Acute brain injury risk prediction models in venoarterial extracorporeal membrane oxygenation patients with tree-based machine learning: An Extracorporeal Life Support Organization Registry analysis.

Objective: We aimed to determine if machine learning can predict acute brain injury and to identify modifiable risk factors for acute brain injury in patients receiving venoarterial extracorporeal membrane oxygenation. Methods: We included adults (age ≥18 years) receiving venoarterial extracorporeal membrane oxygenation or extracorporeal cardiopulmonary resuscitation in the Extracorporeal Life Support Organization Registry (2009-2021). Our primary outcome was acute brain injury: central nervous system ischemia, intracranial hemorrhage, brain death, and seizures. We used Random Forest, CatBoost, LightGBM, and XGBoost machine learning algorithms (10-fold leave-1-out cross-validation) to predict and identify features most important for acute brain injury. We extracted 65 total features: demographics, pre-extracorporeal membrane oxygenation/on-extracorporeal membrane oxygenation laboratory values, and pre-extracorporeal membrane oxygenation/on-extracorporeal membrane oxygenation settings. Results: Of 35,855 patients receiving venoarterial extracorporeal membrane oxygenation (nonextracorporeal cardiopulmonary resuscitation) (median age of 57.8 years, 66% were male), 7.7% (n = 2769) experienced acute brain injury. In venoarterial extracorporeal membrane oxygenation (nonextracorporeal cardiopulmonary resuscitation), the area under the receiver operator characteristic curves to predict acute brain injury, central nervous system ischemia, and intracranial hemorrhage were 0.67, 0.67, and 0.62, respectively. The true-positive, true-negative, false-positive, false-negative, positive, and negative predictive values were 33%, 88%, 12%, 67%, 18%, and 94%, respectively, for acute brain injury. Longer extracorporeal membrane oxygenation duration, higher 24-hour extracorporeal membrane oxygenation pump flow, and higher on-extracorporeal membrane oxygenation partial pressure of oxygen were associated with acute brain injury. Of 10,775 patients receiving extracorporeal cardiopulmonary resuscitation (median age of 57.1 years, 68% were male), 16.5% (n = 1787) experienced acute brain injury. The area under the receiver operator characteristic curves for acute brain injury, central nervous system ischemia, and intracranial hemorrhage were 0.72, 0.73, and 0.69, respectively. Longer extracorporeal membrane oxygenation duration, older age, and higher 24-hour extracorporeal membrane oxygenation pump flow were associated with acute brain injury. Conclusions: In the largest study predicting neurological complications with machine learning in extracorporeal membrane oxygenation, longer extracorporeal membrane oxygenation duration and higher 24-hour pump flow were associated with acute brain injury in nonextracorporeal cardiopulmonary resuscitation and extracorporeal cardiopulmonary resuscitation venoarterial extracorporeal membrane oxygenation.

Neurological monitoring and management for adult extracorporeal membrane oxygenation patients: Extracorporeal Life Support Organization consensus guidelines.

BACKGROUND: Critical care of patients on extracorporeal membrane oxygenation (ECMO) with acute brain injury (ABI) is notable for a lack of high-quality clinical evidence. Here, we offer guidelines for neurological care (neurological monitoring and management) of adults during and after ECMO support. METHODS: These guidelines are based on clinical practice consensus recommendations and scientific statements. We convened an international multidisciplinary consensus panel including 30 clinician-scientists with expertise in ECMO from all chapters of the Extracorporeal Life Support Organization (ELSO). We used a modified Delphi process with three rounds of voting and asked panelists to assess the recommendation levels. RESULTS: We identified five key clinical areas needing guidance: (1) neurological monitoring, (2) post-cannulation early physiological targets and ABI, (3) neurological therapy including medical and surgical intervention, (4) neurological prognostication, and (5) neurological follow-up and outcomes. The consensus produced 30 statements and recommendations regarding key clinical areas. We identified several knowledge gaps to shape future research efforts. CONCLUSIONS: The impact of ABI on morbidity and mortality in ECMO patients is significant. Particularly, early detection and timely intervention are crucial for improving outcomes. These consensus recommendations and scientific statements serve to guide the neurological monitoring and prevention of ABI, and management strategy of ECMO-associated ABI.

