Variation in electroencephalography and neuroimaging for children receiving extracorporeal membrane oxygenation.

BACKGROUND: Seizures, strokes, and intracranial hemorrhage are common and feared complications in children receiving extracorporeal membrane oxygenation (ECMO) support. Researchers and clinicians have proposed and deployed methods for monitoring and detecting neurologic injury, but best practices are unknown. We sought to characterize clinicians' approach to electroencephalography (EEG) and brain imaging modalities in children supported by ECMO. METHODS: We performed a retrospective observational cohort study among US Children's Hospitals participating in the Pediatric Health Information System (PHIS) from 2016 to 2021. We identified hospitalizations containing ECMO support. We stratified these admissions by pediatric, neonatal, cardiac surgery, and non-cardiac surgery. We characterized the frequency of EEG, cranial ultrasound, brain computed tomography (CT), magnetic resonance imaging (MRI), and transcranial Doppler during ECMO hospitalizations. We reported key diagnoses (stroke and seizures) and the prescription of antiseizure medication. To assess hospital variation, we created multilevel logistic regression models. RESULTS: We identified 8746 ECMO hospitalizations. Nearly all children under 1 year of age (5389/5582) received a cranial ultrasound. Sixty-two percent of the cohort received an EEG, and use increased from 2016 to 2021 (52-72% of hospitalizations). There was marked variation between hospitals in rates of EEG use. Rates of antiseizure medication use (37% of hospitalizations) and seizure diagnoses (20% of hospitalizations) were similar across hospitals, including high and low EEG utilization hospitals. Overall, 37% of the cohort received a CT and 36% received an MRI (46% of neonatal patients). Stroke diagnoses (16% of hospitalizations) were similar between high- and low-MRI utilization hospitals (15% vs 17%, respectively). Transcranial Doppler (TCD) was performed in just 8% of hospitalizations, and 77% of the patients who received a TCD were cared for at one of five centers. CONCLUSIONS: In this cohort of children at high risk of neurologic injury, there was significant variation in the approach to EEG and neuroimaging in children on ECMO. Despite the variation in monitoring and imaging, diagnoses of seizures and strokes were similar across hospitals. Future work needs to identify a management strategy that appropriately screens and monitors this high-risk population without overuse of resource-intensive modalities.

Review of Noninvasive Neuromonitoring Modalities in Children II: EEG, qEEG.

Critically ill children with acute neurologic dysfunction are at risk for a variety of complications that can be detected by noninvasive bedside neuromonitoring. Continuous electroencephalography (cEEG) is the most widely available and utilized form of neuromonitoring in the pediatric intensive care unit. In this article, we review the role of cEEG and the emerging role of quantitative EEG (qEEG) in this patient population. cEEG has long been established as the gold standard for detecting seizures in critically ill children and assessing treatment response, and its role in background assessment and neuroprognostication after brain injury is also discussed. We explore the emerging utility of both cEEG and qEEG as biomarkers of degree of cerebral dysfunction after specific injuries and their ability to detect both neurologic deterioration and improvement.

Vascular Thrombosis in Severe COVID-19 Requiring Extracorporeal Membrane Oxygenation: A Multicenter Study.

