Elucidating the binding mode of carboxylate-containing ligands to gold nanoparticles (AuNPs) is crucial to understand their stabilizing role. A detailed picture of the three-dimensional structure and ...coordination modes of citrate, acetate, succinate and glutarate to AuNPs is obtained by
C and
Na solid-state NMR in combination with computational modelling and electron microscopy. The binding between the carboxylates and the AuNP surface is found to occur in three different modes. These three modes are simultaneously present at low citrate to gold ratios, while a monocarboxylate monodentate (1κO
) mode is favoured at high citrate:gold ratios. The surface AuNP atoms are found to be predominantly in the zero oxidation state after citrate coordination, although trace amounts of Au
are observed.
Na NMR experiments show that Na
ions are present near the gold surface, indicating that carboxylate binding occurs as a 2e
L-type interaction for each oxygen atom involved. This approach has broad potential to probe the binding of a variety of ligands to metal nanoparticles.
Abstract
BACKGROUND
Middle meningeal artery (MMA) embolization has emerged as a promising treatment for chronic subdural hematoma (cSDH).
OBJECTIVE
To determine the safety and efficacy of MMA ...embolization.
METHODS
Consecutive patients who underwent MMA embolization for cSDH (primary treatment or recurrence after conventional surgery) at 15 centers were included. Clinical details and follow-up were collected prospectively. Primary clinical and radiographic outcomes were the proportion of patients requiring additional surgical treatment within 90 d after index treatment and proportion with > 50% cSDH thickness reduction on follow-up computed tomography imaging within 90 d. National Institute of Health Stroke Scale and modified Rankin Scale were also clinical outcomes.
RESULTS
A total of 138 patients were included (mean age: 69.8, 29% female). A total of 15 patients underwent bilateral interventions for 154 total embolizations (66.7% primary treatment). At presentation, 30.4% and 23.9% of patients were on antiplatelet and anticoagulation therapy, respectively. Median admission cSDH thickness was 14 mm. A total of 46.1% of embolizations were performed under general anesthesia, and 97.4% of procedures were successfully completed. A total of 70.2% of embolizations used particles, and 25.3% used liquid embolics with no significant outcome difference between embolization materials (P > .05). On last follow-up (mean 94.9 d), median cSDH thickness was 4 mm (71% median thickness reduction). A total of 70.8% of patients had >50% improvement on imaging (31.9% improved clinically), and 9 patients (6.5%) required further cSDH treatment. There were 16 complications with 9 (6.5%) because of continued hematoma expansion. Mortality rate was 4.4%, mostly unrelated to the index procedure but because of underlying comorbidities.
CONCLUSION
MMA embolization may provide a safe and efficacious minimally invasive alternative to conventional surgical techniques.
Graphical Abstract
Graphical Abstract
This study aims to investigate whether the application of a stem cell-derived exosome-laden collagen patch (EXP) during coronary artery bypass grafting (CABG) can recover cardiac function by ...modulating mitochondrial bioenergetics and myocardial inflammation in hibernating myocardium (HIB) that is defined as myocardium with reduced blood flow and function that retains viability and variable contractile reserve.
In vitro methods involved exposing H9C2 cardiomyocytes to hypoxia followed by normoxic co-culture with porcine mesenchymal stem cells (MSCs). Mitochondrial respiration was measured using Seahorse assay. GW4869, an exosomal release antagonist, was used to determine the effect of MSC-derived exosomal signaling on cardiomyocyte recovery. Total exosomal RNA was isolated and differential miRNA expression determined by sequencing. In vivo studies comprised 48 Yorkshire-Landrace juvenile swine (6 normal controls, 17 HIB, 19 CABG, 6 CABG+EXP), which were compared for physiologic and metabolic changes. HIB was created by placing a constrictor on the proximal LAD, causing significant stenosis but preserved viability by 12 weeks. CABG was performed with or without MSC-derived EXP application and animals recovered for 4 weeks. Prior to terminal procedure, cardiac MRI at rest and with low-dose dobutamine assessed diastolic relaxation, systolic function, graft patency and myocardial viability. Tissue studies of inflammation, fibrosis, and mitochondrial morphology were performed post-termination.
