A randomized, triple-blinded, placebo-controlled clinical trial evaluating immune responses of Typhim Vi and PPSV23 vaccines in healthy adults: The PREP study.

Rapid and early identification of emergent infections is essential for delivering prompt clinical care. To advance the development of algorithms for the clinical management of infection identification, we performed a vaccination clinical trial to investigate the potential of using vaccination as a model for studying mild inflammation responses associated with different infections (NCT05346302). We collected data at various time points over 4 weeks from blood samples, wearable devices, and questionnaires. Following a 2-week baseline period, 210 healthy participants, aged 18-40 years, were administered either a Pneumococcal Polysaccharide vaccine (PPSV23), Typhoid Vi Polysaccharide vaccine (Typhim Vi), or placebo. In longitudinal analyses of blood biomarkers, we found that CRP was significantly higher at 2 days post-vaccination, whereas basophils, IL-10, IL-12p40, and MIG were significantly higher at 7 days post-vaccination in the PPSV23 group compared to both other groups (all p < 0.05). MIP-1ß was significantly lower in the PPSV23 group than in the placebo group, while monocytes and MPV were significantly lower in the Typhim Vi group than in the placebo group at 7 days post-vaccination (all p < 0.05). The PPSV3 group showed a higher inflammatory profile, suggesting that PPSV23 induces a stronger immune response compared to Typhim Vi. The distinct immune responses induced by the two vaccines indicate the potential for utilizing vaccines as models for studying inflammation responses associated with different infectious pathogens.

Fast virtual coiling algorithm for intracranial aneurysms using pre-shape path planning.

To aid in predicting and improving treatment outcome of endovascular coiling of intracranial aneurysms, simulation of patient-specific coil deployment should be both accurate and fast. We developed a fast virtual coiling algorithm called Pre-shape Path Planning (P3). It captures the mechanical propensity of a released coil to restore its pre-shape for bending energy minimization, producing coils without unrealistic kinks and bends. A coil is discretized into finite-length segments and extruded from the delivery catheter segment-by-segment following a generic coil pre-shape. With the release of each segment, coil-wall and coil-coil collisions are detected and resolved. Modeling of each case took seconds to minutes. To test the algorithm, we evaluated its output against the literature, experiments, and patient angiograms. The periphery-to-core ratio of coils deployed by P3 decreased with increasing coil packing density, consistent with observations in the literature. Coils deployed by P3 compared well with in vitro experiments, free from unphysical kinks and loops that arose from previous virtual coiling algorithms. Simulations of coiling in four patient-specific aneurysms agreed well with the patient angiograms. To test the influence of coil pre-shape on P3, we performed hemodynamic simulations in aneurysms with coils deployed by P3 using the generic pre-shape, P3 using a coil-specific pre-shape, and full finite-element-method simulation. We found that the generic pre-shape was sufficient to produce results comparable to virtual coiling by finite element modeling. Based on these findings, P3 can rapidly simulate coiling in patient-specific aneurysms with good accuracy and is thus a potential candidate for clinical treatment planning.

Characterization of Long Non-coding RNA Signatures of Intracranial Aneurysm in Circulating Whole Blood.

BACKGROUND AND OBJECTIVE: Long non-coding RNAs (lncRNAs) may serve as biomarkers for complex disease states, such as intracranial aneurysms. In this study, we investigated lncRNA expression differences in the whole blood of patients with unruptured aneurysms. METHODS: Whole blood RNA from 67 subjects (34 with aneurysm, 33 without) was used for next-generation RNA sequencing. Differential expression analysis was used to define a signature of intracranial aneurysm-associated lncRNAs. To estimate the signature's ability to classify aneurysms and to identify the most predictive lncRNAs, we implemented a nested cross-validation pipeline to train classifiers using linear discriminant analysis. Ingenuity pathway analysis was used to study potential biological roles of differentially expressed lncRNAs, and lncRNA ontology was used to investigate ontologies enriched in signature lncRNAs. Co-expression correlation analysis was performed to investigate associated differential protein-coding messenger RNA expression. RESULTS: Of 4639 detected lncRNAs, 263 were significantly different (p < 0.05) between the two groups, and 84 of those had an absolute fold-change ≥ 1.5. An eight-lncRNA signature (q < 0.35, fold-change ≥ 1.5) was able to separate patients with and without aneurysms on principal component analysis, and had an estimated accuracy of 70.9% in nested cross-validation. Bioinformatics analyses showed that networks of differentially expressed lncRNAs (p < 0.05) were enriched for cell death and survival, connective tissue disorders, carbohydrate metabolism, and cardiovascular disease. Signature lncRNAs shared ontologies that reflected regulation of gene expression, signaling, ubiquitin processing, and p53 signaling. Co-expression analysis showed correlations with messenger RNAs related to inflammatory responses. CONCLUSIONS: Differential expression in whole blood lncRNAs is detectable in patients harboring aneurysms, and reflects expression/signaling regulation, and ubiquitin and p53 pathways. Following validation in larger cohorts, these lncRNAs may be potential diagnostic targets for aneurysm detection by blood testing.