OBJECTIVES: Coronavirus disease 2019 has been reported to be a prothrombotic condition; however, multicenter data comparing this with other viral pneumonias in those requiring extracorporeal membrane oxygenation are lacking. We conducted a multicenter study using whole-body CT to examine the prevalence, severity, and nature of vascular complications in coronavirus disease 2019 in comparison with patients with other viral pneumonias. DESIGN: We analyzed whole-body CT scans for the presence of vascular thrombosis (defined as pulmonary artery thrombus, venous thrombus, systemic arterial thrombus, or end-organ infarct). The severity, distribution, and morphology of pulmonary artery thrombus were characterized. Competing risk cumulative incidence analysis was used to compare survival with discharge. SETTING: Three centers of the English national extracorporeal membrane oxygenation service. PATIENTS: Consecutive patients admitted with either coronavirus disease 2019 or noncoronavirus disease 2019 viral pneumonia admitted from January 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One-hundred thirty-six patients (45.2 ± 10.6 yr old, 39/146 [27%] female) requiring extracorporeal membrane oxygenation support underwent whole-body CT scans at admission. Of these, 86 had coronavirus disease 2019 pneumonia, and 50 had noncoronavirus disease 2019 viral pneumonia. Vascular thrombosis was seen more often in patients with coronavirus disease 2019 (odds ratio, 12.9 [95% CI 4.5-36.8]). In those with coronavirus disease 2019, 57 (73%) demonstrated pulmonary artery thrombus or pulmonary perfusion defects. Eighty-two percent of thrombus exhibited emboli-like morphology. The location of pulmonary artery thrombus and parenchymal perfusion defects was only concordant in 30% of cases. The risk of mortality was higher in those with coronavirus disease 2019 compared with noncoronavirus disease 2019 pneumonia (χ2 = 3.94; p = 0.047). Mortality was no different in coronavirus disease 2019 patients with or without vascular thrombosis (χ2 = 0.44; p = 0.51). CONCLUSIONS: In patients who received extracorporeal membrane oxygenation, coronavirus disease 2019 is associated with a higher prevalence of vascular thrombosis compared with noncoronavirus disease viral pneumonias. The pattern of pulmonary vascular changes suggests concurrent embolic disease and small vessel disease. Despite this, vascular thrombosis was not linked to poorer short-term prognosis in those with coronavirus disease 2019.

Pediatric Acute Stroke Protocols in the United States and Canada.

OBJECTIVE: To describe existing pediatric acute stroke protocols to better understand how pediatric centers might implement such pathways within the context of institution-specific structures. STUDY DESIGN: We administered an Internet-based survey of pediatric stroke specialists. The survey included questions about hospital demographics, child neurology and pediatric stroke demographics, acute stroke response, imaging, and hyperacute treatment. RESULTS: Forty-seven surveys were analyzed. Most respondents practiced at a large, freestanding children's hospital with a moderate-sized neurology department and at least 1 neurologist with expertise in pediatric stroke. Although there was variability in how the hospitals deployed stroke protocols, particularly in regard to staffing, the majority of institutions had an acute stroke pathway, and almost all included activation of a stroke alert page. Most institutions preferred magnetic resonance imaging (MRI) over computed tomography (CT) and used abbreviated MRI protocols for acute stroke imaging. Most institutions also had either CT-based or magnetic resonance-based perfusion imaging available. At least 1 patient was treated with intravenous tissue plasminogen activator (IV-tPA) or mechanical thrombectomy at the majority of institutions during the year before our survey. CONCLUSIONS: An acute stroke protocol is utilized in at least 41 pediatric centers in the US and Canada. Most acute stroke response teams are multidisciplinary, prefer abbreviated MRI over CT for diagnosis, and have experience providing IV-tPA and mechanical thrombectomy. Further studies are needed to standardize practices of pediatric acute stroke diagnosis and hyperacute management.

Two years' effect of dimethyl fumarate on focal and diffuse gray matter pathology in multiple sclerosis.

BACKGROUND: Data on the effect of dimethyl fumarate (DMF) on focal and diffuse gray matter (GM) damage, a relevant pathological substrate of multiple sclerosis (MS)-related disability are lacking. OBJECTIVE: To evaluate the DMF effect on cortical lesions (CLs) accumulation and global and regional GM atrophy in subjects with relapsing-remitting MS. METHODS: A total of 148 patients (mean age 38.1 ± 9.7 years) treated with DMF ended a 2-year longitudinal study. All underwent regular Expanded Disability Status Scale (EDSS assessment), and at least two 3T-magnetic resonance imaging (MRI) at 3 and 24 months after DMF initiation. CLs and changes in global and regional atrophy of several brain regions were compared with 47 untreated age and sex-matched patients. RESULTS: DMF-treated patients showed lower CLs accumulation (median 0[0-3] vs 2[0-7], p < 0.001) with respect to controls. Global cortical thickness (p < 0.001) and regional thickness and volume were lower in treated group (cerebellum, hippocampus, caudate, and putamen: p < 0.001; thalamus p = 0.03). Lower relapse rate (14% vs 40%, p < 0.001), EDSS change (0.2 ± 0.4 vs 0.4 ± 0.9, p < 0.001), and new WM lesions (median 0[0-5] vs 2[0-6], p < 0.001) were reported. No severe adverse drug reactions occurred. CONCLUSIONS: Beyond the well-known effect on disease activity, these results provide evidence of the effect of DMF through reduced progression of focal and diffuse GM damage.