In vitro data demonstrated improved cardiomyocyte mitochondrial respiration upon co-culture with MSCs, which was blunted when adding the exosomal antagonist GW4869. RNA-sequencing identified eight differentially expressed miRNAs in normoxia vs hypoxia-induced exosomes that may modulate the expression of key mitochondrial (PGC-1α and ATP synthase) and inflammatory mediators (NFκB, IFN-γ, IL-1β). In vivo animal MRI-studies demonstrated regional systolic function and diastolic relaxation to be improved with CABG + EXP compared to HIB (p = 0.02, p = 0.02 respectively). Histologic analysis showed increased interstitial fibrosis and inflammation in HIB compared to CABG + EXP. Electron microscopy demonstrated increased mitochondrial area, perimeter, and aspect ratio in CABG + EXP compared to HIB or CABG alone (p < 0.0001).
Exosomes recovered cardiomyocyte mitochondrial respiration and reduced myocardial inflammation through paracrine signaling, resulting in improved cardiac function.
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Purpose
Ultrasound of the right lower quadrant for appendicitis requires specific training and practice. Improved visualization of the appendix can result in decreased utilization of computed ...tomography. Increasing the sensitivity of ultrasound for appendicitis thus decreases radiation exposure, reduces cost, and improves the patient healthcare experience in accordance with the three principles of the triple aim designated by the Institute for Healthcare Improvement. The purpose of this study was to examine the effect of a structured training program supplemented by technologist feedback on sonographic visualization of the appendix in a large pediatric health system.
Methods
The baseline ultrasound visualization frequency was computed for 20 ultrasound technologists in a large pediatric health system. Following this, technologists were informed of their individual and relative performance. Those with visualization frequencies less than 75% were provided structured training by a designated sonographer with an appendix visualization frequency above 75% while those with greater than 75% visualization continued to be monitored and informed of their monthly frequency. Following this structured training, appendix visualization frequencies were monitored over the next 5 months.
Results
There was no significant effect of sonographer career experience on the baseline appendix visualization frequency. Fourteen of 20 technologists demonstrated improved visualization frequencies post-intervention. The composite visualization frequency among these 20 technologists improved from 66.55 to 69.14%. This resulted in a potential savings of 38 CT scans during the post-intervention period.
Conclusion
An appendix visualization rate monitoring program coupled with structured training was successful in improving the appendix visualization rate throughout a large pediatric health system. This program demonstrates the positive effect that monitoring and targeted intervention can have on a quality improvement program. The program continues to be carried out as part of a plan-study-do-act cycle.
Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer’s disease. A key component of the design involved a ...2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aβ42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid β (Aβ) 42 in cerebrospinal fluid (CSF).
Hemodynamic factors have long been associated with clinical outcomes in the treatment of cerebral aneurysms. Computational studies of cerebral aneurysm hemodynamics have provided valuable estimates ...of the mechanical environment experienced by the endothelium in both the parent vessel and aneurysmal dome walls and have correlated them with disease state. These computational-clinical studies have recently been correlated with the response of endothelial cells (EC) using either idealized or patient-specific models. Here, we present a robust workflow for generating anatomic-scale aneurysm models, establishing luminal cultures of ECs at physiological relevant flow profiles, and comparing EC responses to curvature mediated flow. We show that flow patterns induced by parent vessel curvature produce changes in wall shear stress (WSS) and wall shear stress gradients (WSSG) that are correlated with differences in cell morphology and cellular protein localization. Cells in higher WSS regions align better with the flow and display strong Notch1-extracellular domain (ECD) polarization, while, under low WSS, differences in WSSG due to curvature change were associated with less alignment and attenuation of Notch1-ECD polarization in ECs of the corresponding regions. These proof-of-concept results highlight the use of engineered cellularized aneurysm models for connecting computational fluid dynamics to the underlying endothelial biology that mediates disease.
Abstract
BACKGROUND
Though the Pipeline Embolization Device (Medtronic) is approved for use in adults 22 yr and older, the high efficacy and long-term durability of the device is attractive for ...treatment of intracranial aneurysms in younger patients who often have aneurysms less amenable to traditional endovascular treatments.