EEG reactivity in neurologic prognostication in post-cardiac arrest patients: A narrative review.

Electroencephalographic reactivity (EEG-R) is a promising early predictor of arousal in comatose patients after cardiac arrest. Despite recent guidelines advocating for the integration of EEG-R into the multimodal prognostication model, EEG-R testing methods remain heterogeneous across studies. While efforts towards standardization have been made to reduce interrater variability by the development of quantitative approaches and machine learning models, future validation studies are needed to increase clinical applicability. Furthermore, the specific neurophysiological mechanisms and neuroanatomical correlates underlying EEG-R are not fully understood. In this narrative review, we explore the value and possible mechanisms of EEG-R, focusing on post-cardiac arrest comatose patients. We aim to discuss the current standard of knowledge and future directions, as well as elucidate possible implications for patient care and research.

Prevalence and Neurological Outcomes of Comatose Patients With Extracorporeal Membrane Oxygenation.

OBJECTIVES: To investigate prevalence, risk factors, and in-hospital outcomes of comatose extracorporeal membrane oxygenation (ECMO) patients. DESIGN: Retrospective observational. SETTING: Tertiary academic hospital. PARTICIPANTS: Adults received venoarterial (VA) or venovenous (VV) ECMO support between November 2017 and April 022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We defined 24-hour off sedation as no sedative infusion (except dexmedetomidine) or paralytics administration over a continuous 24-hour period while on ECMO. Off-sedation coma (comaoff) was defined as a Glasgow Coma Scale score of ≤8 after achieving 24-hour off sedation. On-sedation coma (comaon) was defined as a Glasgow Coma Scale score of ≤8 during the entire ECMO course without off sedation for 24 hours. Neurological outcomes were assessed at discharge using the modified Rankin scale (good, 0-3; poor, 4-6). We included 230 patients (VA-ECMO 143, 65% male); 24-hour off sedation was achieved in 32.2% VA-ECMO and 26.4% VV-ECMO patients. Among all patients off sedation for 24 hours (n = 69), 56.5% VA-ECMO and 52.2% VV-ECMO patients experienced comaoff. Among those unable to be sedation free for 24 hours (n = 161), 50.5% VA-ECMO and 17.2% VV-ECMO had comaon. Comaoff was associated with poor outcomes (p < 0.05) in VA-ECMO and VV-ECMO groups, whereas comaon only impacted the VA-ECMO group outcomes. In a multivariable analysis, requirement of renal replacement therapy was an independent risk factor for comaoff after adjusting for ECMO configuration, after adjusting for ECMO configuration, acute brain injury, pre-ECMO partial pressure of oxygen in arterial blood, partial pressure of carbon dioxide in arterial blood, pH, and bicarbonate level (worst value within 24 hours before cannulation). CONCLUSIONS: Comaoff was common and associated with poor outcomes at discharge. Requirement of renal replacement therapy was an independent risk factor.