CT-derived radiomic features to discriminate histologic characteristics of pancreatic neuroendocrine tumors.

PURPOSE: To assess the ability of radiomic features (RF) extracted from contrast-enhanced CT images (ceCT) and non-contrast-enhanced (non-ceCT) in discriminating histopathologic characteristics of pancreatic neuroendocrine tumors (panNET). METHODS: panNET contours were delineated on pre-surgical ceCT and non-ceCT. First- second- and higher-order RF (adjusted to eliminate redundancy) were extracted and correlated with histological panNET grade (G1 vs G2/G3), metastasis, lymph node invasion, microscopic vascular infiltration. Mann-Whitney with Bonferroni corrected p values assessed differences. Discriminative power of significant RF was calculated for each of the end-points. The performance of conventional-imaged-based-parameters was also compared to RF. RESULTS: Thirty-nine patients were included (mean age 55-years-old; 24 male). Mean diameters of the lesions were 24 × 27 mm. Sixty-nine RF were considered. Sphericity could discriminate high grade tumors (AUC = 0.79, p = 0.002). Tumor volume (AUC = 0.79, p = 0.003) and several non-ceCT and ceCT RF were able to identify microscopic vascular infiltration: voxel-alignment, neighborhood intensity-difference and intensity-size-zone families (AUC ≥ 0.75, p < 0.001); voxel-alignment, intensity-size-zone and co-occurrence families (AUC ≥ 0.78, p ≤ 0.002), respectively). Non-ceCT neighborhood-intensity-difference (AUC = 0.75, p = 0.009) and ceCT intensity-size-zone (AUC = 0.73, p = 0.014) identified lymph nodal invasion; several non-ceCT and ceCT voxel-alignment family features were discriminative for metastasis (p < 0.01, AUC = 0.80-0.85). Conventional CT 'necrosis' could discriminate for microscopic vascular invasion (AUC = 0.76, p = 0.004) and 'arterial vascular invasion' for microscopic metastasis (AUC = 0.86, p = 0.001). No conventional-imaged-based-parameter was significantly associated with grade and lymph node invasion. CONCLUSIONS: Radiomic features can discriminate histopathology of panNET, suggesting a role of radiomics as a non-invasive tool for tumor characterization. TRIAL REGISTRATION NUMBER: NCT03967951, 30/05/2019.

Early T1 Myocardial MRI Mapping: Value in Detecting Myocardial Hyperemia in Acute Myocarditis.