Evaluation of Two Fast Virtual Stenting Algorithms for Intracranial Aneurysm Flow Diversion.

BACKGROUND: Endovascular treatment of intracranial aneurysms (IAs) by flow diverter (FD) stents depends on flow modification. Patient-specific modeling of FD deployment and computational fluid dynamics (CFD) could enable a priori endovascular strategy optimization. We developed a fast, simplistic, expansion-free balls-weeping algorithm to model FDs in patientspecific aneurysm geometry. However, since such strong simplification could result in less accurate simulations, we also developed a fast virtual stenting workflow (VSW) that explicitly models stent expansion using pseudo-physical forces. METHODS: To test which of these two fast algorithms more accurately simulates real FDs, we applied them to virtually treat three representative patient-specific IAs. We deployed Pipeline Embolization Device into 3 patient-specific silicone aneurysm phantoms and simulated the treatments using both balls-weeping and VSW algorithms in computational aneurysm models. We then compared the virtually deployed FD stents against experimental results in terms of geometry and post-treatment flow fields. For stent geometry, we evaluated gross configurations and porosity. For post-treatment aneurysmal flow, we compared CFD results against experimental measurements by particle image velocimetry. RESULTS: We found that VSW created more realistic FD deployments than balls-weeping in terms of stent geometry, porosity and pore density. In particular, balls-weeping produced unrealistic FD bulging at the aneurysm neck, and this artifact drastically increased with neck size. Both FD deployment methods resulted in similar flow patterns, but the VSW had less error in flow velocity and inflow rate. CONCLUSION: In conclusion, modeling stent expansion is critical for preventing unrealistic bulging effects and thus should be considered in virtual FD deployment algorithms. Also endowed with its high computational efficiency and superior accuracy, the VSW algorithm is a better candidate for implementation into a bedside clinical tool for FD deployment simulation.

Aneurysm characteristics, coil packing, and post-coiling hemodynamics affect long-term treatment outcome.

BACKGROUND: Recurrence of intracranial aneurysms after endovascular coiling is a serious clinical concern. OBJECTIVE: We hypothesized that recurrence is associated with aneurysm morphology and flow, as well as the coil intervention and the induced flow modifications. METHODS: We collected 52 primary-coiling aneurysm cases that were either occluded (n=34) or recurrent (n=18) at >1 year follow-up. We created aneurysm models from pre-coiling digital subtraction angiographic images, calculated aneurysm morphology, simulated pre-coiling hemodynamics, modeled coil deployment, and obtained post-coiling hemodynamics for each case. We performed univariable analysis on 26 morphologic, treatment-specific, and hemodynamic parameters to distinguish between recurrent and occluded groups, and multivariable analysis to identify independently significant parameters associated with recurrence. Univariable analysis was also performed on ruptured and unruptured aneurysm subcohorts separately to investigate if they shared specific significant parameters. RESULTS: Recurrence was associated with pre-coiling aneurysm morphologic and flow parameters including larger size (maximum dimension and volume), larger neck (diameter, area, and neck-to-parent-artery ratio), and higher flow momentum and kinetic energy. Recurrence was also associated with lower coil packing (packing density and uncoiled volume), higher post-treatment flow (velocity, momentum, and kinetic energy), lower post-treatment washout time, and higher post-treatment impingement force at the neck. Multivariable analysis identified two aneurysmal characteristics (neck diameter and pre-coiling flow kinetic energy), one coil packing parameter (uncoiled volume), and one post-treatment hemodynamic parameter (flow momentum) that were independently associated with recurrence. In ruptured aneurysms, recurrence was associated with larger neck (diameter and area), whereas in unruptured aneurysms, recurrence was associated with larger size (maximum dimension and volume). In both subcohorts, recurrence was associated with higher post-coiling flow momentum and kinetic energy. CONCLUSION: Recurrence at >1 year after coil treatment is associated with intrinsic aneurysm characteristics, coiling itself, and flow changes induced by coiling. Larger aneurysm size and neck, less coil packing, and higher intra-aneurysmal flow before and after coiling predict recurrence.

Improving accuracy for finite element modeling of endovascular coiling of intracranial aneurysm.

