, -5.4 to -2.5) in the mechanical thrombectomy cohort, with a mean difference of -1.5 points (95% CI, 3.2 to -0.8; P = .06). Significant treatment effects of mechanical thrombectomy were observed in the subgroup of patients who had higher NIHSS scores on admission of 10 points or higher (mean difference, -5.6; 95% CI, -10.9 to -0.2; P = .04) and in the subgroup of patients without IVT (mean difference, -3.0; 95% CI, -5.0 to -0.9; P = .005). Symptomatic intracranial hemorrhage occurred in 4 of 92 patients (4.3%) in each treatment cohort. Conclusions and Relevance/UNASSIGNED:This study suggested that, although rarely performed at comprehensive stroke centers, mechanical thrombectomy for posterior circulation DMVO is a safe, and technically feasible treatment option for occlusions of the P2 or P3 segment of the PCA compared with standard medical treatment with or without IVT.

OBJECTIVES/OBJECTIVE:To identify research priorities in the management, pathophysiology, and host response of coronavirus disease 2019 in critically ill patients. DESIGN/METHODS:The Surviving Sepsis Research Committee, a multiprofessional group of 17 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine, was virtually convened during the coronavirus disease 2019 pandemic. The committee iteratively developed the recommendations and subsequent document. METHODS:Each committee member submitted a list of what they believed were the most important priorities for coronavirus disease 2019 research. The entire committee voted on 58 submitted questions to determine top priorities for coronavirus disease 2019 research. RESULTS:The Surviving Sepsis Research Committee provides 13 priorities for coronavirus disease 2019. Of these, the top six priorities were identified and include the following questions: 1) Should the approach to ventilator management differ from the standard approach in patients with acute hypoxic respiratory failure?, 2) Can the host response be modulated for therapeutic benefit?, 3) What specific cells are directly targeted by severe acute respiratory syndrome coronavirus 2, and how do these cells respond?, 4) Can early data be used to predict outcomes of coronavirus disease 2019 and, by extension, to guide therapies?, 5) What is the role of prone positioning and noninvasive ventilation in nonventilated patients with coronavirus disease?, and 6) Which interventions are best to use for viral load modulation and when should they be given? CONCLUSIONS:Although knowledge of both biology and treatment has increased exponentially in the first year of the coronavirus disease 2019 pandemic, significant knowledge gaps remain. The research priorities identified represent a roadmap for investigation in coronavirus disease 2019.

Background/UNASSIGNED:People living with multiple sclerosis (MS) experience a high symptom burden that interferes with daily functioning. Virtual reality (VR) is an emerging technology with a range of potential therapeutic applications that may include ameliorating the experience of some common MS symptoms. Objective/UNASSIGNED:We tested the feasibility and tolerability of a VR intervention and its preliminary effects on affect. Methods/UNASSIGNED:Participants with MS were recruited to complete a pilot study of eight sessions of VR over four weeks. Results/UNASSIGNED: = 0.040). Conclusion/UNASSIGNED:VR interventions are feasible, safe, and tolerable for individuals living with MS and may improve affect.

OBJECTIVE:We sought to identify similarities and differences in the diagnostic requirements for ancillary testing for determination of brain death/death by neurologic criteria (BD/DNC) around the world. METHODS:We reviewed diagnostic requirements for ancillary testing for BD/DNC in 78 unique official national BD/DNC protocols obtained from contacts worldwide between January 2018 and April 2019. RESULTS:Details provided on the performance and interpretation of ancillary tests for determination of BD/DNC were variably provided and inconsistent. Approximately half of all protocols that included each ancillary test provided details about study performance: 63% of protocols that included conventional cerebral angiography, 55% of protocols that included electroencephalography, 50% of protocols that included somatosensory evoked potentials, 48% of protocols that included transcranial Doppler ultrasonography, 43% of protocols that included nuclear medicine flow study and 41% of protocols that included brainstem auditory evoked potentials. Similarly, about half of all protocols that included each ancillary test provided details about study interpretation: 66% of protocols that included electroencephalography, 59% of protocols that included brainstem auditory evoked potentials, 56% of protocols that included somatosensory evoked potentials, 55% of protocols that included transcranial Doppler ultrasonography, 52% of protocols that included conventional cerebral angiography and 49% of protocols that included nuclear medicine flow study. INTERPRETATION/CONCLUSIONS:Diagnostic requirements for ancillary testing in BD/DNC determination vary around the world. We hope that the World Brain Death Project will improve worldwide consensus on the diagnostic requirements for ancillary testing in BD/DNC, both for performance and interpretation.