Epidemiology of Seizures and Association With Mortality in Adult Patients Undergoing ECMO: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) provides lifesaving support to patients with cardiopulmonary failure. Although seizures increase mortality risks among critically ill patients broadly, studies specific to adult ECMO patients have largely been limited to single-center studies. Thus, we aimed to perform a systematic review and meta-analyses of seizure prevalence, mortality, and their associations in adult ECMO patients. METHODS: PubMed, EMBASE, Cochrane trial registry, Web of Science, and SCOPUS were searched on August 5, 2023. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we included studies of adults undergoing venovenous ECMO (VV-ECMO), venoarterial ECMO (VA-ECMO), or extracorporeal cardiopulmonary resuscitation (ECPR) that reported seizures during ECMO. The extracted data included study characteristics, patient demographics, ECMO support, EEG monitoring, and seizures, organized by ECMO types. Forest plot and meta-regression analyses were performed. Bias assessment was performed with the Egger test and Newcastle-Ottawa Scale. RESULTS: Twenty-three studies (n = 40,420, mean age = 51.8 years, male = 62%) were included. Data were extracted by ECMO type as follows: VV-ECMO (n = 16,633), non-ECPR VA-ECMO (n = 11,082), ECPR (n = 3,369), combination of VA-ECMO and ECPR (n = 240), and combination of all types (n = 9,096). The pooled seizure prevalence for all ECMO types was 3.0%, not significantly different across ECMO types (VV-ECMO = 2.0% [95% CI 0.8-4.5]; VA-ECMO = 3.5% [95% CI 1.7-7.0]; ECPR = 4.9% [95% CI 1.3-17.2]). The pooled mortality was lower for VV-ECMO (46.2% [95% CI 39.3-53.2]) than VA-ECMO (63.4% [95% CI 56.6-69.6]) and ECPR (61.5% [95% CI 57.3-65.6]). Specifically, for VV-ECMO, the pooled mortality of patients with and without seizures was 55.1% and 36.7%, respectively (relative risk = 1.5 [95% CI 1.3-1.7]). Similarly, for VA-ECMO, the pooled mortality of patients with and without seizures was 74.4% and 56.1%, respectively (relative risk = 1.3 [95% CI 1.2-1.5]). Meta-regression analyses demonstrated that seizure prevalence was not associated with prior neurologic comorbidities, adjusted for ECMO type and study year. DISCUSSION: Seizures are infrequent during ECMO support. However, they were associated with increased mortality when present. Multi-institutional, larger-scale studies using standardized EEG monitoring are necessary to further understand the risk factors of specific classes of seizures for individual ECMO types, and their effects on mortality. Limitations of our study include missing data for details on seizure types, sedating/antiseizure medications used during ECMO, other ECMO-related complications, and EEG recording protocols.

Methods of Evaluating EEG Reactivity in Adult Intensive Care Units: A Review.

PURPOSE: EEG reactivity (EEG-R) has become widely used in intensive care units for diagnosing and prognosticating patients with disorders of consciousness. Despite efforts toward standardization, including the establishment of terminology for critical care EEG in 2012, the processes of testing and interpreting EEG-R remain inconsistent. METHODS: A review was conducted on PubMed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria consisted of articles published between January 2012, and November 2022, testing EEG-R on adult intensive care unit patients. Exclusion criteria included articles focused on highly specialized stimulation equipment or animal, basic science, or small case report studies. The Quality In Prognostic Studies tool was used to assess risk of bias. RESULTS: One hundred and five articles were identified, with 26 variables collected for each. EEG-R testing varied greatly, including the number of stimuli (range: 1-8; 26 total described), stimulus length (range: 2-30 seconds), length between stimuli (range: 10 seconds-5 minutes), frequency of stimulus application (range: 1-9), frequency of EEG-R testing (range: 1-3 times daily), EEG electrodes (range: 4-64), personnel testing EEG-R (range: neurophysiologists to nonexperts), and sedation protocols (range: discontinuing all sedation to no attempt). EEG-R interpretation widely varied, including EEG-R definitions and grading scales, personnel interpreting EEG-R (range: EEG specialists to nonneurologists), use of quantitative methods, EEG filters, and time to detect EEG-R poststimulation (range: 1-30 seconds). CONCLUSIONS: This study demonstrates the persistent heterogeneity of testing and interpreting EEG-R over the past decade, and contributing components were identified. Further many institutional efforts must be made toward standardization, focusing on the reproducibility and unification of these methods, and detailed documentation in the published literature.

Predicting Acute Brain Injury in Venoarterial Extracorporeal Membrane Oxygenation Patients with Tree-Based Machine Learning: Analysis of the Extracorporeal Life Support Organization Registry.