Background Hyperemia is a key component of acute myocarditis (AM). Early gadolinium uptake because of myocardial hyperemia may be quantified by using T1 mapping. Purpose To evaluate the value of early enhanced T1 shortening for the diagnosis of acute myocarditis. Materials and Methods Study participants suspected of having AM and healthy control (HC) participants were prospectively enrolled from September 2016 to May 2019. Participants underwent 1.5-T cardiac MRI including Lake Louise criteria, T2 mapping, native T1, and extracellular volume, with the addition of early enhanced T1 mapping (2 minutes after intravenous administration of 0.15 mmol/kg gadobutrol). Color-coded maps of the percentage of T1 shortening from precontrast to early postcontrast were generated. Optimal early T1 shortening cut-off value and its diagnostic performance in the identification of acute myocarditis were calculated. Results Forty-five study participants with AM (median age, 40 years; interquartile range [IQR], 20-46 years; 22 women) diagnosed according to multidisciplinary clinical evaluation, electrocardiography, laboratory test, echocardiography, cardiac MRI, and coronary CT and/or invasive angiography. Findings were confirmed by endomyocardial biopsy in 64% (29 of 45) of participants. MRI parameters were compared with 19 HC participants (median age, 39 years; IQR, 28-46 years; seven women). Median early T1 shortening was 75% (IQR, 72%-78%) in participants with AM versus 65% (IQR, 61%-66%) in HC participants (P < .001). Early T1 shortening showed high diagnostic performance (area under the receiver operating characteristic curve [AUC], 0.97; 95% confidence interval [CI]: 0.94, 1.00) and excellent interobserver reproducibility (intraclass correlation coefficient: 0.98; 95% CI: 0.96, 1.00). Early T1 shortening of 70% or greater identified acute myocarditis with 93% sensitivity, 100% specificity, and 95% diagnostic accuracy. Early T1 shortening had better diagnostic performance than late percentage T1 shortening (AUC, 0.97 vs 0.90, respectively; P = .03) and extracellular volume (AUC, 0.97 vs 0.88, respectively; P = .046), and similar to native T1 (AUC, 0.97 vs 0.93, respectively; P = .63) and T2 mapping (AUC, 0.97 vs 0.97, respectively; P > .99). Conclusion In this proof-of-concept study, percentage of T1 shortening at early enhanced T1 mapping showed high accuracy for the diagnosis of acute myocarditis. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by De Cecco and Monti in this issue.

Early Electroencephalogram Background Could Guide Tailored Duration of Monitoring for Neonatal Encephalopathy Treated with Therapeutic Hypothermia.

OBJECTIVE: To evaluate whether features of the early electroencephalographic (EEG) background could guide the optimal duration of continuous video EEG monitoring for seizure detection in newborn infants treated with therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: Retrospective cohort study of 114 consecutive infants treated with therapeutic hypothermia for moderate to severe HIE at a level IV neonatal intensive care unit (NICU) between 2012 and 2018. All infants were monitored with continuous video EEG through cooling and rewarming. Archived samples from the first 24 hours of these EEG traces were reviewed systematically and classified by background characteristics. RESULTS: Electrographic seizures occurred in 56 of the 114 infants (49%). Seizure onset was within the first 24 hours after initiation of continuous video EEG in 49 if these 56 infants (88%), between 24 and 48 hours in 4 infants (7%), and >72 hours in 3 infants (5%). Infants with a normal or mildly abnormal EEG background either had seizure onset within the first 24 hours or never developed seizures. Four patients with seizure onset between 24 and 48 hours had markedly abnormal EEG backgrounds. The 3 patients with seizure onset beyond 72 hours had moderate or severely abnormal early continuous video EEG backgrounds. CONCLUSIONS: The use of early continuous video EEG background categorization may be appropriate to guide the duration of continuous video EEG for infants with HIE treated with therapeutic hypothermia. Some infants may reasonably be monitored for 24 hours rather than throughout cooling and rewarming without a significant risk of missed seizures. This could have significant implications for continuous video EEG resource utilization.

T1 mapping performance and measurement repeatability: results from the multi-national T1 mapping standardization phantom program (T1MES).

