Delineating the conformational landscape of the adenosine A2A receptor during G protein coupling.

G-protein-coupled receptors (GPCRs) represent a ubiquitous membrane protein family and are important drug targets. Their diverse signaling pathways are driven by complex pharmacology arising from a conformational ensemble rarely captured by structural methods. Here, fluorine nuclear magnetic resonance spectroscopy (19F NMR) is used to delineate key functional states of the adenosine A2A receptor (A2AR) complexed with heterotrimeric G protein (Gαsß1γ2) in a phospholipid membrane milieu. Analysis of A2AR spectra as a function of ligand, G protein, and nucleotide identifies an ensemble represented by inactive states, a G-protein-bound activation intermediate, and distinct nucleotide-free states associated with either partial- or full-agonist-driven activation. The Gßγ subunit is found to be critical in facilitating ligand-dependent allosteric transmission, as shown by 19F NMR, biochemical, and computational studies. The results provide a mechanistic basis for understanding basal signaling, efficacy, precoupling, and allostery in GPCRs.

Treatment and Outcomes of Cervical Artery Dissection in Adults: A Scientific Statement From the American Heart Association.

Cervical artery dissection is an important cause of stroke, particularly in young adults. Data conflict on the diagnostic evaluation and treatment of patients with suspected cervical artery dissection, leading to variability in practice. We aim to provide an overview of cervical artery dissection in the setting of minor or no reported mechanical trigger with a focus on summarizing the available evidence and providing suggestions on the diagnostic evaluation, treatment approaches, and outcomes. Writing group members drafted their sections using a literature search focused on publications between January 1, 1990, and December 31, 2022, and included randomized controlled trials, prospective and retrospective observational studies, meta-analyses, opinion papers, case series, and case reports. The writing group chair and vice chair compiled the manuscript and obtained writing group members' approval. Cervical artery dissection occurs as a result of the interplay among risk factors, minor trauma, anatomic and congenital abnormalities, and genetic predisposition. The diagnosis can be challenging both clinically and radiologically. In patients with acute ischemic stroke attributable to cervical artery dissection, acute treatment strategies such as thrombolysis and mechanical thrombectomy are reasonable in otherwise eligible patients. We suggest that the antithrombotic therapy choice be individualized and continued for at least 3 to 6 months. The risk of recurrent dissection is low, and preventive measures may be considered early after the diagnosis and continued in high-risk patients. Ongoing longitudinal and population-based observational studies are needed to close the present gaps on preferred antithrombotic regimens considering clinical and radiographic prognosticators of cervical artery dissection.

Comparing Functional Outcomes and Safety Profiles of First-Line Aspiration Thrombectomy Versus Stentriever for Acute Basilar Artery Occlusion: Propensity Analysis of the PC-SEARCH Thrombectomy Registry.