Objective: To determine if machine learning (ML) can predict acute brain injury (ABI) and identify modifiable risk factors for ABI in venoarterial extracorporeal membrane oxygenation (VA-ECMO) patients. Design: Retrospective cohort study of the Extracorporeal Life Support Organization (ELSO) Registry (2009-2021). Setting: International, multicenter registry study of 676 ECMO centers. Patients: Adults (≥18 years) supported with VA-ECMO or extracorporeal cardiopulmonary resuscitation (ECPR). Interventions: None. Measurements and Main Results: Our primary outcome was ABI: central nervous system (CNS) ischemia, intracranial hemorrhage (ICH), brain death, and seizures. We utilized Random Forest, CatBoost, LightGBM and XGBoost ML algorithms (10-fold leave-one-out cross-validation) to predict and identify features most important for ABI. We extracted 65 total features: demographics, pre-ECMO/on-ECMO laboratory values, and pre-ECMO/on-ECMO settings.Of 35,855 VA-ECMO (non-ECPR) patients (median age=57.8 years, 66% male), 7.7% (n=2,769) experienced ABI. In VA-ECMO (non-ECPR), the area under the receiver-operator characteristics curves (AUC-ROC) to predict ABI, CNS ischemia, and ICH was 0.67, 0.67, and 0.62, respectively. The true positive, true negative, false positive, false negative, positive, and negative predictive values were 33%, 88%, 12%, 67%, 18%, and 94%, respectively for ABI. Longer ECMO duration, higher 24h ECMO pump flow, and higher on-ECMO PaO2 were associated with ABI.Of 10,775 ECPR patients (median age=57.1 years, 68% male), 16.5% (n=1,787) experienced ABI. The AUC-ROC for ABI, CNS ischemia, and ICH was 0.72, 0.73, and 0.69, respectively. The true positive, true negative, false positive, false negative, positive, and negative predictive values were 61%, 70%, 30%, 39%, 29% and 90%, respectively, for ABI. Longer ECMO duration, younger age, and higher 24h ECMO pump flow were associated with ABI. Conclusions: This is the largest study predicting neurological complications on sufficiently powered international ECMO cohorts. Longer ECMO duration and higher 24h pump flow were associated with ABI in both non-ECPR and ECPR VA-ECMO.

Epidemiology of ischemic stroke and hemorrhagic stroke in venoarterial extracorporeal membrane oxygenation.

BACKGROUND: While venoarterial extracorporeal membrane oxygenation (V-A ECMO) provides lifesaving support for cardiopulmonary failure, complications may increase mortality, with few studies focusing on ischemic/hemorrhagic stroke. We aimed to determine the trends and associations of stroke incidence and mortality, and their risk factors, including the effects of annual case volumes of ECMO centers. METHODS: Retrospective analysis was performed on the Extracorporeal Life Support Organization (ELSO) registry, including adult V-A ECMO patients from 534 international centers between 2012 and 2021, excluding extracorporeal cardiopulmonary resuscitation. Temporal trend analyses were performed for stroke incidence and mortality. Univariate testing, multivariable regression, and survival analysis were used to evaluate the associations of stroke, 90-day mortality, and impact of annual center volume. RESULTS: Of 33,041 patients, 20,297 had mortality data, and 12,327 were included in the logistic regression. Between 2012 and 2021, ischemic stroke incidence increased (p < 0.0001), hemorrhagic stroke incidence remained stable, and overall 90-day mortality declined (p < 0.0001). Higher 24-h PaO2 and greater decrease between pre-ECMO PaCO2 and post-cannulation 24-h PaCO2 were associated with greater ischemic stroke incidence, while annual case volume was not. Ischemic/hemorrhagic strokes were associated with increased 90-day mortality (both p < 0.0001), while higher annual case volume was associated with lower 90-day mortality (p = 0.001). Hazard of death was highest in the first several days of V-A ECMO. CONCLUSION: In V-A ECMO patients between 2012 and 2021, 90-day mortality decreased, while ischemic stroke incidence increased. ELSO centers with higher annual case volumes had lower mortality, but were not associated with ischemic/hemorrhagic stroke incidence. Both ischemic/hemorrhagic strokes were associated with increased mortality.

Epidemiology of Ischemic Stroke and Hemorrhagic Stroke in Venoarterial Extracorporeal Membrane Oxygenation.