BACKGROUND: The T1 Mapping and Extracellular volume (ECV) Standardization (T1MES) program explored T1 mapping quality assurance using a purpose-developed phantom with Food and Drug Administration (FDA) and Conformité Européenne (CE) regulatory clearance. We report T1 measurement repeatability across centers describing sequence, magnet, and vendor performance. METHODS: Phantoms batch-manufactured in August 2015 underwent 2 years of structural imaging, B0 and B1, and "reference" slow T1 testing. Temperature dependency was evaluated by the United States National Institute of Standards and Technology and by the German Physikalisch-Technische Bundesanstalt. Center-specific T1 mapping repeatability (maximum one scan per week to minimum one per quarter year) was assessed over mean 358 (maximum 1161) days on 34 1.5 T and 22 3 T magnets using multiple T1 mapping sequences. Image and temperature data were analyzed semi-automatically. Repeatability of serial T1 was evaluated in terms of coefficient of variation (CoV), and linear mixed models were constructed to study the interplay of some of the known sources of T1 variation. RESULTS: Over 2 years, phantom gel integrity remained intact (no rips/tears), B0 and B1 homogenous, and "reference" T1 stable compared to baseline (% change at 1.5 T, 1.95 ± 1.39%; 3 T, 2.22 ± 1.44%). Per degrees Celsius, 1.5 T, T1 (MOLLI 5s(3s)3s) increased by 11.4 ms in long native blood tubes and decreased by 1.2 ms in short post-contrast myocardium tubes. Agreement of estimated T1 times with "reference" T1 was similar across Siemens and Philips CMR systems at both field strengths (adjusted R2 ranges for both field strengths, 0.99-1.00). Over 1 year, many 1.5 T and 3 T sequences/magnets were repeatable with mean CoVs < 1 and 2% respectively. Repeatability was narrower for 1.5 T over 3 T. Within T1MES repeatability for native T1 was narrow for several sequences, for example, at 1.5 T, Siemens MOLLI 5s(3s)3s prototype number 448B (mean CoV = 0.27%) and Philips modified Look-Locker inversion recovery (MOLLI) 3s(3s)5s (CoV 0.54%), and at 3 T, Philips MOLLI 3b(3s)5b (CoV 0.33%) and Siemens shortened MOLLI (ShMOLLI) prototype 780C (CoV 0.69%). After adjusting for temperature and field strength, it was found that the T1 mapping sequence and scanner software version (both P < 0.001 at 1.5 T and 3 T), and to a lesser extent the scanner model (P = 0.011, 1.5 T only), had the greatest influence on T1 across multiple centers. CONCLUSION: The T1MES CE/FDA approved phantom is a robust quality assurance device. In a multi-center setting, T1 mapping had performance differences between field strengths, sequences, scanner software versions, and manufacturers. However, several specific combinations of field strength, sequence, and scanner are highly repeatable, and thus, have potential to provide standardized assessment of T1 times for clinical use, although temperature correction is required for native T1 tubes at least.

Late iodine enhancement cardiac computed tomography for detection of myocardial scars: impact of experience in the clinical practice.

BACKGROUND: Cardiac CT with late iodine enhancement (LIE-CT) may characterize the scarred myocardium, but the role of readers' experience and scar pattern on LIE-CT diagnostic performance is unknown. Aim was to assess the diagnostic performance of LIE-CT according to readers' experience, scar pattern and contrast-to-noise ratio (CNR) using late gadolinium enhancement MRI (LGE-MRI) as reference. METHODS: LIE-CT and LGE-MRI images of 40 consecutive patients were analyzed. Two readers with different experience (8 and 2 years) independently analyzed LIE-CT images defining the presence/absence of scar and scar CNR, segmental involvement, transmural pattern and scar etiology. The same parameters were extracted from LGE-MRI by two expert readers in consensus, blinded to the LIE-CT results. RESULTS: Scars were identified at LGE-MRI in 29/40 patients and 141/680 segments. Scar burden at LIE-CT versus LGE-MRI correlated better for the most experienced reader than for the least experienced one (ρ = 0.954 and ρ = 0.797, p < 0.001). The most experienced reader missed scars in 2 patients and in 21/141 segments; the least experienced in 5 patients and 53/141 segments. The most experienced reader showed higher accuracy and sensitivity compared to the least experienced in per-patient (accuracy: 95% vs. 88%; sensitivity: 93% vs. 83%) and per-segment analysis (accuracy: 96% vs. 92%; sensitivity: 85% vs. 62%). Specificity was excellent (100% per-patient, 99% per-segment,) regardless of readers' experience. Missed scars had non-ischemic pattern, low scar burden (< 6%) and lower CNR compared to ischemic scars (2.33 vs. 3.54, p = 0.005). CONCLUSION: LIE-CT represents an alternative to LGE-MRI, although the impact of readers' experience on sensitivity for small non-ischemic scars should be considered.