BACKGROUND: Aspiration catheters (ASPs) and stentriever thrombectomy devices have comparable safety and efficacy in anterior circulation ischemic strokes. However, there is lack of high-quality comparative data in acute basilar artery occlusions. Our objective is to compare the outcomes and safety of ASPs and stentriever devices in acute basilar artery occlusions. METHODS: This is an analysis of the retrospectively established PC-SEARCH Thrombectomy (Posterior-Circulation Ischemic Stroke Evaluation: Analyzing Radiographic and Intraprocedural Predictors for Mechanical Thrombectomy) registry. Patients were dichotomized based on their first-line thrombectomy device (ASP and stentriever) and associated with their 90-day functional outcomes, intraprocedural metrics, and safety measures. Propensity analysis based on unequal baseline characteristics was performed. Consecutive patients with acute basilar artery occlusions who received mechanical thrombectomy were included from January 2015 to December 2021. Patients received either first-line contact aspiration or stentriever mechanical thrombectomy. Primary clinical and safety outcomes were 90-day functional independence measured by a modified Rankin Scale score of 0 to 3 and symptomatic intracranial hemorrhage, respectively. Secondary outcomes included puncture-recanalization times, first-pass recanalization rates, crossovers to other thrombectomy device, and neurological/hospital complications. RESULTS: Five hundred eighteen patients were included in the registry, and a total of 383 patients were included (mean [SD] age, 65.5 [15] years; 228 [59%] men) in this analysis. Of these, 219 patients were first-line ASP while 164 patients received first-line stentriever devices. Median premorbid modified Rankin Scale was zero and median presenting National Institutes of Health Stroke Scale was 17 (interquartile range, 8-26). The proportion of favorable functional outcome was similar between the 2 techniques before (47.3% versus 42.5%; odds ratio, 1.22 [95% CI, 0.78-1.89]; P=0.38) and after propensity matching (odds ratio, 1.46 [95% CI, 0.85-2.49]; P=0.17). In our propensity-matched cohorts, puncture-recanalization times (18 versus 52 minutes; P<0.01) favored first-line ASP; however, first-pass recanalization rates (43.5% versus 44.5%; P=0.90) were similar between groups. First-line ASP was associated with higher rates of crossover (22% versus 6%; P<0.01), whereas stentriever was associated with higher rates of symptomatic intracranial hemorrhage (9.8% versus 3.4%; P=0.04). CONCLUSIONS: First-line ASP and stentriever methods demonstrated similar functional outcome and recanalization rates. Stentriever methods were associated with higher rates of symptomatic intracranial hemorrhage, whereas ASPs were associated with higher rates of crossover to alternative technique in patients with acute basilar occlusions.

KIT D816V is dimerization-independent and activates downstream pathways frequently perturbed in mastocytosis.

KIT, a type III tyrosine kinase receptor, plays a crucial role in haematopoietic development. The KIT receptor forms a dimer after ligand binding; this activates tyrosine kinase activity leading to downstream signal transduction. The D816V KIT mutation is extensively implicated in haematological malignancies, including mastocytosis and leukaemia. KIT D816V is constitutively active, but the molecular nuances that lead to constitutive tyrosine kinase activity are unclear. For the first time, we present experimental evidence that the KIT D816V mutant does not dimerize like KIT wild type. We further show evidence of decreased stabilization of the tyrosine kinase domain in the KIT D816V mutant, a phenomenon that might contribute to its constitutive activity. Since the mechanism of KIT D816V activation varies from that of the wild type, we explored downstream signal transduction events and found that even though KIT D816V targets similar signalling moieties, the signalling is amplified in the mutant compared to stem cell factor-activated wild type receptor. Uniquely, KIT D816V induces infection-related pathways and the spliceosome pathway, providing alternate options for selective as well as combinatorial therapeutic targeting.

Transcranial histotripsy parameter study in primary and metastatic murine brain tumor models.

OBJECTIVE: This study investigated the effect of various histotripsy dosages on tumor cell kill and associated bleeding in two murine brain tumor models (glioma [Gl261] and lung metastasis [LL/2-Luc2]). METHODS AND MATERIALS: GL261 or LL/2-Luc2 cells were cultured and implanted into the brains of C57BL/6 mice. Histotripsy (1-cycle pulses, 5 Hz PRF, 30 MPa-P) was performed using a 1 MHz transducer for five different dosages for each cell line: 5, 20 or 200 pulses per location (PPL) at a single treatment point, or 5 or 10-20 PPL at multiple treatment points. MRI, bioluminescence imaging and histology were used to assess tumor ablation and treatment effects within 4-6 h post-treatment. RESULTS: All treatment groups resulted in a reduction of BLI intensity for the LL/2-Luc2 tumors, with significant signal reductions for the multi-point groups. The average pre-/post-treatment BLI flux (photons/s, ×108) for the different treatment groups were: 4.39/2.19 (5 PPL single-point), 5.49/1.80 (20 PPL single-point), 3.86/1.73 (200 PPL single-point), 2.44/1.11 (5 PPL multi-point) and 5.85/0.80 (10 PPL multi-point). MRI and H&E staining showed increased tumor damage and hemorrhagic effects with increasing histotripsy dose for both GL261 and LL/2-Luc2 tumors, but the increase in tumor damage was diminished beyond 10-20 PPL for single-point treatments and outweighed by increased hemorrhage. In general, hemorrhage was confined to be within 1 mm of the treatment boundary for all groups. CONCLUSIONS: Our results suggest that a lower number of histotripsy pulses at fewer focal locations can achieve substantial tumor kill while minimizing hemorrhage.