Background: While venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides lifesaving support for cardiopulmonary failure, complications may arise that increase mortality, with few studies focusing on ischemic/hemorrhagic stroke. We aimed to determine the trends of stroke incidence and mortality, associations with each other, and associations with total case volume at each Extracorporeal Life Support Organization (ELSO) center. Methods: Retrospective analysis of ELSO registry, including adult VA-ECMO patients from 534 international centers between 2012-2021, excluding extracorporeal cardiopulmonary resuscitation. Cochran-Armitage test and Poisson regression were used for trend analysis of stroke incidence and mortality. Kaplan-Meier curves, hazard functions, and multivariable logistic regression were used to study the impact of stroke on 90-day mortality. Results: Of 33,041 patients (median age = 58 years, female = 32%), 4% developed ischemic stroke, and 2% developed hemorrhagic stroke. Ischemic stroke incidence increased (×1.21/year, p < 0.0001), while hemorrhagic stroke incidence remained stable, and overall 90-day mortality declined (1.78%/year, p < 0.0001). Ischemic/hemorrhagic strokes were associated with increased overall 90-day mortality (OR = 3.29, 3.99 respectively, both p < 0.0001) after controlling for pre-selected covariates, including age, pre/post-cannulation lab values, ECMO duration, center volume, and on-ECMO complications. Total center volume was associated positively with ischemic/hemorrhagic stroke incidences (OR = 1.039, 1.053 per-additional-100-cases respectively, both p = 0.022), but inversely with 90-day mortality (OR = 0.909 per-additional-100-cases, p < 0.0001). Hazard of death was highest in the first several days of VA-ECMO. Conclusion: In VA-ECMO patients, while the reported ischemic stroke incidence steadily increased over time, 90-day mortality decreased. ELSO centers with higher case volumes reported greater stroke incidence, but lower mortality. Both ischemic/hemorrhagic strokes were associated with increased mortality.

Utilizing Machine Learning to Predict Neurological Injury in Venovenous Extracorporeal Membrane Oxygenation Patients: An Extracorporeal Life Support Organization Registry Analysis.

Background: Venovenous extracorporeal membrane oxygenation (VV-ECMO) is associated with acute brain injury (ABI), including central nervous system (CNS) ischemia (defined as ischemic stroke or hypoxic-ischemic brain injury) and intracranial hemorrhage (ICH). There is limited data on prediction models for ABI and neurological outcomes in VV-ECMO. Research Question: Can machine learning (ML) accurately predict ABI and identify modifiable factors of ABI in VV-ECMO? Study Design and Methods: We analyzed adult (≥18 years) VV-ECMO patients in the Extracorporeal Life Support Organization Registry (2009-2021) from 676 centers. ABI was defined as CNS ischemia, ICH, brain death, and seizures. Overall, 65 total variables were extracted including clinical characteristics and pre-ECMO and on-ECMO variables. Random Forest, CatBoost, LightGBM, and XGBoost ML algorithms (10-fold leave-one-out cross-validation) were used to predict ABI. Feature Importance Scores were used to pinpoint variables most important for predicting ABI. Results: Of 37,473 VV-ECMO patients (median age=48.1 years, 63% male), 2,644 (7.1%) experienced ABI: 610 (2%) and 1,591 (4%) experienced CNS ischemia and ICH, respectively. The median ECMO duration was 10 days (interquartile range=5-20 days). The area under the receiver-operating characteristics curves to predict ABI, CNS ischemia, and ICH were 0.67, 0.63, and 0.70, respectively. The accuracy, positive predictive, and negative predictive values for ABI were 79%, 15%, and 95%, respectively. ML identified pre-ECMO cardiac arrest as the most important risk factor for ABI while ECMO duration and bridge to transplantation as an indication for ECMO were associated with lower risk of ABI. Interpretation: This is the first study to use machine learning to predict ABI in a large cohort of VV-ECMO patients. Performance was sub-optimal due to the low reported prevalence of ABI with lack of standardization of neuromonitoring/imaging protocols and data granularity in the ELSO Registry. Standardized neurological monitoring and imaging protocols may improve machine learning performance to predict ABI.

Recent applications of quantitative electroencephalography in adult intensive care units: a comprehensive review.

