Basilar artery stenting in hyperacute stroke: A systematic review of published cases.

BACKGROUND AND PURPOSE: Basilar artery stenting is a rescue therapy in the management of hyperacute stroke. Published data on efficacy and safety are limited. METHODS: A systematic review of published studies was performed in accordance with PRISMA guidelines. Inclusion criteria were adult patients with ischemic stroke with permanent basilar artery stent placement within 48 h of onset. Data were extracted by two independent reviewers. Additional cases from our institution were identified via a local stroke registry. RESULTS: Of 212 screened articles, patient-level data was reported in 35 studies (87 individuals) and six additional patients were included from our registry. Patients (n = 93, 63 % male; median age 64) most often presented with mid-basilar occlusion (52 %) and 76 % received treatment within 12 hours of onset. Favorable angiographic results occurred in 67 %. The final modified Rankin Scale score (mRS) was 0-3 for 56 % of patients; mortality was 29 %. Those with complete flow post-procedure were more likely to have a final mRS of 0-3 (p = 0.05). CONCLUSIONS: In 93 cases of basilar stenting in hyperacute stroke, favourable angiographic and functional outcomes were reported in 67 % and 56 % of patients, respectively. International multicenter registries are required to establish benefit and identify patient and technical factors that predict favorable outcomes.

Cerebrovascular disease case identification in inpatient electronic medical record data using natural language processing.

BACKGROUND: Abstracting cerebrovascular disease (CeVD) from inpatient electronic medical records (EMRs) through natural language processing (NLP) is pivotal for automated disease surveillance and improving patient outcomes. Existing methods rely on coders' abstraction, which has time delays and under-coding issues. This study sought to develop an NLP-based method to detect CeVD using EMR clinical notes. METHODS: CeVD status was confirmed through a chart review on randomly selected hospitalized patients who were 18 years or older and discharged from 3 hospitals in Calgary, Alberta, Canada, between January 1 and June 30, 2015. These patients' chart data were linked to administrative discharge abstract database (DAD) and Sunrise™ Clinical Manager (SCM) EMR database records by Personal Health Number (a unique lifetime identifier) and admission date. We trained multiple natural language processing (NLP) predictive models by combining two clinical concept extraction methods and two supervised machine learning (ML) methods: random forest and XGBoost. Using chart review as the reference standard, we compared the model performances with those of the commonly applied International Classification of Diseases (ICD-10-CA) codes, on the metrics of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULT: Of the study sample (n = 3036), the prevalence of CeVD was 11.8% (n = 360); the median patient age was 63; and females accounted for 50.3% (n = 1528) based on chart data. Among 49 extracted clinical documents from the EMR, four document types were identified as the most influential text sources for identifying CeVD disease ("nursing transfer report," "discharge summary," "nursing notes," and "inpatient consultation."). The best performing NLP model was XGBoost, combining the Unified Medical Language System concepts extracted by cTAKES (e.g., top-ranked concepts, "Cerebrovascular accident" and "Transient ischemic attack"), and the term frequency-inverse document frequency vectorizer. Compared with ICD codes, the model achieved higher validity overall, such as sensitivity (25.0% vs 70.0%), specificity (99.3% vs 99.1%), PPV (82.6 vs. 87.8%), and NPV (90.8% vs 97.1%). CONCLUSION: The NLP algorithm developed in this study performed better than the ICD code algorithm in detecting CeVD. The NLP models could result in an automated EMR tool for identifying CeVD cases and be applied for future studies such as surveillance, and longitudinal studies.

Chimeric Antigen Receptor-T Cell Mediated Bilateral Facial Nerve Palsy: A Case Report.