International controlled study of revascularization and outcomes following COVID-positive mechanical thrombectomy.

BACKGROUND AND PURPOSE: Previous studies suggest that mechanisms and outcomes in patients with COVID-19-associated stroke differ from those in patients with non-COVID-19-associated strokes, but there is limited comparative evidence focusing on these populations. The aim of this study, therefore, was to determine if a significant association exists between COVID-19 status with revascularization and functional outcomes following thrombectomy for large vessel occlusion (LVO), after adjustment for potential confounding factors. METHODS: A cross-sectional, international multicenter retrospective study was conducted in consecutively admitted COVID-19 patients with concomitant acute LVO, compared to a control group without COVID-19. Data collected included age, gender, comorbidities, clinical characteristics, details of the involved vessels, procedural technique, and various outcomes. A multivariable-adjusted analysis was conducted. RESULTS: In this cohort of 697 patients with acute LVO, 302 had COVID-19 while 395 patients did not. There was a significant difference (p < 0.001) in the mean age (in years) and gender of patients, with younger patients and more males in the COVID-19 group. In terms of favorable revascularization (modified Thrombolysis in Cerebral Infarction [mTICI] grade 3), COVID-19 was associated with lower odds of complete revascularization (odds ratio 0.33, 95% confidence interval [CI] 0.23-0.48; p < 0.001), which persisted on multivariable modeling with adjustment for other predictors (adjusted odds ratio 0.30, 95% CI 0.12-0.77; p = 0.012). Moreover, endovascular complications, in-hospital mortality, and length of hospital stay were significantly higher among COVID-19 patients (p < 0.001). CONCLUSION: COVID-19 was an independent predictor of incomplete revascularization and poor functional outcome in patients with stroke due to LVO. Furthermore, COVID-19 patients with LVO were more often younger and had higher morbidity/mortality rates.

Considerations for Reduction of Risk of Perioperative Stroke in Adult Patients Undergoing Cardiac and Thoracic Aortic Operations: A Scientific Statement From the American Heart Association.

Perioperative stroke is one of the most severe and feared complications of cardiac surgery. Based on the timing of onset and detection, perioperative stroke can be classified as intraoperative or postoperative. The pathogenesis of perioperative stroke is multifactorial, which makes prediction and prevention challenging. However, information on its incidence, mechanisms, diagnosis, and treatment can be helpful in minimizing the perioperative neurological risk for individual patients. We herein provide suggestions on preoperative, intraoperative, and postoperative strategies aimed at reducing the risk of perioperative stroke and at improving the outcomes of patients who experience a perioperative stroke.

Trends in acute ischemic stroke treatments and mortality in the United States from 2012 to 2018.