Quantitative electroencephalography (qEEG) refers to the numerical analysis and/or visual transformations of raw electroencephalography (EEG) signals. Evaluation of qEEG in intensive care units (ICU) faces unique challenges that warrant investigation separate from those conducted in other settings. Additionally, the pathophysiology, management, and EEG patterns of critically ill conditions often significantly differ between adults and children. Thus, it is important to distinguish the literature on qEEGs specifically performed in adult ICUs. The aim of this review is to summarize the studies using qEEG for clinical evaluation of patients in adult ICUs performed over the past decade (since 2010), and to present the state of the art of these techniques. Overall, these studies have reported that qEEG can reveal important information faster than typically possible with traditional methods of reviewing the raw EEG only, with reasonable accuracy. However, it is crucial to emphasize that qEEG must be reviewed in conjunction with raw EEG and in context of understanding the patients' clinical status. Because each qEEG panel only focuses on a few aspects of the entire EEG, different combinations of qEEG panels may be required for optimal analyses of each medical condition and individual patient. Currently in practical terms, qEEG can serve as a complementary, valuable tool for portions of the EEG that require more detailed review. Further multi-center collaborative studies are needed to ultimately develop standardized methods of employing qEEG that are generalizable across institutions. As qEEG techniques continue to advance, including those involving machine learning, qEEG will further benefit from algorithms specifically suited for ICUs.

Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma.

How the glioma immune microenvironment fosters tumorigenesis remains incompletely defined. Here, we use single-cell RNA-sequencing and multiplexed tissue-imaging to characterize the composition, spatial organization, and clinical significance of extracellular purinergic signaling in glioma. We show that microglia are the predominant source of CD39, while tumor cells principally express CD73. In glioblastoma, CD73 is associated with EGFR amplification, astrocyte-like differentiation, and increased adenosine, and is linked to hypoxia. Glioblastomas enriched for CD73 exhibit inflammatory microenvironments, suggesting that purinergic signaling regulates immune adaptation. Spatially-resolved single-cell analyses demonstrate a strong spatial correlation between tumor-CD73 and microglial-CD39, with proximity associated with poor outcomes. Similar spatial organization is present in pediatric high-grade gliomas including H3K27M-mutant diffuse midline glioma. These data reveal that purinergic signaling in gliomas is shaped by genotype, lineage, and functional state, and that core enzymes expressed by tumor and myeloid cells are organized to promote adenosine-rich microenvironments potentially amenable to therapeutic targeting.

The effect of tranexamic acid in open reduction and internal fixation of pelvic and acetabular fracture: A systematic review and meta-analysis.

BACKGROUND: Pelvic bone fractures may cause extensive bleeding; however, the efficacy of tranexamic acid (TXA) usage in pelvic fracture surgery remains unclear. In this systematic review and meta-analysis, we aimed to evaluate the efficacy of TXA in open reduction and internal fixation surgery for pelvic and acetabular fracture. METHODS: MEDLINE, Embase, and Cochrane Library databases were systematically searched for studies published before April 22, 2020, that investigated the effect of TXA in the treatment of pelvic and acetabular fracture with open reduction and internal fixation. A pooled analysis was used to identify the differences between a TXA usage group and a control group in terms of estimated blood loss (EBL), transfusion rates, and postoperative complications. RESULTS: We included 6 studies involving 764 patients, comprising 293 patients who received TXA (TXA group) and 471 patients who did not (control group). The pooled analysis showed no differences in EBL between the groups (mean difference -64.67, 95% confidence interval [CI] -185.27 to -55.93, P = .29). The study period transfusion rate showed no significant difference between the groups (odds ratio [OR] 0.77, 95% CI 0.19-3.14, P = .71, I2 = 82%), nor in venous thromboembolism incidence (OR 1.53, 95% CI 0.44-5.25, P = .50, I2 = 0%) or postoperative infection rates (OR 1.15, 95% CI 0.13-9.98, P = .90, I2 = 48%). CONCLUSIONS: Despite several studies having recommended TXA administration in orthopedic surgery, our study did not find TXA usage to be more effective than not using TXA in pelvic and acetabular fracture surgery, especially in terms of EBL reduction, transfusion rates, and the risk of postoperative complications.

Continuous Electroencephalography Markers of Prognostication in Comatose Patients on Extracorporeal Membrane Oxygenation.