Chimeric antigen receptor (CAR-T) cell therapy is highly effective against hematological cancers but is associated with immune mediated side effects, including neurotoxicity. The most commonly described presentations of immune cell mediated neurotoxicity syndrome (ICANS) include cortical symptoms and generally localize to the central nervous system. In this report, we present a patient with acute onset of bilateral facial nerve palsy following CAR-T cell therapy, followed by a complete clinical recovery. Aside from a temporary anisocoria, he had no other neurologic symptoms and no encephalopathy or seizures. MRI Brain was non-contributory and cerebrospinal fluid revealed a modest increase in lymphocytes without systemic leukocytosis and viral studies were all negative. He was diagnosed with bilateral facial nerve palsy secondary to CAR-T cell therapy and subsequently treated with a course of steroids. Several weeks after presentation he returned to his neurological baseline. The presentation of CAR-T cell mediated facial nerve palsy is both clinically and scientifically relevant for physicians, patients, and researchers.

Strongman - At Home.

A neurologist reflects on the unintended heartlessness of keeping a patient with terminal cancer in hospital for further tests at a time when families are not permitted to visit. Peripherally involved in a patient's care, he witnesses the suffering brought about by pandemic-related visitation restrictions in the final weeks of a patient's life. In reviewing the course of events with the patient's widow, the physician has many of his assumptions overturned and more completely grasps the consequences of visitation restrictions on hospitalized patients.

Cerebral fat embolism syndrome at a single trauma center.

OBJECTIVES: Based on a 16-year case series, we sought lessons about diagnosis and treatment of cerebral fat embolism syndrome. MATERIALS AND METHODS: Using discharge codes at a Level 1 Trauma Center, we performed a retrospective chart review of clinical characteristics, diagnostic studies, treatments, and outcome in cerebral fat embolism syndrome. RESULTS: Thirty-nine (40%) of 97 patients with fat embolism syndrome were diagnosed with cerebral fat embolism syndrome, with 29 (74%) presenting with coma. All had abnormal brain magnetic resonance imaging, with scattered cytotoxic edema (starfield pattern) in 29 (74%). All but two of the 21 patients with dilated fundoscopy showed retinal embolism. Among 29 patients with transcranial Doppler, the presence of microembolic signals in 15 (52%) was associated with fever (p = 0.039), right-to-left intracardiac shunting (p = 0.046) and a trend towards initial coma. In 11 patients with serial transcranial Dopplers and treatment with high-intensity statin therapy, the frequency of microembolic signals tended to decrease after therapy was initiated. Of the 28 (72%) of the 39 patients discharged, 16 (57%) had mild to moderate disability at last follow up. CONCLUSIONS: The recognition of cerebral fat embolism syndrome may be improved with routine inclusion of brain magnetic resonance imaging, dilated fundoscopy, and transcranial Doppler. We share our empiric management algorithm for cerebral fat embolism syndrome using these studies and with consideration of experimental therapies in select patients to prevent ongoing cerebral injury.

Characterization of an archaeal inorganic pyrophosphatase from Sulfolobus islandicus using a [31P]-NMR-based assay.

Inorganic pyrophosphatase catalyzes the conversion of pyrophosphate to phosphate and is often critical for driving reactions forward in cellular processes such as nucleic acid and protein synthesis. Commonly used methods for quantifying pyrophosphatase enzyme activity employ reacting liberated phosphate with a second molecule to produce absorbance changes or employing a second enzyme in coupled reactions to produce a product with a detectable absorbance. In this investigation, a novel [31P]-NMR spectroscopy-based assay was used to quantitatively measure the formation of phosphate and evaluate the activity of inorganic pyrophosphatase from the thermoacidophilic Crenarchaeota Sulfolobus islandicus. The enzymatic activity was directly measured via integration of the [31P] resonance associated with the phosphate product (δ = 2.1 ppm). Sulfolobus islandicus inorganic pyrophosphatase preferentially utilized Mg2+ as divalent cation and had pH and temperature optimums of 6.0 of 50 °C, respectively. The Vmax value was 850 µmol/min/mg and the Km for pyrophosphate was 1.02 mM. Sequence analysis indicates the enzyme is a Family I pyrophosphatase. Sulfolobus islandicus inorganic pyrophosphatase was shown to be inhibited by sodium fluoride with a IC50 of 2.26 mM, compared to a IC50 of 0.066 mM for yeast inorganic pyrophosphatase. These studies reveal that a [31P]-NMR spectroscopy-based assay is an effective method for analyzing catalysis by phosphate-producing enzymes.