A medical device-grade T1 and ECV phantom for global T1 mapping quality assurance-the T1 Mapping and ECV Standardization in cardiovascular magnetic resonance (T1MES) program.

BACKGROUND: T1 mapping and extracellular volume (ECV) have the potential to guide patient care and serve as surrogate end-points in clinical trials, but measurements differ between cardiovascular magnetic resonance (CMR) scanners and pulse sequences. To help deliver T1 mapping to global clinical care, we developed a phantom-based quality assurance (QA) system for verification of measurement stability over time at individual sites, with further aims of generalization of results across sites, vendor systems, software versions and imaging sequences. We thus created T1MES: The T1 Mapping and ECV Standardization Program. METHODS: A design collaboration consisting of a specialist MRI small-medium enterprise, clinicians, physicists and national metrology institutes was formed. A phantom was designed covering clinically relevant ranges of T1 and T2 in blood and myocardium, pre and post-contrast, for 1.5 T and 3 T. Reproducible mass manufacture was established. The device received regulatory clearance by the Food and Drug Administration (FDA) and Conformité Européene (CE) marking. RESULTS: The T1MES phantom is an agarose gel-based phantom using nickel chloride as the paramagnetic relaxation modifier. It was reproducibly specified and mass-produced with a rigorously repeatable process. Each phantom contains nine differently-doped agarose gel tubes embedded in a gel/beads matrix. Phantoms were free of air bubbles and susceptibility artifacts at both field strengths and T1 maps were free from off-resonance artifacts. The incorporation of high-density polyethylene beads in the main gel fill was effective at flattening the B 1 field. T1 and T2 values measured in T1MES showed coefficients of variation of 1 % or less between repeat scans indicating good short-term reproducibility. Temperature dependency experiments confirmed that over the range 15-30 °C the short-T1 tubes were more stable with temperature than the long-T1 tubes. A batch of 69 phantoms was mass-produced with random sampling of ten of these showing coefficients of variations for T1 of 0.64 ± 0.45 % and 0.49 ± 0.34 % at 1.5 T and 3 T respectively. CONCLUSION: The T1MES program has developed a T1 mapping phantom to CE/FDA manufacturing standards. An initial 69 phantoms with a multi-vendor user manual are now being scanned fortnightly in centers worldwide. Future results will explore T1 mapping sequences, platform performance, stability and the potential for standardization.

Interleukin 17 contributes to the chronicity of inflammatory diseases such as rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and bone resorption. The proinflammatory cytokine interleukin 17 (IL-17), primarily produced by Th17 cells, has been shown to be involved in all stages of the disease and to be an important contributor of RA chronicity. Three major processes drive the IL-17-mediated chronicity. Several epigenetic events, enhanced in RA patients, lead to the increased production of IL-17 by Th17 cells. IL-17 then induces the production of several inflammatory mediators in the diseased synovium, which are further synergistically enhanced via combinations of IL-17 with other cytokines. IL-17 also promotes the survival of both the synoviocytes and inflammatory cells and promotes the maturation of these immune cells. This leads to an increased number of synoviocytes and inflammatory cells in the synovial fluid and in the synovium leading to the hyperplasia and exacerbated inflammation observed in joints of RA patients. Furthermore, these IL-17-driven events initiate several feedback-loop mechanisms leading to increased expansion of Th17 cells and thereby increased production of IL-17. In this review, we aim to depict a complete picture of the IL-17-driven vicious circle leading to RA chronicity and to pinpoint the key aspects that require further exploration.

The nuclear factor κB family member RelB facilitates apoptosis of renal epithelial cells caused by cisplatin/tumor necrosis factor α synergy by suppressing an epithelial to mesenchymal transition-like phenotypic switch.