OBJECTIVE: The establishment of mechanical thrombectomy (MT) as a first-line treatment for select patients with acute ischemic stroke (AIS) and the expansion of stroke systems of care have been major advancements in the care of patients with AIS. In this study, the authors aimed to identify temporal trends in the usage of tissue-type plasminogen activator (tPA) and MT within the AIS population from 2012 to 2018, and the relationship to mortality. METHODS: Using a nationwide private health insurance database, 117,834 patients who presented with a primary AIS between 2012 and 2018 in the United States were identified. The authors evaluated temporal trends in tPA and MT usage and clinical outcomes stratified by treatment and age using descriptive statistics. RESULTS: Among patients presenting with AIS in this population, the mean age was 69.1 years (SD ± 12.3 years), and 51.7% were female. Between 2012 and 2018, the use of tPA and MT increased significantly (tPA, 6.3% to 11.8%, p < 0.0001; MT, 1.6% to 5.7%, p < 0.0001). Mortality at 90 days decreased significantly in the overall AIS population (8.7% to 6.7%, p < 0.0001). The largest reduction in 90-day mortality was seen in patients treated with MT (21.4% to 14.1%, p = 0.0414) versus tPA (11.8% to 7.0%, p < 0.0001) versus no treatment (8.3% to 6.3%, p < 0.0001). Age-standardized mortality at 90 days decreased significantly only in patients aged 71-80 years (11.4% to 7.8%, p < 0.0001) and > 81 years (17.8% to 11.6%, p < 0.0001). Mortality at 90 days stagnated in patients aged 18 to 50 years (3.0% to 2.2%, p = 0.4919), 51 to 60 years (3.8% to 3.9%, p = 0.7632), and 61 to 70 years (5.5% to 5.2%, p = 0.2448). CONCLUSIONS: From 2012 to 2018, use of tPA and MT increased significantly, irrespective of age, while mortality decreased in the entire AIS population. The most dramatic decrease in mortality was seen in the MT-treated population. Age-standardized mortality improved only in patients older than 70 years, with no change in younger patients.

Neurosurgical patients admitted via the emergency department initiating comfort care measures: a prospective cohort analysis.

BACKGROUND: Given the serious nature of many neurosurgical pathologies, it is common for hospitalized patients to elect comfort care (CC) over aggressive treatment. Few studies have evaluated the incidence and risk factors of CC trends in patients admitted for neurosurgical emergencies. OBJECTIVES: To analyze all neurosurgical patients admitted to a tertiary care academic referral center via the emergency department (ED) to determine incidence and characteristics of those who initiated CC measures during their initial hospital admission. METHODS: We performed a prospective, cohort analysis of all consecutive adult patients admitted to the neurosurgical service via the ED between October 2018 and May 2019. The primary outcome was the initiation of CC measures during the patient's hospital admission. CC was defined as cessation of life-sustaining measures and a shift in focus to maintaining the comfort and dignity of the patient. RESULTS: Of the 428 patients admitted during the 7-month period, 29 (6.8%) initiated CC measures within 4.0 ± 4.0 days of admission. Patients who entered CC were significantly more likely to have a medical history of cerebrovascular disease (58.6% vs. 33.3%, p = 0.006), dementia (17.2% vs. 1.5%, p = 0.0004), or cancer with metastatic disease (24.1% vs. 7.0%, p = 0.001). Patients with a presenting pathology associated with cerebrovascular disease were significantly more likely to initiate CC (62.1% vs. 35.3, p = 0.04). Patients who underwent emergent surgery were significantly more likely to enter CC compared with those who had elective surgery (80.0% vs. 42.7%, p = 0.02). Only 10 of the 29 (34.5%) patients who initiated CC underwent a neurosurgical operation (p = 0.002). Twenty of the 29 (69.0%) patients died within 0.8 ± 0.8 days after the initiation of CC measures. CONCLUSION: CC measures were initiated in 6.8% of patients admitted to the neurosurgical service via the ED, with the majority of patients entering CC before an operation and presenting with a cerebrovascular pathology.

Cerebrospinal Fluid from Aneurysmal Subarachnoid Hemorrhage Patients Leads to Hydrocephalus in Nude Mice.

OBJECTIVE: Our prior studies have found that intracerebroventricular injection of blood components can cause hydrocephalus and choroid plexus epiplexus cell activation in rats. To minimize the cross-species reaction, the current study examines whether intraventricular injection of acellular components of cerebrospinal fluid (CSF) from subarachnoid hemorrhage patients can cause hydrocephalus and epiplexus macrophage activation in nude mice which lack a T cell inflammatory response. METHODS: Adult male nude mice received intraventricular injections of acellular CSF from subarachnoid hemorrhage patients or a control patient. All mice had preoperative magnetic resonance imaging as baseline and postoperative scans at 24 h after CSF injection to determine ventricular volume. Brains were harvested at 24 h for brain histology, immunohistochemistry, and electron microscopy. RESULTS: Intraventricular injection of CSF from two of five subarachnoid hemorrhage patients obtained < 48 h from ictus resulted in ventricular enlargement at 24 h. CSF-related hydrocephalus was associated with activation of epiplexus macrophages and ependymal injury. CONCLUSIONS: Components of the acellular CSF of subarachnoid hemorrhage patients can cause epiplexus macrophage activation, ependymal cell damage, and ventricular enlargement in nude mice. This may serve as a unique model to study mechanisms of hydrocephalus development following subarachnoid hemorrhage.

