Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

Purpose: To evaluate the sensitivity and specificity of a panel of quantitative EEG (qEEG) trends for seizure detection in adult intensive care unit (ICU) patients when reviewed by neurophysiologists and non-neurophysiologists. Methods: One hour qEEG panels (n ¼ 180) were collected retrospectively from 45 ICU patients and were distributed to 5 neurophysiologists, 7 EEG technologists, and 5 Neuroscience ICU nurses for evaluation of seizures. Each panel consisted of the following qEEG tools, displayed separately for left and right hemisphere electrodes: rhythmicity spectrogram (rhythmic run detection and display; Persyst Inc), color density spectral array, EEG asymmetry index, and amplitude integrated EEG. The reviewers did not have access to the raw EEG data. Results: For the reviewer's ability to detect the presence of seizures on qEEG panels when compared with the gold standard of independent raw EEG review, the sensitivities and specificities are as follows: neurophysiologists 0.87 and 0.61, EEG technologists 0.80 and 0.80, and Neuroscience ICU nurses 0.87 and 0.61, respectively. There was no statistical difference among the three groups regarding sensitivity. Conclusions: Quantitative EEG display panels are a promising tool to aid detection of seizures by non-neurophysiologists as well as by neurophysiologists. However, even when used as a panel, qEEG trends do not appear to be adequate as the sole method for reviewing continuous EEG data.

BackgroundThe PCSK9 antibody alirocumab (75 mg every 2 weeks; Q2W) as monotherapy reduced low‐density lipoprotein‐cholesterol (LDL‐C) levels by 47%. Because the option of a monthly dosing regimen is convenient, ODYSSEY CHOICE II evaluated alirocumab 150 mg Q4W in patients with inadequately controlled hypercholesterolemia and not on statin (majority with statin‐associated muscle symptoms), receiving treatment with fenofibrate, ezetimibe, or diet alone.Methods and ResultsPatients were randomly assigned to placebo, alirocumab 150 mg Q4W or 75 mg Q2W (calibrator arm), with dose adjustment to 150 mg Q2W at week (W) 12 if W8 predefined LDL‐C target levels were not met. The primary efficacy endpoint was LDL‐C percentage change from baseline to W24. Mean baseline LDL‐C levels were 163.9 mg/dL (alirocumab 150 mg Q4W, n=59), 154.5 mg/dL (alirocumab 75 mg Q2W, n=116), and 158.5 mg/dL (placebo, n=58). In the alirocumab 150 mg Q4W and 75 mg Q2W groups (49.1% and 36.0% of patients received dose adjustment, respectively), least‐squares mean LDL‐C changes from baseline to W24 were −51.7% and −53.5%, respectively (placebo [+4.7%]; both groups P<0.0001 versus placebo). In total, 63.9% and 70.3% of alirocumab‐treated patients achieved their LDL‐C targets at W24. Treatment‐emergent adverse events occurred in 77.6% (alirocumab 150 mg Q4W), 73.0% (alirocumab 75 mg Q2W), and 63.8% (placebo) of patients, with injection‐site reactions among the most common treatment‐emergent adverse events.ConclusionsAlirocumab 150 mg Q4W can be considered in patients not on statin with inadequately controlled hypercholesterolemia as a convenient option for lowering LDL‐C.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02023879.

Key Points• Nearly 80% of the warfarintreated patients with ICH had an INR within or below therapeutic range around 2 weeks before the event.• We can reduce ICH by using apixaban rather than warfarin and by avoiding concomitant aspirin, especially in patients with older age.We investigated the frequency and characteristics of intracranial hemorrhage (ICH), the factors associated with the risk of ICH, and outcomes post-ICH overall and by randomized treatment. We identified patients with ICH from the overall trial population enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial who received ‡1 dose of the study drug (n 5 18 140). ICH was adjudicated by a central committee. Cox regression models were used to identify factors associated with ICH. ICH occurred in 174 patients; most ICH events were spontaneous (71.7%) versus traumatic (28.3%). Apixaban resulted in significantly less ICH (0.33% per year), regardless of type and location, than warfarin (0.80% per year). Independent factors associated with increased risk of ICH were enrollment in Asia or Latin America, older age, prior stroke/transient ischemic attack, and aspirin use at baseline. Among warfarin-treated patients, the median (25th, 75th percentiles) time from most recent international normalized ratio (INR) to ICH was 13 days (6, 21 days). Median INR prior to ICH was 2.6 (2.1, 3.0); 78.5% of patients had a pre-ICH INR <3.0. After ICH, the modified Rankin scale score at discharge was ‡4 in 55.7% of patients, and the overall mortality rate at 30 days was 43.3% with no difference between apixaban-and warfarin-treated patients. ICH occurred at a rate of 0.80% per year with warfarin regardless of INR control and at a rate of 0.33% per year with apixaban and was associated with high short-term morbidity and mortality. This highlights the clinical relevance of reducing ICH by using apixaban rather than warfarin and avoiding concomitant aspirin, especially in patients of older age. This trial was registered at www.clinicaltrials.gov as