BACKGROUND: We aimed to identify continuous electroencephalogram (cEEG) markers associated with survival and death in patients with extracorporeal membrane oxygenation (ECMO) support under standardized sedation cessation protocol. METHODS: Prospectively collected records of adult patients (age ≥ 18 years) who were started on ECMO support in July 2016 to December 2020 at a single tertiary center were analyzed. cEEGs were performed on patients on the basis of inclusion and exclusion criteria. Patients receiving sedation that affect cEEG reactivity at the start of cEEG recording, including propofol, ketamine, or benzodiazepines, were excluded. We allowed fentanyl and dexmedetomidine during cEEG monitoring. cEEGs were evaluated for frequency, amplitude, variability, reactivity, and state changes. RESULTS: Of 290 patients, 40 underwent cEEG in the absence of confounding sedation (median age 60 years, 85% venoarterial-ECMO, 15% venovenous-ECMO). The median length of ECMO support and analyzable cEEG were 143 h and 24 h, respectively. A total of 27 patients underwent withdrawal of life-sustaining therapies (WOLST) during ECMO support. Of the 13 who weaned off ECMO, 9 underwent WOLST later in the hospitalization and 4 survived at hospital discharge. Decisions of WOLST were not influenced by cEEG features' results. Proportions of present EEG reactivity, present state changes, and fair/good variability were significantly higher in patients who survived compared with those who died (odds ratios infinity, infinity, and 13.57, respectively; p values < 0.001, < 0.001, and 0.0299, respectively). Sensitivity and specificity for survival at discharge were 100% and 91.67% for intact reactivity, 100% and 97.20% for present state changes, and 75% and 83.3% for fair/good variability. CONCLUSIONS: Although future multicenter studies with larger patient cohorts are certainly warranted, we were able to validate the feasibility of protocolized sedation cessation and cEEG analyses in the absence of a confounding effect from sedating medications. Moreover, we demonstrate some evidence that cEEG features of intact reactivity, present state changes, and fair/good variability in comatose patients on ECMO may be associated with survival at hospital discharge.

Cerebral Microbleeds and Intracranial Hemorrhages in Adult Patients on Extracorporeal Membrane Oxygenation-Autopsy Study.

Current studies lack robust information on the prevalence and associated factors of cerebral microbleeds in patients who underwent extracorporeal membrane oxygenation. DESIGN: Retrospective analysis. SETTING: We reviewed patients who underwent (extracorporeal membrane oxygenation) and subsequent brain autopsy with gross and microscopic examinations from January 2009 to December 2018 from a single tertiary center. PATIENTS: Twenty-five extracorporeal membrane oxygenation patients (median age, 53 yr; interquartile range, 36-61 yr; 17 women and 8 men) underwent brain autopsy. INTERVENTIONS: Descriptive analysis of neuropathologic findings. Cerebral microbleed was defined as a small focus (< 10 mm diameter) of accumulation of blood product in the brain tissue. Macrohemorrhage was defined as any of the grossly identifiable epidural, subdural, subarachnoid, or intraparenchymal hemorrhages larger than 10 mm. MEASUREMENT AND MAIN RESULTS: Of 25 (22 venoarterial extracorporeal membrane oxygenation; three venovenous extracorporeal membrane oxygenation), 15 patients (60%) were found to have cerebral microbleeds, whereas 13 (52%) had macrohemorrhages, of whom five (20%) had both. Overall, 92% of brains demonstrated the presence of either cerebral microbleeds or macrohemorrhages after extracorporeal membrane oxygenation support. Of the patients with cerebral microbleeds, lobar cerebral microbleeds (80%) occurred more frequently than deep cerebral microbleeds (60%), with 40% of patients having both types. The cases of macrohemorrhages consisted of one epidural (8%), two subdural (15%), and 10 subarachnoid hemorrhages (77%). In univariate analyses, the presence of macrohemorrhages was significantly associated with the presence of cerebral microbleeds (p = 0.03) with odds ratio of 0.13 (CI, 0.02-0.82). Age, sex, extracorporeal membrane oxygenation duration, extracorporeal membrane oxygenation type, use of aspirin or dialysis during extracorporeal membrane oxygenation support, bloodstream infections, hemoglobin, platelets, and coagulopathy profiles were not associated with cerebral microbleeds. CONCLUSIONS: In patients with postmortem neuropathologic evaluation, 92% sustained acute cerebral microbleeds or macrohemorrhages after extracorporeal membrane oxygenation support. Cerebral microbleeds were commonly present in the majority of extracorporeal membrane oxygenation nonsurvivors. Further research is necessary to study the long-term sequelae, such as cognitive outcome of extracorporeal membrane oxygenation-associated cerebral microbleeds in extracorporeal membrane oxygenation survivors.