Direct electrical stimulation can modulate the activity of brain networks for the treatment of several neurological and neuropsychiatric disorders and for restoring lost function. However, precise neuromodulation in an individual requires the accurate modelling and prediction of the effects of stimulation on the activity of their large-scale brain networks. Here, we report the development of dynamic input-output models that predict multiregional dynamics of brain networks in response to temporally varying patterns of ongoing microstimulation. In experiments with two awake rhesus macaques, we show that the activities of brain networks are modulated by changes in both stimulation amplitude and frequency, that they exhibit damping and oscillatory response dynamics, and that variabilities in prediction accuracy and in estimated response strength across brain regions can be explained by an at-rest functional connectivity measure computed without stimulation. Input-output models of brain dynamics may enable precise neuromodulation for the treatment of disease and facilitate the investigation of the functional organization of large-scale brain networks.

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H₂O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (C_max > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H₂O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

Large hemispheric infarcts occur in up to 10% of all ischemic strokes and can cause devastating disability. Significant research and clinical efforts have been made in hopes of mitigating the morbidity and mortality of this disease. Areas of interest include identifying predictors of malignant edema, optimizing medical and surgical techniques, selecting the patient population that would benefit most from decompressive hemicraniectomy, and studying the impact on quality of life of those who survive. Decompressive surgery can be a life-saving measure, and here we discuss the most up-to-date literature and provide a review on the surgical management of large hemispheric ischemic strokes.

Purpose: African American (AA) patients are at risk for increased rates of rejection after heart transplantation (HT).We compared cell-free DNA (cf-DNA) levels after HT by recipient race.
Method(s): This was a retrospective analysis of 96 HT recipients from the Genomic Research Alliance for Transplantation (GRAFT) Registry, of which 63 patients had cf-DNA values. Cf-DNA values were compared by race withan exponential decay model and Kaplan-Meier (KM) analysis was performed to compare time-to-first rejection.
Result(s): Compared to non-AA patients, AA recipients had a similar prevalence of diabetes and hypertension,proportion of males, and donor characteristics. AA recipients had higher cf-DNA values compared to non-AA recipients for the first five days following transplant (8.3% vs. 3.2% p=0.001 Table 1/figure 1). The stable state cf-DNA values decayed rapidly for AA patients and equalized to non-AA patients over the first 7 days (0.46% vs 0.45%, p=0.8 Table 1). Cellular rejection did not differ by race (HR [CI]=1.4 [0.62,3.2], p=0.4). However AA were at higher risk of antibody mediated rejection (HR [CI]=3.8 [1.3,10.9], p=0.01).
Conclusion(s): African American patients had increased cf-DNA values in the first week following heart transplant. This may be a marker of early injury contributing to increased rates of allograft rejection in AA patients. Further analysisadjusting for confounding variables and determining predictors of clinical outcomes will be included at the time of presentation once follow-up of the GRAFT registry is complete.
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OBJECTIVE:Many people with new-onset focal epilepsy initially seek evaluation in emergency departments (EDs), and treatment decisions in EDs can influence likelihood of seizure recurrence. Using data collected for the Human Epilepsy Project (HEP), we assessed the effect of clinical seizure characteristics on ED clinical management. METHODS:There were 447 participants with new-onset focal epilepsy seen within four months of treatment initiation who were eligible and enrolled in HEP. Seizure calendars and medical records were collected. Based on clinical descriptions, seizures were categorized by semiology according to International League Against Epilepsy (ILAE) classifications as either focal non-motor or focal motor seizures. RESULTS:Overall, 279/447(62%) of participants had presented to an ED prior to or at time of epilepsy diagnosis. 132 /246 (53%) with initial non-motor seizures presented to an ED. Of these, 8 (6%) presented with a first-lifetime non-motor seizure. The other 124 (94%) presented after multiple seizures: 7 (5%) with multiple non-motor seizures, and 117 (89%) with a first-lifetime motor seizure after having prior non-motor seizures. 147/ 201 (73%) of participants with initial motor seizures presented to an ED. Of these, 134 (92%) presented with a first-lifetime motor seizure, and 13 (9%) with multiple motor seizures. There was no difference in the likelihood of anti-seizure medication (ASM) initiation between participants who had multiple prior non-motor seizures followed by a motor seizure (thereby fulfilling the criterion for an epilepsy diagnosis), vs those presenting with a single lifetime motor seizure (39% vs 43%). There was no difference in recognition of seizures as the presenting complaint (85% vs 87%), or whether the participant was admitted or referred to a neurologist (87% vs 79%). CONCLUSIONS:This study contributes to evidence of under-recognition of non-motor focal seizure semiologies in ED settings, which can support large-scale interventions aimed at improving recognition, specialist consultation, and treatment in ED settings.