Electron Distribution in 1,2,3-Benzotriazole and 1,2,3-Triazole Anion Radical Isomers: An EPR and DFT Study.

The anion radicals of N1- and N2-alkylbenzotriazoles and alkyltriazoles (alkyl = methyl or isopropyl) have been generated by low-temperature potassium metal reduction in tetrahydrofuran. Electron paramagnetic resonance (EPR) analysis and density functional theory calculations reveal that the electron spin distribution within the triazole ring of these systems is markedly different. The magnitude of the electron-nitrogen couplings along with the calculated spin densities reveals that the N2-alkylbenzotriazole and N2-alkyltriazole anion radicals have significantly greater electron spin residing within the N3 portion of the triazole ring compared with that of the respective N1 isomers. These differences impact the overall geometry of the triazole ring where both N2-isomers lose planarity upon reduction. Experimental and computational results reveal that the N2-methyltriazole anion radical has the largest concentration of electron spin residing in the N3 moiety compared to that of the other three anion radicals studied. Significant anisotropic line broadening is observed in the EPR spectrum of the N2-methyltriazole anion radical, which is a consequence of the large nitrogen hyperfine couplings and sufficiently slow rotational motion of this species in solution.

Acute Cryptogenic Stroke During West Nile Virus Infection: Case Report.

West Nile virus is an emerging infection in North America but has not traditionally been associated with acute vascular events. We report a 57-year-old healthy male who developed pharyngitis and a corporeal rash, followed 1 week later by an acute cryptogenic stroke. Following successful endovascular thrombectomy, cerebrospinal fluid analysis revealed acute West Nile virus infection. While severe cases of vasculopathy have been described with flavivirus infection, stroke associated with relatively mild symptoms has not been. Given increasing evidence that viral and bacterial infections of many varieties may be stroke triggers, West Nile virus and other flaviviruses may represent an uncommon but underappreciated trigger of cryptogenic stroke. We review indirect evidence that viral endothelial tropism or a nonspecific peri-infectious inflammatory state may be causative mechanisms.

Twice Negative PCR in a Patient With Herpes Simplex Virus Type 1 (HSV-1) Encephalitis.

Untreated herpes simplex virus type 1 (HSV-1) encephalitis is associated with high mortality. Missed cases can have devastating consequences. Detection of HSV-1 in cerebrospinal fluid (CSF) with polymerase chain reaction (PCR) is reported to have high sensitivity and specificity and is considered the diagnostic gold standard for HSV-1 encephalitis. In this article, we report a case of autopsy-confirmed HSV-1 encephalitis where CSF PCR returned negative on 2 occasions. A 64-year-old man presented with fever, left-sided weakness, and altered level of consciousness. Magnetic resonance imaging demonstrated right mesial temporal lobe diffusion restriction and electroencephalography showed right lateralized periodic discharges. Lumbar puncture was performed on day 1 for which CSF PCR returned negative for HSV-1. Empiric antiviral and antibiotic treatments were continued due to high clinical suspicion of HSV-1 encephalitis. Repeat lumbar puncture on day 5 was unchanged and empiric treatments were discontinued. On day 13, he developed status epilepticus requiring intensive care unit admission. A third CSF sample returned positive for HSV-1. Acyclovir was restarted but he continued to clinically worsen and supportive care was withdrawn. Autopsy confirmed widespread HSV-1 meningoencephalitis. Negative CSF PCR should be interpreted with caution in cases where there is high clinical suspicion of HSV-1 encephalitis. Current guidelines suggest repeating CSF HSV-1 PCR within 3 to 7 days in suspicious cases while continuing empiric therapy. However, missed cases can occur even with repeated testing. Empiric treatment with acyclovir should be considered in cases with high clinical suspicion of HSV-1 encephalitis, while investigations for alternate treatable diagnoses are continued.