Risk factors and morbidity associated with surgical site infection subtypes following adult neurosurgical procedures.

OBJECTIVE: Studies on surgical site infection (SSI) in adult neurosurgery have presented all subtypes of SSIs as the general 'SSI'. Given that SSIs constitute a broad range of infections, we hypothesized that clinical outcomes and management vary based on SSI subtype. METHODS: A retrospective analysis of all neurosurgical SSI from 2012-2019 was conducted at a tertiary care institution. SSI subtypes were categorized as deep and superficial incisional SSI, brain, dural or spinal abscesses, meningitis or ventriculitis, and osteomyelitis. RESULTS: 9620 craniotomy, shunt, and fusion procedures were studied. 147 procedures (1.5%) resulted in postoperative SSI. 87 (59.2%) of these were associated with craniotomy, 36 (24.5%) with spinal fusion, and 24 (16.3%) with ventricular shunting. Compared with superficial incisional primary SSI, rates of reoperation to treat SSI were highest for deep incisional primary SSI (91.2% vs 38.9% for superficial, p < 0.001) and second-highest for intracranial SSI (90.9% vs 38.9%, p = 0.0001). Postoperative meningitis was associated with the highest mortality rate (14.9%). Compared with superficial incisional SSI, the rate of readmission for intracranial SSI was highest (57.6% vs 16.7%, p = 0.022). CONCLUSION: Deep incisional and organ space SSI demonstrate a greater association with morbidity relative to superficial incisional SSI. Future studies should assess subtypes of SSI given these differences.

Mechanical Thrombectomy Improves Outcome for Large Vessel Occlusion Stroke after Cardiac Surgery.

BACKGROUND: Stroke is a feared complication of cardiac surgery. Modern clot-retrieval techniques provide effective treatment for large vessel occlusion (LVO) strokes. The purpose of this study was to 1) report the incidence of LVO stroke after cardiac surgery at a large academic center, and 2) describe outcomes of postoperative LVO strokes. METHODS: All patients experiencing stroke within 30 days after undergoing cardiac surgery at a single center in 2014-2018 were reviewed. LVOs were identified through review of imaging and medical records, and their characteristics and clinical courses were examined. RESULTS: Over the study period, 7,112 cardiac surgeries, including endovascular procedures, were performed. Acute ischemic stroke within 30 days after surgery was noted in 163 patients (2.3%). Among those with a stroke, 51/163 (31.3%) had a CTA or MRA, and 15/163 (9.2%) presented with LVO stroke. For all stroke patients, the median time from surgery to stroke was 2 days (interquartile range, IQR, 0-6 days), and for patients with LVO, the median time from surgery to stroke was 4 days (IQR 0-6 days). The overall rate of postoperative LVO was 0.2% (95% CI 0.1-0.4%), though only 6/15 received thrombectomy. LVO patients receiving thrombectomy were significantly more likely to return to independent living compared to those managed medically (n = 4/6, 66.6% for mechanical thrombectomy vs. n = 0/9, 0% for medical management, P = .01). Of the 9 patients who did not get thrombectomy, 6 may currently be candidates for thrombectomy given new expanded treatment windows. CONCLUSIONS: The rate of LVO after cardiac surgery is low, though substantially elevated above the general population, and the majority do not receive thrombectomy currently. Patients receiving thrombectomy had improved neurologic outcomes compared to patients managed medically. Optimized postoperative care may increase the rate of LVO recognition, and cardiac surgery patients and their caregivers should be aware of this effective therapy.