BACKGROUND: Computer modeling of endovascular coiling intervention for intracranial aneurysm could enable a priori patient-specific treatment evaluation. To that end, we previously developed a finite element method (FEM) coiling technique, which incorporated simplified assumptions. To improve accuracy in capturing real-life coiling, we aimed to enhance the modeling strategies and experimentally test whether improvements lead to more accurate coiling simulations. METHODS: We previously modeled coils using a pre-shape based on mathematical curves and mechanical properties based on those of platinum wires. In the improved version, to better represent the physical properties of coils, we model coil pre-shapes based on how they are manufactured, and their mechanical properties based on their spring-like geometric structures. To enhance the deployment mechanics, we include coil advancement to the aneurysm in FEM simulations. To test if these new strategies produce more accurate coil deployments, we fabricated silicone phantoms of 2 patient-specific aneurysms in duplicate, deployed coils in each, and quantified coil distributions from intra-aneurysmal cross-sections using coil density (CD) and lacunarity (L). These deployments were simulated 9 times each using the original and improved techniques, and CD and L were calculated for cross-sections matching those in the experiments. To compare the 2 simulation techniques, Euclidean distances (dMin, dMax, and dAvg) between experimental and simulation points in standardized CD-L space were evaluated. Univariate tests were performed to determine if these distances were significantly different between the 2 simulations. RESULTS: Coil deployments using the improved technique agreed better with experiments than the original technique. All dMin, dMax, and dAvg values were smaller for the improved technique, and the average values across all simulations for the improved technique were significantly smaller than those from the original technique (dMin: p = 0.014, dMax: p = 0.013, dAvg: p = 0.045). CONCLUSION: Incorporating coil-specific physical properties and mechanics improves accuracy of FEM simulations of endovascular intracranial aneurysm coiling.

Novel Geometric Approach for Virtual Coiling.

Endovascular coiling is a primary treatment for intra-cranial aneurysm, which deploys a thin and detachable metal wire inside the aneurysm so as to prevent its rupture. Emerging evidence from medical research and clinical practice has suggested that the coil configuration inside the aneurysm plays a vital role in properly treating aneurysm and predicting its outcome. In this paper, we propose a novel virtual coiling technique, called Ball Winding, for generating a coil configuration with ensured blocking ability. It can be used as an automatic tool for virtually simulating coiling before its implantation and thus optimizes such treatments. Our approach is based on integer linear programming and computational geometry techniques, and takes into consideration the packing density and coil distribution as the performance measurements. The resulting coiling is deployable (with the help of coil pre-shaping) and with minimized energy. Experimental results on both random and real aneurysm data suggest that our proposed method yields near optimal solution.

Methodology for Computational Fluid Dynamic Validation for Medical Use: Application to Intracranial Aneurysm.

Computational fluid dynamics (CFD) is a promising tool to aid in clinical diagnoses of cardiovascular diseases. However, it uses assumptions that simplify the complexities of the real cardiovascular flow. Due to high-stakes in the clinical setting, it is critical to calculate the effect of these assumptions in the CFD simulation results. However, existing CFD validation approaches do not quantify error in the simulation results due to the CFD solver's modeling assumptions. Instead, they directly compare CFD simulation results against validation data. Thus, to quantify the accuracy of a CFD solver, we developed a validation methodology that calculates the CFD model error (arising from modeling assumptions). Our methodology identifies independent error sources in CFD and validation experiments, and calculates the model error by parsing out other sources of error inherent in simulation and experiments. To demonstrate the method, we simulated the flow field of a patient-specific intracranial aneurysm (IA) in the commercial CFD software star-ccm+. Particle image velocimetry (PIV) provided validation datasets for the flow field on two orthogonal planes. The average model error in the star-ccm+ solver was 5.63 ± 5.49% along the intersecting validation line of the orthogonal planes. Furthermore, we demonstrated that our validation method is superior to existing validation approaches by applying three representative existing validation techniques to our CFD and experimental dataset, and comparing the validation results. Our validation methodology offers a streamlined workflow to extract the "true" accuracy of a CFD solver.

Association between hemodynamic modifications and clinical outcome of intracranial aneurysms treated using flow diverters.

Treatment of intracranial aneurysms (IAs) has been revolutionized by the advent of endovascular Flow Diverters (FDs), which disrupt blood flow within the aneurysm to induce pro-thrombotic conditions, and serves as a scaffold for endothelial ingrowth and arterial remodeling. Despite good clinical success of FDs, complications like incomplete occlusion and post-treatment rupture leading to subarachnoid hemorrhage have been reported. In silico computational fluid dynamic analysis of the pre- and post-treated geometries of IA patients can shed light on the contrasting blood hemodynamics associated with different clinical outcomes. In this study, we analyzed hemodynamic modifications in 15 IA patients treated using a single FD; 10 IAs were completely occluded (successful) and 5 were partially occluded (unsuccessful) at 12-month follow-up. An in-house virtual stenting workflow was used to recapitulate the clinical intervention on these cases, followed by CFD to obtain pre- and post-treatment hemodynamics. Bulk hemodynamic parameters showed comparable reductions in both groups with average inflow rate and aneurysmal velocity reduction of 40.3% and 52.4% in successful cases, and 34.4% and 49.2% in unsuccessful cases. There was a substantial reduction in localized parameter like vortex coreline length and Energy Loss for successful cases, 38.2% and 42.9% compared to 10.1% and 10.5% for unsuccessful cases. This suggest that for successfully treated IAs, the localized complex blood flow is disrupted more prominently by the FD as compared to unsuccessful cases. These localized hemodynamic parameters can be potentially used in prediction of treatment outcome, thus aiding the clinicians in a priori assessment of different treatment strategies.