OBJECTIVE
To report technical, angiographic, and clinical outcomes in patients aged 21 or below undergoing flow-diversion treatment for intracranial aneurysms.
METHODS
Retrospective review across 16 institutions identified 39 patients aged 21 or below undergoing 46 treatment sessions with Pipeline Embolization Device placement between 2012 and 2018. A total of 50 intracranial aneurysms were treated. Details regarding patient demographics, aneurysm characteristics, treatment considerations, clinical outcomes, and aneurysm occlusion were obtained and analyzed in a multicenter database.
RESULTS
A total of 70% of patients were male. Nonsaccular morphology was seen in half of identified aneurysms. Six aneurysms were giant, and five patients were treated acutely after ruptured presentation. Eight patients were younger than 10 yr of age. Complete aneurysm occlusion was seen in 74% of treated aneurysms. Three aneurysms (6%) were retreated. A total of 83% of patients had a modified Rankin Scale scores of ≤2 at last clinical follow-up. There were 2 early mortalities (4.3%) in the immediate postprocedure period because of rerupture of a treated ruptured aneurysm. No recanalization of a previously occluded aneurysm was observed.
CONCLUSION
Flow-diversion treatment is a safe and effective treatment for intracranial aneurysms in patients younger than 22 yr. Rates of complete aneurysm occlusion and adverse events are comparable for rates seen in older patients.
Graphical Abstract
Graphical Abstract
To study the correlation between wall shear stress and endothelial cell expression in a patient-specific, three-dimensional (3D)-printed model of a cerebral aneurysm.
A 3D-printed model of a cerebral ...aneurysm was created from a patient's angiogram. After populating the model with human endothelial cells, it was exposed to media under flow for 24 hours. Endothelial cell morphology was characterized in five regions of the 3D-printed model using confocal microscopy. Endothelial cells were then harvested from distinct regions of the 3D-printed model for mRNA collection and gene analysis via quantitative polymerase chain reaction (qPCR.) Cell morphology and mRNA measurement were correlated with computational fluid dynamics simulations.
The model was successfully populated with endothelial cells, which survived under flow for 24 hours. Endothelial morphology showed alignment with flow in the proximal and distal parent vessel and aneurysm neck, but disorganization in the aneurysm dome. Genetic analysis of endothelial mRNA expression in the aneurysm dome and distal parent vessel was compared with the proximal parent vessels. ADAMTS-1 and NOS3 were downregulated in the aneurysm dome, while GJA4 was upregulated in the distal parent vessel. Disorganized morphology and decreased ADAMTS-1 and NOS3 expression correlated with areas of substantially lower wall shear stress and wall shear stress gradient in computational fluid dynamics simulations.
Creating 3D-printed models of patient-specific cerebral aneurysms populated with human endothelial cells is feasible. Analysis of these cells after exposure to flow demonstrates differences in both cell morphology and genetic expression, which correlate with areas of differential hemodynamic stress.
Flow-diverting stents (FDS) are used to treat cerebral aneurysms. They promote the formation of a stable thrombus within the aneurysmal sac and, if successful, isolate the aneurysmal dome from ...mechanical stresses to prevent rupture. Platelet activation, a mechanism necessary for thrombus formation, is known to respond to biomechanical stimuli, particularly to the platelets’ residence time and shear stress exposure. Currently, there is no reliable method for predicting FDS treatment outcomes, either
a priori
or after the procedure. Eulerian computational fluid dynamic (CFD) studies of aneurysmal flow have searched for predictors of endovascular treatment outcome; however, the hemodynamics of thrombus formation cannot be fully understood without considering the platelets’ trajectories and their mechanics-triggered activation. Lagrangian analysis of the fluid mechanics in the aneurysmal vasculature provides novel metrics by tracking the platelets’ residence time (RT) and shear history (SH). Eulerian and Lagrangian parameters are compared for 19 patient-specific cases, both pre- and post-treatment, to assess the degree of change caused by the FDS and subsequent treatment efficacy.
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