Endovascular Treatment of Arteriovenous Malformations of the Head and Neck: Focus on the Yakes Classification and Outcomes.

PURPOSE: To evaluate endovascular treatment of head and neck arteriovenous malformations (AVMs) based on the Yakes AVM classification and correlate treatment approach with clinical and angiographic outcomes. MATERIALS AND METHODS: A retrospective single-center study was performed in patients who underwent endovascular treatment of head and neck AVMs between January 2005 and December 2017. Clinical and operative records, imaging, and postoperative courses of patients were reviewed. Clinical stage was determined according to the Schobinger classification. AVM architecture and treatment approaches were determined according to the Yakes classification. Primary outcomes were clinical and angiographic treatment success rates and complication rates, with analysis according to the Yakes classification. RESULTS: A total of 29 patients (15 females) were identified, with a mean age of 30.6 years. Downgrading of the Schobinger clinical classification was achieved in all patients. Lesions included 8 Yakes type IIa, 5 type IIb, 1 type IIIa and IIIb, and 14 type IV. Lesions were treated using an intra-arterial, nidal, or transvenous approach, using ethanol and liquid embolic agents. Arteriovenous shunt eradication of >90% was achieved in 22 of 28 patients (79%), including 9 of 13 (69%) of Yakes type IV lesions and 13 of 15 (87%) of the other types. There were 5 significant complications in 79 procedures (6%), including 4 of 50 (8%) in Yakes type IV lesions. CONCLUSIONS: Schobinger stage was downgraded in all patients. Arteriovenous shunt eradication of >90% was achieved in most patients. Yakes type IV lesions required more sessions, and shunt eradication was higher in the Yakes II and III groups.

MgC6H2 Isomers: Potential Candidates for Laboratory and Radioastronomical Studies.

Eighty three stationary points of MgC6H2 isomers spanning from 0 to 215 kcal mol-1 have been theoretically identified using density functional theory at the B3LYP/6-311++G(2d,2p) level of theory. Among them, four low-lying isomers lying within 23.06 kcal mol-1 (1 eV) have been further characterized in detail using high-level coupled-cluster (CC) methods. The thermodynamically most stable isomer turns out to be 1-magnesacyclohepta-4-en-2,6-diyne (1). The other three isomers, 3-magnesahepta-1,4,6-triyne (2), 1-magnesacyclohepta-2,3,4-trien-6-yne (3), and 1-magnesahepta-2,4,6-triyne (4) lie 8.24, 19.76, and 21.36 kcal mol-1, respectively, above 1 at the ae-CCSD(T)/cc-pCVTZ level of theory. All the four isomers are polar with a permanent electric dipole moment (µ ≠ 0). Hence, they are potential candidates for rotational spectroscopic studies. Considering the recent identification of magnesium-bearing hydrocarbons such as, MgC2H and MgC4H in IRC+10216, it is believed that the current theoretical data may be of relevance to laboratory molecular spectroscopic and radioastronomical studies on MgC6H2 isomers. The energetic and spectroscopic information gathered in this study would aid the detection of low-lying MgC6H2 isomers in the laboratory, which are indispensable for radioastronomical studies. It is also noted here that neither the National Institute of Standards and Technology Chemistry WebBook nor the Kinetic Database for Astrochemistry lists any isomer of MgC6H2 at the moment. Therefore, these isomers are studied here theoretically for the very first time.

Middle meningeal artery embolization treatment of nonacute subdural hematomas in the elderly: a multiinstitutional experience of 151 cases.