Cis-diamminedichloroplatinum(II) (cisplatin)-induced renal proximal tubular apoptosis is known to be preceded by actin cytoskeleton reorganization, in conjunction with disruption of cell-matrix and cell-cell adhesion. In the present study, we show that the proinflammatory cytokine tumor necrosis factor α (TNF-α) aggravated these cisplatin-induced F-actin and cell adhesion changes, which was associated with enhanced cisplatin-induced apoptosis of immortalized proximal tubular epithelial cells. TNF-α-induced RelB expression and lentiviral small hairpin RNA (shRNA)-mediated knockdown of RelB, but not other nuclear factor κB members, abrogated the synergistic apoptosis observed with cisplatin/TNF-α treatment to the level of cisplatin-induced apoptosis. This protective effect was associated with increased stress fiber formation, cell-matrix, and cell-cell adhesion in the shRNARelB (shRelB) cells during cisplatin/TNF-α treatment, mimicking an epithelial-to-mesenchymal phenotypic switch. Indeed, gene array analysis revealed that knockdown of RelB was associated with upregulation of several actin regulatory genes, including Snai2 and the Rho GTPase proteins Rhophilin and Rho guanine nucleotide exchange factor 3 (ARHGEF3). Pharmacological inhibition of Rho kinase signaling re-established the synergistic apoptosis induced by combined cisplatin/TNF-α treatment of shRelB cells. In conclusion, our study shows for the first time that RelB is required for the cisplatin/TNF-α-induced cytoskeletal reorganization and apoptosis in renal cells by controlling a Rho kinase-dependent signaling network.

Role of pulmonary perfusion magnetic resonance imaging for the diagnosis of pulmonary hypertension: A review.

Among five types of pulmonary hypertension, chronic thromboembolic pulmonary hypertension (CTEPH) is the only curable form, but prompt and accurate diagnosis can be challenging. Computed tomography and nuclear medicine-based techniques are standard imaging modalities to non-invasively diagnose CTEPH, however these are limited by radiation exposure, subjective qualitative bias, and lack of cardiac functional assessment. This review aims to assess the methodology, diagnostic accuracy of pulmonary perfusion imaging in the current literature and discuss its advantages, limitations and future research scope.

A Multidisciplinary Pediatric Neurology Clinic for Systematic Follow-up of Children with Neurologic Sequelae of COVID-19.

Clinical guidance on outpatient follow-up of children hospitalized with acute neurologic complications of SARS-CoV2 infection is needed. We describe the clinical infrastructure of our pediatric neurology post-Covid clinic, including our clinical evaluation and cognitive testing battery specific to this patient population, and a case series of our initial patient cohort. Our findings demonstrate cognitive sequelae in all 4 of our patients months following acute SARS-CoV2 infection with neurologic complications including acute disseminated encephalomyelitis, posterior reversible encephalopathy syndrome, viral encephalitis, and gait difficulties. Verbal and executive function domains were predominantly affected in our cohort, even in patients who did not endorse symptomatic or academic complaints at follow-up. Our recommendations include systematic clinical follow-up for children following hospitalization with SARS-CoV2 infection with a comprehensive cognitive battery to monitor for cognitive sequalae and to assist with developing an individualized education plan for the child as they return to school.

The Spectrum of Quantitative EEG Utilization Across North America: A Cross-Sectional Survey.

BACKGROUND: Continuous electroencephalography (cEEG) is commonly used for neuromonitoring in pediatric intensive care units (PICU); however, there are barriers to real-time interpretation of EEG data. Quantitative EEG (qEEG) transforms the EEG signal into time-compressed graphs, which can be displayed at the bedside. A survey was designed to understand current PICU qEEG use. METHODS: An electronic survey was sent to the Pediatric Neurocritical Care Research Group and Pediatric Status Epilepticus Research Group, and intensivists in 16 Canadian PICUs. Questions addressed demographics, qEEG acquisition and storage, clinical use, and education. RESULTS: Fifty respondents from 39 institutions completed the survey (response rate 53% [39 of 74 institutions]), 76% (37 of 50) from the United States and 24% (12 of 50) from Canada. Over half of the institutions (22 of 39 [56%]) utilize qEEG in their ICUs. qEEG use was associated with having a neurocritical care (NCC) service, ≥200 NCC consults/year, ≥1500 ICU admissions/year, and ≥4 ICU EEGs/day (P < 0.05 for all). Nearly all users (92% [24 of 26]) endorsed that qEEG enhanced care of children with acute neurological injury. Lack of training in qEEG was identified as a common barrier [85% (22 of 26)]. Reviewing and reporting of qEEG was not standard at most institutions. Training was required by 14% (three of 22) of institutions, and 32% (seven of 22) had established curricula. CONCLUSIONS: ICU qEEG was used at more than half of the institutions surveyed, but review, reporting, and application of this tool remained highly variable. Although providers identify qEEG as a useful tool in patient management, further studies are needed to define clinically meaningful pediatric trends, standardize reporting, and enhance educate bedside providers.