DNA-Engineerable Ultraflat-Faceted Core-Shell Nanocuboids with Strong, Quantitative Plasmon-Enhanced Fluorescence Signals for Sensitive, Reliable MicroRNA Detection.

There has been enormous interest in understanding and utilizing plasmon-enhanced fluorescence (PEF) with metal nanostructures, but maximizing the enhancement in a reproducible, quantitative manner while reliably controlling the distance between dyes and metal particle surface for practical applications is highly challenging. Here, we designed and synthesized fluorescence-amplified nanocuboids (FANCs) with highly enhanced and controlled PEF signals, and fluorescent silica shell-coated FANCs (FS-FANCs) were then formed to fixate the dye position and increase particle stability and fluorescence signal intensity for biosensing applications. By uniformly modifying fluorescently labeled DNA on Au nanorods and forming ultraflat Ag shells on them, we were able to reliably control the distance between fluorophores and Ag surface and obtained an ∼186 fluorescence enhancement factor with these FANCs. Importantly, FS-FANCs were utilized as fluorescent nanoparticle tags for microarray-based miRNA detection, and we achieved >103-fold higher sensitivity than commercially available chemical fluorophores with 100 aM to 1 pM dynamic range.

Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies.

Muscular dystrophy is a group of genetic disorders characterised by degeneration of muscles. Different forms of muscular dystrophy can show varying phenotypes with a wide range of age, severity and location of muscle deterioration. Many palliative care options are available for muscular dystrophy patients, but no curative treatment is available. Exon-skipping therapy aims to induce skipping of exons with disease-causing mutations and/or nearby exons to restore the reading frame, which results in an internally truncated, partially functional protein. In antisense-mediated exon-skipping synthetic antisense oligonucleotide binds to pre-mRNA to induce exon skipping. Recent advances in exon skipping have yielded promising results; the US Food and Drug Administration (FDA) approved eteplirsen (Exondys51) as the first exon-skipping drug for the treatment of Duchenne muscular dystrophy, and in vivo exon skipping has been demonstrated in animal models of dysferlinopathy, limb-girdle muscular dystrophy type 2C and congenital muscular dystrophy type 1A. Novel methods that induce exon skipping utilizing Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are also being developed where splice site mutations are created within the genome to induce exon skipping. Challenges remain as exon-skipping agents can have deleterious non-specific effects and different in-frame deletions show phenotypic variance. This article reviews the state of the art of exon skipping for treating muscular dystrophy and discusses challenges and future prospects.

Spinal cord α-synuclein deposition associated with myoclonus in patients with MSA-C.

OBJECTIVE: To test the hypothesis that myoclonus in patients with multiple system atrophy with predominant cerebellar ataxia (MSA-C) is associated with a heavier burden of α-synuclein deposition in the motor regions of the spinal cord, we compared the degree of α-synuclein deposition in spinal cords of 3 patients with MSA-C with myoclonus and 3 without myoclonus. METHODS: All human tissue was obtained by the Massachusetts General Hospital Department of Pathology with support from and according to neuropathology guidelines of the Massachusetts Alzheimer's Disease Research Center. Tissue was stained with Luxol fast blue and hematoxylin & eosin for morphologic evaluation, and with a mouse monoclonal antibody to α-synuclein and Vectastain DAB kit. Images of the spinal cord sections were digitized using a 10× objective lens. Grayscale versions of these images were transferred to ImageJ software for quantitative analysis of 8 different regions of interest (ROIs) in the spinal cord: dorsal column, anterior white column, left and right dorsal horns, left and right anterior horns, and left and right lateral corticospinal tracts. A mixed-effect, multiple linear regression model was constructed to determine if patients with and without myoclonus had significantly different distributions of α-synuclein deposition across the various ROIs. RESULTS: Patients with myoclonus had more α-synuclein in the anterior horns (p < 0.001) and lateral corticospinal tracts (p = 0.02) than those without myoclonus. CONCLUSIONS: In MSA-C, myoclonus appears to be associated with a higher burden of α-synuclein deposition within spinal cord motor regions. Future studies with more patients will be needed to confirm these findings.