OBJECTIVE: The incidence of already common chronic subdural hematomas (CSDHs) and other nonacute subdural hematomas (NASHs) in the elderly is expected to rise as the population ages over the coming decades. Surgical management is associated with recurrence and exposes elderly patients to perioperative and operative risks. Middle meningeal artery (MMA) embolization offers the potential for a minimally invasive, less morbid treatment in this age group. The clinical and radiographic outcomes after MMA embolization treatment for NASHs have not been adequately described in elderly patients. In this paper, the authors describe the clinical and radiographic outcomes after 151 cases of MMA embolization for NASHs among 121 elderly patients. METHODS: In a retrospective review of a prospectively maintained database across 15 US academic centers, the authors identified patients aged ≥ 65 years who underwent MMA embolization for the treatment of NASHs between November 2017 and February 2020. Patient demographics, comorbidities, clinical and radiographic factors, treatment factors, and clinical outcomes were abstracted. Subgroup analysis was performed comparing elderly (age 65-79 years) and advanced elderly (age > 80 years) patients. RESULTS: MMA embolization was successfully performed in 98% of NASHs (in 148 of 151 cases) in 121 patients. Seventy elderly patients underwent 87 embolization procedures, and 51 advanced elderly patients underwent 64 embolization procedures. Elderly and advanced elderly patients had similar rates of embolization for upfront (46% vs 61%), recurrent (39% vs 33%), and prophylactic (i.e., with concomitant surgical intervention; 15% vs 6%) NASH treatment. Transfemoral access was used in most patients, and the procedure time was approximately 1 hour in both groups. Particle embolization with supplemental coils was most common, used in 51% (44/87) and 44% (28/64) of attempts for the elderly and advanced elderly groups, respectively. NASH thickness decreased significantly from initial thickness to 6 weeks, with additional decrease in thickness observed in both groups at 90 days. At longest follow-up, the treated NASHs had stabilized or improved in 91% and 98% of the elderly and advanced elderly groups, respectively, with > 50% improvement seen in > 60% of patients for each group. Surgical rescue was necessary in 4.6% and 7.8% of cases, and the overall mortality was 8.6% and 3.9% for elderly and advanced elderly patients, respectively. CONCLUSIONS: MMA embolization can be used safely and effectively as an alternative or adjunctive minimally invasive treatment for NASHs in elderly and advanced elderly patients.

Standardized Fabrication Method of Human-Derived Emboli with Histologic and Mechanical Quantification for Stroke Research.

BACKGROUND: As access to patient emboli is limited, embolus analogs (EAs) have become critical to the research of large vessel occlusion (LVO) stroke and the development of thrombectomy technology. To date, techniques for fabricating standardized human blood-derived EAs are limited in the variety of compositions, and the mechanical properties relevant to thrombectomy are not quantified. METHODS: EAs were made by mixing human banked red blood cells (RBCs), plasma, and platelet concentrate in 10 different volumetric percentage combinations to mimic the broad range of patient emboli causing LVO strokes. The samples underwent histologic analysis and tensile testing to mimic the pulling action of thrombectomy devices, and were compared to patient emboli. RESULTS: EAs had histologic compositions of 0-96% RBCs, 0.78%-92% fibrin, and 2.1%-22% platelets, which can be correlated with the ingredients using a regression model. At fracture, EAs elongated from 81% to 136%, and the ultimate tensile stress ranged from 16 to 949 kPa. These EAs' histologic compositions and tensile properties showed great similarity to those of emboli retrieved from LVO stroke patients, indicating the validity of such EA fabrication methods. EAs with lower RBC and higher fibrin contents are more extensible and can withstand higher tensile stress. CONCLUSIONS: EAs fabricated and tested using the proposed new methods provide a platform for stroke research and pre-clinical development of thrombectomy devices.

Seizure Prophylaxis in Unruptured Aneurysm Repair: A Randomized Controlled Trial.