Isolated convergence-retraction nystagmus secondary to intralesional haemorrhage of a pineal cyst: an easily missed neurological finding with potentially life-threatening consequences.

This case report describes a patient who presented to the emergency department with intermittent visual disturbance and was found to have convergence-retraction nystagmus. This occurred in the setting of supratherapeutic anticoagulation on warfarin for an aortic dissection graft repair. Urgent imaging demonstrated haemorrhagic transformation of a previously identified incidental pineal cyst. After close monitoring given the risk of secondary hydrocephalus, the patient was discharged in stable condition with symptom resolution and without any further significant complications. This case report highlights the importance of identifying subtle clinical findings and the risk of secondary haemorrhage of pineal cysts when on anticoagulation. While the risk of secondary hydrocephalus is a significant concern, clinically stable patients can be followed without need for neurosurgical intervention.

Development of a new and reliable assay for choline kinase using 31P NMR.

Choline kinase catalyzes the conversion of choline to phosphocholine (PC) by transferring a phosphate group from adenosine triphosphate (ATP) as the first step in the biosynthetic pathway for the membrane phospholipid phosphatidylcholine, an essential pathway in the Leishmania parasitic protozoan. Commonly used methods for kinetically quantifying the enzyme include a radioisotope assay utilizing labeled choline and a coupled spectrophotometric assay with multiple enzymes and substrates that indirectly measures choline kinase activity. When testing potential inhibitors with the coupled assay, results can cast doubt on whether choline kinase is being inhibited or one of the coupled enzymes. Therefore, 31P NMR spectroscopy was used to quantitatively measure the formation of the key product, phosphocholine, and to evaluate choline kinase activity. Interrogation of 31P NMR spectroscopy offers a number of benefits. Since this isotope is 100% abundant and has a relatively large gyromagnetic ratio, it is considered one of the more sensitive nuclides. As such, the need for costly isotopic enriched phosphorous is not required and detection of the 31P signal is possible even at relatively low concentrations. The enzymatic activity of Leishmania infantum choline kinase was able to be directly measured via integration of the 31P resonance associated with the phosphocholine product (δ = 3.94 ppm). These initial studies reveal that a 31P NMR spectroscopic-based assay could be used for testing substrate or transition state analogs as competitive inhibitors of Leishmania choline kinase that may prevent phosphatidylcholine synthesis in the parasite.

Influence of Annulation on the Electron Spin within the 1,2,3-Triazole Ring in Annulenotriazole Anion Radicals.

The low temperature (-100 °C) single electron reduction of N1-phenylbenzotriazole in liquid ammonia, and the room temperature reduction of N1-phenylcyclooctatetraenotriazole in hexamethylphosphoramide, yields stable solutions of both anion radicals, which were studied via EPR spectroscopy. The amount of electron spin localized within the triazole ring, and how spin is distributed within this ring, is greatly influenced by the size of the annulene ring attached. UB3LYP/6-31++G(d,p) geometry optimizations using DFT methods were carried out for both anion radicals, and the calculated coupling constants (and electron spin densities) are in good agreement with the EPR spectroscopic results. Both theory and experiment show that much of the unpaired electron spin in the N1-phenylbenzotriazole anion radical is delocalized over the entire π system of benzotriazole ring including the phenyl ring attached, but that a significant percentage of total spin is found to reside within triazole ring with much of it located on the second nitrogen (N2). With the N1-phenylcyclooctatetraenotriazole anion radical, the majority of spin is localized over the π system of the COT ring, however a relatively small amount of total spin, found within the triazole moiety, is largely concentrated on two of the nitrogens (N1 and N3) within the ring.

Palliative Care for Hospitalized Patients With Stroke: Results From the 2010 to 2012 National Inpatient Sample.