Finite element modeling of endovascular coiling and flow diversion enables hemodynamic prediction of complex treatment strategies for intracranial aneurysm.

Endovascular interventions using coil embolization and flow diversion are becoming the mainstream treatment for intracranial aneurysms (IAs). To help assess the effect of intervention strategies on aneurysm hemodynamics and treatment outcome, we have developed a finite-element-method (FEM)-based technique for coil deployment along with our HiFiVS technique for flow diverter (FD) deployment in patient-specific IAs. We tested four clinical intervention strategies: coiling (1-8 coils), single FD, FD with adjunctive coils (1-8 coils), and overlapping FDs. By evaluating post-treatment hemodynamics using computational fluid dynamics (CFD), we compared the flow-modification performance of these strategies. Results show that a single FD provides more reduction in inflow rate than low packing density (PD) coiling, but less reduction in average velocity inside the aneurysm. Adjunctive coils add no additional reduction of inflow rate beyond a single FD until coil PD exceeds 11%. This suggests that the main role of FDs is to divert inflow, while that of coils is to create stasis in the aneurysm. Overlapping FDs decreases inflow rate, average velocity, and average wall shear stress (WSS) in the aneurysm sac, but adding a third FD produces minimal additional reduction. In conclusion, our FEM-based techniques for virtual coiling and flow diversion enable recapitulation of complex endovascular intervention strategies and detailed hemodynamics to identify hemodynamic factors that affect treatment outcome.

High-fidelity virtual stenting: modeling of flow diverter deployment for hemodynamic characterization of complex intracranial aneurysms.

OBJECT: Flow diversion via Pipeline Embolization Device (PED) represents the most recent advancement in endovascular therapy of intracranial aneurysms. This exploratory study aims at a proof of concept for an advanced device-modeling tool in conjunction with computational fluid dynamics (CFD) to evaluate flow modification effects by PED in actual, treated cases. METHODS: The authors performed computational modeling of 3 PED-treated complex aneurysm cases. The patient in Case 1 had a fusiform vertebral aneurysm treated with a single PED. In Case 2 the patient had a giant internal carotid artery (ICA) aneurysm treated with 2 PEDs. Case 3 consisted of tandem ICA aneurysms (III-a and III-b) treated by a single PED. The authors' recently developed high-fidelity virtual stenting (HiFiVS) technique was used to recapitulate the clinical deployment process of PEDs in silico for these 3 cases. Pretreatment and posttreatment aneurysmal hemodynamics studies performed using CFD simulation were analyzed. Changes in aneurysmal flow velocity, inflow rate, wall shear stress (WSS), and turnover time were calculated and compared with the clinical outcome. RESULTS: In Case 1 (occluded within the first 3 months), the aneurysm had the most drastic flow reduction after PED placement; the aneurysmal average velocity, inflow rate, and average WSS were decreased by 76.3%, 82.5%, and 74.0%, respectively, whereas the turnover time was increased to 572.1% of its pretreatment value. In Case 2 (occluded at 6 months), aneurysmal average velocity, inflow rate, and average WSS were decreased by 39.4%, 38.6%, and 59.1%, respectively, and turnover time increased to 163.0%. In Case 3, Aneurysm III-a (occluded at 6 months) had a decrease by 38.0%, 28.4%, and 50.9% in average velocity, inflow rate, and average WSS, respectively, and turnover time increased to 139.6%, which was quite similar to Aneurysm II. Surprisingly, the adjacent Aneurysm III-b had more substantial flow reduction (a decrease by 77.7%, 53.0%, and 84.4% in average velocity, inflow rate, and average WSS, respectively, and an increase to 213.0% in turnover time) than Aneurysm III-a, which qualitatively agreed with angiographic observation at 3-month follow-up. However, Aneurysm III-b remained patent at both 6 months and 9 months. A closer examination of the vascular anatomy in Case 3 revealed blood draining to the ophthalmic artery off Aneurysm III-b, which may have prevented its complete thrombosis. CONCLUSIONS: This proof-of-concept study demonstrates that HiFiVS modeling of flow diverter deployment enables detailed characterization of hemodynamic alteration by PED placement. Posttreatment aneurysmal flow reduction may be correlated with aneurysm occlusion outcome. However, predicting aneurysm treatment outcome by flow diverters also requires consideration of other factors, including vascular anatomy.