Summary:Purpose: Because of the high incidence of nonconvulsive status epilepticus (NCSE), the attraction of a "quick and easy" screening electroencephalogram (EEG) is obvious. Previous studies have shown utility of hairline EEG in diagnosing epilepsy. However, this technique has not been evaluated as a screening tool for NCSE. We wanted to provide proof of principle that a screening hairline EEG has sufficient sensitivity to use as a screening tool for diagnosing NCSE.Methods: A total of 120, 2-to 3-min EEG samples of normal and various abnormal digital EEG studies were reformatted in three six-channel montages (A, longitudinal bipolar; B, referential to ipsilateral ear; C, referential to contralateral ear) that mimicked a hairline recording and were interpreted by five neurophysiologists. The test data interpretation was compared with the original EEG interpretation.Results: Performance was best with montages A and B; 71% and 70.5% of the samples were interpreted correctly by using these montages. Only 65% of the samples were correctly interpreted by using montage C. With the best montage (A), the sensitivities ranged from 91% for normal EEG to 54% for periodic lateralized epileptiform discharges (PLEDs). The sensitivity for seizures was only 72%. Seizures were frequently misinterpreted as more benign patterns such as normal and diffuse slowing.Conclusions: EEG data reformatted to resemble a hairline EEG had low sensitivity for detecting seizures. As a result, we do not recommend further pursuit of hairline EEG as a "quick and easy" screening tool for NCSE. Key Words: Hairline EEG-Emergency EEG-Screening EEG-Nonconvulsive status epilepticus.Nonconvulsive status epilepticus (NCSE) has an alarmingly high incidence in hospitalized and critically ill patients (Towne et al., 2000). Studies have found that of patients admitted to intensive care units who undergo electroencephalography (EEG) monitoring, 20-40% may be in NCSE (Jordan, 1993;Young et al., 1996;Jordan, 1999;Varelas and Mirski, 2001;Hirsch and Kull, 2004). A similar incidence of NCSE has been shown for hospitalized patients with altered mental status (Privitera et al., 1994). The high incidence of NCSE was previously unappreciated, as patients in NCSE often do not have clinical evidence of ongoing seizure activity, and EEG is needed to confirm the diagnosis. Without widespread availability and use of EEG, it is difficult to make a diagnosis of NCSE.Obtaining an emergency EEG for the diagnosis of NCSE raises logistic problems in most hospitals. A qualified technologist must be available; even if the study is requested after business hours. Once with the patient, the technologist measures the head and applies electrodes per protocol. The EEG is then run for ≥20 min. The study must then be interpreted by a qualified clinician, who then communicates the results to the referring physician. This process is not only time consuming (often taking in excess of 1-2 h), but also not available in many hospitals (Quigg et al., 2001). If a reliable screening EEG could b...

Objective This study investigated inter-rater agreement (IRA) among EEG experts for the identification of electrographic seizures and periodic discharges (PDs) in continuous ICU EEG recordings. Methods Eight board-certified EEG experts independently identified seizures and PDs in thirty 1-hour EEG segments which were selected from ICU EEG recordings collected from three medical centers. IRA was compared between seizure and PD identifications, as well as among rater groups that have passed an ICU EEG Certification Test, developed by the Critical Care EEG Monitoring Research Consortium (CCEMRC). Results Both kappa and event-based IRA statistics showed higher mean values in identification of seizures compared to PDs (k = 0.58 vs. 0.38; p < 0.001). The group of rater pairs who had both passed the ICU EEG Certification Test had a significantly higher mean IRA in comparison to rater pairs in which neither had passed the test. Conclusions IRA among experts is significantly higher for identification of electrographic seizures compared to PDs. Additional instruction, such as the training module and certification test developed by the CCEMRC, could enhance this IRA. Significance This study demonstrates more disagreement in the labeling of PDs in comparison to seizures. This may be improved by education about standard EEG nomenclature.

At present, there are no proven pharmacological treatments demonstrated to improve long term functional outcomes following traumatic brain injury(TBI). In the setting of non-penetrating TBI, sterile brain inflammatory responses are associated with the development of cerebral edema, intracranial hypertension, and secondary neuronal injury. There is increasing evidence that endogenous apolipoprotein E(apoE) modifies the neuroinflammatory response through its role in downregulating glial activation, however, the intact apoE holoprotein does not cross the blood-brain barrier due to its size. To address this limitation, we developed a small 5 amino acid apoE mimetic peptide(CN-105) that mimics the polar face of the apoE helical domain involved in receptor interactions. The goal of this study was to investigate the therapeutic potential of CN-105 in a murine model of closed head injury. Treatment with CN-105 was associated with a durable improvement in functional outcomes as assessed by Rotarod and Morris Water Maze and a reduction in positive Fluoro-Jade B stained injured neurons and microglial activation. Administration of CN-105 was also associated with reduction in mRNA expression of a subset of inflammatory and immune-related genes.

The concurrence of COVID-19 with Guillain-Barre syndrome (GBS) can increase the likelihood of neuromuscular respiratory failure, autonomic dysfunction, and other life-threatening symptoms. Currently, very little is known about the underlying mechanisms, clinical course, and prognostic implications of comorbid COVID-19 in patients with GBS. We reviewed COVID-19associated GBS case reports published since the outbreak of the pandemic, with a database search up to August 2020, including a manual search of the reference lists for additional relevant cases. Fifty-one (51) case reports of COVID-19 patients (aged 23-84 years) diagnosed with GBS in 11 different countries were included in this review. The results revealed atypical manifestations of GBS, including para-infectious profiles and onset of GBS without antecedent COVID-19 symptoms. Although all tested patients had signs of neuroinflammation, none had SARS-CoV-2 in the cerebrospinal fluid (CSF), and only four (4) patients had antiganglioside antibodies. The majority had a 1-to 10-day time interval between the onset of COVID-19 and GBS symptoms, and many had a poor outcome, with 20 out of the 51 (39.2%) requiring mechanical ventilation, and two deaths within 12 to 24 h. The atypical manifestations of COVID-19-associated GBS, especially the para-infectious profile and short time interval between the onset of the COVID-19 and GBS symptoms, increase the likelihood of symptom overlap, which can complicate the treatment and result in worsened disease progression and/or higher mortality rates. Inclusion of a neurological assessment during diagnosis of COVID-19 might facilitate timely identification and effective management of the GBS symptoms and improve treatment outcome.