BACKGROUND AND PURPOSE: Substantial variability exists in the use of life-prolonging treatments for patients with stroke, especially near the end of life. This study explores patterns of palliative care utilization and death in hospitalized patients with stroke across the United States. METHODS: Using the 2010 to 2012 nationwide inpatient sample databases, we included all patients discharged with stroke identified by International Classification of Diseases-Ninth Revision codes. Strokes were subclassified as ischemic, intracerebral, and subarachnoid hemorrhage. We compared demographics, comorbidities, procedures, and outcomes between patients with and without a palliative care encounter (PCE) as defined by the International Classification of Diseases-Ninth Revision code V66.7. Pearson χ2 test was used for categorical variables. Multivariate logistic regression was used to account for hospital, regional, payer, and medical severity factors to predict PCE use and death. RESULTS: Among 395 411 patients with stroke, PCE was used in 6.2% with an increasing trend over time (P<0.05). We found a wide range in PCE use with higher rates in patients with older age, hemorrhagic stroke types, women, and white race (all P<0.001). Smaller and for-profit hospitals saw lower rates. Overall, 9.2% of hospitalized patients with stroke died, and PCE was significantly associated with death. Length of stay in decedents was shorter for patients who received PCE. CONCLUSIONS: Palliative care use is increasing nationally for patients with stroke, especially in larger hospitals. Persistent disparities in PCE use and mortality exist in regards to age, sex, race, region, and hospital characteristics. Given the variations in PCE use, especially at the end of life, the use of mortality rates as a hospital quality measure is questioned.

Timing of Permanent Ventricular Shunt Placement Following External Ventricular Drain Placement in Primary Intracerebral Hemorrhage.

BACKGROUND: Intraventricular hemorrhage requiring ventriculostomy placement is a frequent complication of spontaneous intracerebral hemorrhage. Although a subset of patients will require permanent ventricular shunt placement, little is known about contemporary practices regarding the timing of ventriculostomy and ventricular shunt placement after intracerebral hemorrhage. METHODS: Using the 2010-2012 National Inpatient Sample, we identified patients with International Classification of Diseases, Ninth Revision codes for intracerebral hemorrhage, excluded secondary causes, and examined procedure dates. RESULTS: Of 35,899 patients with primary intracerebral hemorrhage, 2443 (6.8%) received ventriculostomy, 93% within the first 3 days of admission and 66% within the first day. Permanent shunt placement occurred in 173 (7.1%) patients following ventriculostomy at a median interval of 15 days (interquartile range: 11-20). Among those remaining alive and in hospital at 14, 21, and 28 days, 5%, 11%, and 15%, respectively, underwent shunt placement following ventriculostomy, and 24% of those with multiple ventriculostomy insertions required permanent shunt by 4 weeks of hospitalization. Multiple ventriculostomies, tracheostomy, and black race were associated with longer time to permanent shunt. CONCLUSIONS: A wide variation in delay to permanent shunt placement is present, with substantial and increasing prevalence with time in hospital. Better understanding of the risk factors associated with persistent hydrocephalus will help optimize patient selection and timing of treatment.

Tris-[8]annulenyl Isocyanurate Trianion Triradical and Hexa-anion from the Alkali Metal Reduction of [8]Annulenyl Isocyanate.

The solution phase alkali metal reduction of [8]annulenyl isocyanate (C8H7NCO) yields an EPR spectrum, which reveals electron couplings to seven protons and only one nitrogen. Although this strongly suggested that the C8H7NCO anion radical was generated, experiments on the oxidized product reveal the actual reduced species to be tris-[8]annulenyl isocyanurate. Unlike the previously studied phenyl isocyanurate anion radical, the unpaired electron(s) is now localized within an [8]annulenyl moiety. Further exposure to metal results in the formation of an equilibrium mixture of trianion triradical and trianion radical species. The cyclotrimerization to form the isocyanurate is proposed to be driven by a reactive C8H7NCO dianion, which is produced from the large equilibrium disproportionation of the anion radical. Exhaustive reduction of the tris-[8]annulenyl isocyanurate with potassium in THF generates the first-ever observed hexa-anion of an isocyanurate. NMR analysis reveals that the polarity of the carbonyl bonds within this hexa-anion is augmented and is caused by the close proximity of K(+) ions, which are tightly ion paired to the three [8]annulenyl dianion rings. These preliminary studies on the reduction of C8H7NCO suggest that polymeric materials (e.g., polyisocyanates) made from this isocyanate might exhibit unique properties.