Diclofenac inhibits tumor necrosis factor-α-induced nuclear factor-κB activation causing synergistic hepatocyte apoptosis.

UNLABELLED: Drug-induced liver injury (DILI) is an important clinical problem. It involves crosstalk between drug toxicity and the immune system, but the exact mechanism at the cellular hepatocyte level is not well understood. Here we studied the mechanism of crosstalk in hepatocyte apoptosis caused by diclofenac and the proinflammatory cytokine tumor necrosis factor α (TNF-α). HepG2 cells were treated with diclofenac followed by TNF-α challenge and subsequent evaluation of necrosis and apoptosis. Diclofenac caused a mild apoptosis of HepG2 cells, which was strongly potentiated by TNF-α. A focused apoptosis machinery short interference RNA (siRNA) library screen identified that this TNF-α-mediated enhancement involved activation of caspase-3 through a caspase-8/Bid/APAF1 pathway. Diclofenac itself induced sustained activation of c-Jun N-terminal kinase (JNK) and inhibition of JNK decreased both diclofenac and diclofenac/TNF-α-induced apoptosis. Live cell imaging of GFPp65/RelA showed that diclofenac dampened the TNF-α-mediated nuclear factor kappaB (NF-κB) translocation oscillation in association with reduced NF-κB transcriptional activity. This was associated with inhibition by diclofenac of the TNF-α-induced phosphorylation of the inhibitor of NF-κB alpha (IκBα). Finally, inhibition of IκB kinase ß (IKKß) with BMS-345541 as well as stable lentiviral short hairpin RNA (shRNA)-based knockdown of p65/RelA sensitized hepatocytes towards diclofenac/TNF-α-induced cytotoxicity. CONCLUSION: Together, our data suggest a model whereby diclofenac-mediated stress signaling suppresses TNF-α-induced survival signaling routes and sensitizes cells to apoptosis.

Improving outcomes of surgery in advanced infiltrative thymic tumours: the benefits of multidisciplinary approach.

BACKGROUND: For stage III or IVa thymic tumours, a multimodality approach is recommended. The role of surgery is to achieve complete resection. AIM: To present the outcomes of patients undergoing surgery for stage III or IVa thymoma. METHODS: Retrospective review of patients undergoing open surgery for stage III or IVa thymoma between 2016 and 2020 at a single centre was performed. Preoperative imaging, treatment plan, surgical approach, and postoperative outcomes were analyzed. RESULTS: Forty-seven patients underwent surgery for thymoma. Patients with clinical stage I/II thymoma or minimally invasive thymectomy were excluded. Thirteen patients with clinical stage III or IVa were included. Median sternotomy approach was used in four patients, of which one was redo sternotomy; a hemi-clamshell in four; and a combination of approaches in the remaining five patients. There was no postoperative mortality. Four patients had postoperative complications. Complete resection was achieved in all but two patients. At a median follow-up of 17.9 months, all patients were alive with no evidence of recurrence except one who died 4 months after surgery from coronavirus disease 2019 (COVID-19) pneumonia. CONCLUSIONS: Surgery for stage III and IVa thymoma is safe and can be achieved with complete macroscopic resection. To obtain adequate exposure of all structures involved in the tumour, combined surgical approaches can be used with no increased morbidity. The majority of patients, even after extrapleural pneumonectomy, did not receive adjuvant radiotherapy and had no evidence of local relapse.