BACKGROUND: Prophylactic antiepileptic drugs (pAEDs) are often prescribed for seizure prophylaxis in patients undergoing surgical treatment of unruptured intracranial aneurysms (UIAs). We aimed to evaluate the benefit of pAEDs in patients undergoing surgical repair of UIAs. METHODS: We randomly assigned eligible patients undergoing surgical repair of UIAs to receive levetiracetam for seven days post-operatively or standard care alone. The primary outcome was the evaluation of seizures in the perioperative period (within 4 weeks). We also evaluated seizure occurrence throughout follow-up and assessed functional outcomes using the modified Rankin scale score (mRS). RESULTS: 35 patients were randomized to the "no-levetiracetam" group and 41 patients were randomized to receive levetiracetam. The two study groups had similar overall baseline characteristics and the surgical complication rate was similar for both groups (p = 0.8). One patient in the "no-levetiracetam" group had a seizure in the perioperative period versus 2 patients in the group randomized to receive levetiracetam (2.9% vs 4.9%, respectively, p = 1.00). No patients in the "no-levetiracetam" group had any additional late seizures (mean follow-up of 20.4 months), but three patients in the levetiracetam group had late seizures during follow-up (mean follow-up of 19.1 months) (0% vs 7.3%, p = 0.2). mRS score of 0-2 at 90 days and at the latest follow-up were similar between the two groups (p = 1.00). CONCLUSIONS: Perioperative seizure prophylaxis with levetiracetam does not reduce the rate of seizures as compared to controls in patients undergoing surgical repair of UIAs.

Stereotactic Radiosurgery for Brain Arteriovenous Malformations: Evaluation of Obliteration and Review of Associated Predictors.

BACKGROUND: High arteriovenous malformation (AVM) obliteration rates have been reported with stereotactic radiosurgery (SRS), and multiple factors have been found to be associated with AVM obliteration. These predictors have been inconsistent throughout studies. We aimed to analyze our experience with linear accelerator (LINAC)-based SRS for brain AVMs, evaluate outcomes, assess factors associated with AVM obliteration and review the various reported predictors of AVM obliteration. METHODS: Electronic medical records were retrospectively reviewed to identify consecutive patients with brain AVMs treated with SRS over a 27-year period with at least 2 years of follow-up. Logistic regression analysis was performed to identify factors associated with AVM obliteration. RESULTS: One hundred twenty-eight patients with 142 brain AVMs treated with SRS were included. Mean age was 34.4 years. Fifty-two percent of AVMs were associated with a hemorrhage before SRS, and 14.8% were previously embolized. Mean clinical and angiographic follow-up times were 67.8 months and 58.6 months, respectively. The median Spetzler-Martin grade was 3. Mean maximal AVM diameter was 2.8 cm and mean AVM target volume was 7.4 cm3 with a median radiation dose of 16 Gy. Complete AVM obliteration was achieved in 80.3%. Radiation-related signs and symptoms were encountered in 32.4%, only 4.9% of which consisted of a permanent deficit. Post-SRS AVM-related hemorrhage occurred in 6.3% of cases. In multivariate analysis, factors associated with AVM obliteration included younger patient age (P = .019), male gender (P = .008), smaller AVM diameter (P = .04), smaller AVM target volume (P = .009), smaller isodose surface volume (P = .005), a higher delivered radiation dose (P = .013), and having only one major draining vein (P = .04). CONCLUSIONS: AVM obliteration with LINAC-based radiosurgery was safe and effective and achieved complete AVM obliteration in about 80% of cases. The most prominent predictors of AVM success included AVM size, AVM volume, radiation dose, number of draining veins and patient age.

Activation processes in ligand-activated G protein-coupled receptors: A case study of the adenosine A2A receptor.

Here we review concepts related to an ensemble description of G-protein-coupled receptors (GPCRs). The ensemble is characterized by both inactive and active states, whose equilibrium populations and exchange rates depend sensitively on ligand, environment, and allosteric factors. This review focuses on the adenosine A2 receptor (A2A R), a prototypical class A GPCR. 19 F Nuclear Magnetic Resonance (NMR) studies show that apo A2A R is characterized by a broad ensemble of conformers, spanning inactive to active states, and resembling states defined earlier for rhodopsin. In keeping with ideas associated with a conformational selection mechanism, addition of agonist serves to allosterically restrict the overall degrees of freedom at the G protein binding interface and bias both states and functional dynamics to facilitate G protein binding and subsequent activation. While the ligand does not necessarily "induce" activation, it does bias sampling of states, increase the cooperativity of the activation process and thus, the lifetimes of functional activation intermediates, while restricting conformational dynamics to that needed for activation.