Experimental and computational studies of the neutral and reduced states of indeno[1,2-b]fluorene.

This study examines the intrinsic structural and optoelectronic properties of the neutral indeno[1,2-b]fluorene skeleton as well as those of the corresponding anion radical and dianion. We report their characterization by analysis of solid-state structures and EPR, NMR, and absorbance spectra. Additionally, 20 popular density functional theory methods are used to evaluate their performance for predicting NMR chemical shifts, EPR hyperfine coupling constants, and low-energy transitions of the absorbance spectrum to act as a guide for future studies. This information can be used for a better understanding and tuning of the electron-transporting/accepting ability of the indenofluorene core for use in organic photovoltaics and organic field effect transistors.

Phenyl isocyanate anion radicals and their cyclotrimerization to triphenyl isocyanurate anion radicals.

Room-temperature sodium metal reduction of phenyl isocyanate (PhNCO) in hexamethylphosphoramide yields the anion radical (PhNCO(•-)) where the unpaired electron exhibits coupling to one nitrogen and five unique protons. The extent of coupling to the carbon in the NCO group was obtained via the reduction of (13)C-labeled PhN(13)CO. Remarkably, this coupling is over 2 orders of magnitude smaller than that found for the alkyl-substituted analogue. This large attenuation indicates that the electron is not localized within the isocyanate group (as in the alkyl analogues) but is distributed throughout the entire π system including the phenyl ring. The consequence of this delocalization is that the isocyanate is expected to remain linear upon reduction of PhNCO. The anion radicals of p-tolyl- and p-methoxyphenyl isocyanate have also been generated. We find that these electron-donating substituents on the phenyl ring have little effect on the nitrogen coupling. Hence, the NCO group has the same geometry as the PhNCO(•-). When PhNCO is reduced in tetrahydrofuran, a solvent where ion association effects are common, PhNCO(•-) is not observed. Here, a cyclotrimerization occurs (initiated by PhNCO(•-)), generating the triphenyl isocyanurate anion radical where the unpaired electron is predominately localized in one of the carbonyl moieties.

Discovery of (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide, a potent and orally efficacious mGlu5 receptor negative allosteric modulator.

A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.

3-Phenyl-5-isothiazole carboxamides with potent mGluR1 antagonist activity.

The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy.

Beta-amino alcohol derived beta-hydroxy- and beta-(o-diphenylphosphino)benzoyloxy(o-diphenylphosphino)benzamides: an ester-amide ligand structural model for the palladium-catalyzed allylic alkylation reaction.

A commercially available collection of beta-amino alcohols have been converted to their corresponding beta-hydroxy- and beta-(o-diphenylphosphino)benzoyloxy(o-diphenylphosphino)benzamides 11a-f and 12a-f and have been employed in the Tsuji-Trost asymmetric alkylation reaction with 1,3-diphenylpropenyl acetate. With the exception of ligands 11b and 11f, the beta-hydroxybenzoyloxy(o-diphenylphosphino)benzamide ligands 11a-f primarily afforded the (R)-enantiomer of the product. In contrast, the bis(phosphine) ligands 12a-f consistently afforded the (S)-enantiomer. The best ligand (12c) was derived from cis-(1R,2S)-2-amino-1,2-diphenyl-1-ethanol, and when applied in the asymmetric allylic alkylation reaction, it yielded the product in an enantiomeric ratio of 97.8.22 favoring the (S)-enantiomer. A computational study was conducted on the conformation that this ligand might adopt in the palladium-catalyzed alkylation reaction as compared to that of the Trost ligand 1a.