Inferior Ophthalmic Vein-Dominant Dural Cavernous Fistula Embolization via Combined Orbitotomy and Direct Puncture of Inferior Ophthalmic Vein: A Case Report and Literature Review.

Dural carotid-cavernous fistulas (DCF) typically drain into the superior ophthalmic vein. Predominant involvement of the inferior ophthalmic vein (IOV) is rare, with only 4 documented cases in the literature. Here, the authors describe a case of a 51-year-old man who presented with acute left-sided proptosis, dysmotility, and vision loss and was found to have an IOV-dominant type D dural carotid-cavernous fistulas. The fistula could not be embolized by transfemoral endovascular access or orbitotomy alone and was ultimately managed with combined orbitotomy and direct IOV puncture. All previous reports of IOV-dominant dural carotid-cavernous fistulas in the literature were similarly inaccessible via the transfemoral approach. This case highlights the challenges of IOV cutdown and proposes an alternative management strategy. When IOV cutdown is precluded by the fragile, collapsed, or deep nature of the vessel, conversion to percutaneous IOV puncture may offer a safe and effective approach and mitigate the risks of direct puncture alone.

Cerebral venous disorders: Diagnosis and endovascular management.

The role of the venous circulation in neurological diseases has been underestimated. In this review, we present an overview of the intracranial venous anatomy, venous disorders of the central nervous system, and options for endovascular management. We discuss the role the venous circulation plays in various neurological diseases including cerebrospinal fluid (CSF) disorders (intracranial hypertension and intracranial hypotension), arteriovenous diseases, and pulsatile tinnitus. We also shed light on emergent cerebral venous interventions including transvenous brain-computer interface implantation, transvenous treatment of communicating hydrocephalus, and the endovascular treatment of CSF-venous disorders.

Acute ischaemic stroke associated with SARS-CoV-2 infection in North America.

BACKGROUND: To analyse the clinical characteristics of COVID-19 with acute ischaemic stroke (AIS) and identify factors predicting functional outcome. METHODS: Multicentre retrospective cohort study of COVID-19 patients with AIS who presented to 30 stroke centres in the USA and Canada between 14 March and 30 August 2020. The primary endpoint was poor functional outcome, defined as a modified Rankin Scale (mRS) of 5 or 6 at discharge. Secondary endpoints include favourable outcome (mRS ≤2) and mortality at discharge, ordinal mRS (shift analysis), symptomatic intracranial haemorrhage (sICH) and occurrence of in-hospital complications. RESULTS: A total of 216 COVID-19 patients with AIS were included. 68.1% (147/216) were older than 60 years, while 31.9% (69/216) were younger. Median [IQR] National Institutes of Health Stroke Scale (NIHSS) at presentation was 12.5 (15.8), and 44.2% (87/197) presented with large vessel occlusion (LVO). Approximately 51.3% (98/191) of the patients had poor outcomes with an observed mortality rate of 39.1% (81/207). Age >60 years (aOR: 5.11, 95% CI 2.08 to 12.56, p<0.001), diabetes mellitus (aOR: 2.66, 95% CI 1.16 to 6.09, p=0.021), higher NIHSS at admission (aOR: 1.08, 95% CI 1.02 to 1.14, p=0.006), LVO (aOR: 2.45, 95% CI 1.04 to 5.78, p=0.042), and higher NLR level (aOR: 1.06, 95% CI 1.01 to 1.11, p=0.028) were significantly associated with poor functional outcome. CONCLUSION: There is relationship between COVID-19-associated AIS and severe disability or death. We identified several factors which predict worse outcomes, and these outcomes were more frequent compared to global averages. We found that elevated neutrophil-to-lymphocyte ratio, rather than D-Dimer, predicted both morbidity and mortality.

Arginine-deprivation-induced oxidative damage sterilizes Mycobacterium tuberculosis.

Reactive oxygen species (ROS)-mediated oxidative stress and DNA damage have recently been recognized as contributing to the efficacy of most bactericidal antibiotics, irrespective of their primary macromolecular targets. Inhibitors of targets involved in both combating oxidative stress as well as being required for in vivo survival may exhibit powerful synergistic action. This study demonstrates that the de novo arginine biosynthetic pathway in Mycobacterium tuberculosis (Mtb) is up-regulated in the early response to the oxidative stress-elevating agent isoniazid or vitamin C. Arginine deprivation rapidly sterilizes the Mtb de novo arginine biosynthesis pathway mutants ΔargB and ΔargF without the emergence of suppressor mutants in vitro as well as in vivo. Transcriptomic and flow cytometry studies of arginine-deprived Mtb have indicated accumulation of ROS and extensive DNA damage. Metabolomics studies following arginine deprivation have revealed that these cells experienced depletion of antioxidant thiols and accumulation of the upstream metabolite substrate of ArgB or ArgF enzymes. ΔargB and ΔargF were unable to scavenge host arginine and were quickly cleared from both immunocompetent and immunocompromised mice. In summary, our investigation revealed in vivo essentiality of the de novo arginine biosynthesis pathway for Mtb and a promising drug target space for combating tuberculosis.

Pivotal Trial of the Neuroform Atlas Stent for Treatment of Anterior Circulation Aneurysms: One-Year Outcomes.

BACKGROUND AND PURPOSE: Stent-assisted coil embolization using the new generation Neuroform Atlas Stent System has shown promising safety and efficacy. The primary study results of the anterior circulation aneurysm cohort of the treatment of wide-neck, saccular, intracranial, aneurysms with the Neuroform Atlas Stent System (ATLAS trial [Safety and Effectiveness of the Treatment of Wide Neck, Saccular Intracranial Aneurysms With the Neuroform Atlas Stent System]) are presented. METHODS: ATLAS IDE trial (Investigational Device Exemption) is a prospective, multicenter, single-arm, open-label study of wide-neck (neck ≥4 mm or dome-to-neck ratio <2) intracranial aneurysms in the anterior circulation treated with the Neuroform Atlas Stent and approved coils. The primary efficacy end point was complete aneurysm occlusion (Raymond-Roy class 1) on 12-month angiography, in the absence of retreatment or parent artery stenosis (>50%) at the target location. The primary safety end point was any major stroke or ipsilateral stroke or neurological death within 12 months. Adjudication of the primary end points was performed by an independent Imaging Core Laboratory and the Clinical Events Committee. RESULTS: A total of 182 patients with wide-neck anterior circulation aneurysms at 25 US centers were enrolled. The mean age was 60.3±11.4 years, 73.1% (133/182) women, and 80.8% (147/182) white. Mean aneurysm size was 6.1±2.2 mm, mean neck width was 4.1±1.2 mm, and mean dome-to-neck ratio was 1.2±0.3. The most frequent aneurysm locations were the anterior communicating artery (64/182, 35.2%), internal carotid artery ophthalmic artery segment (29/182, 15.9%), and middle cerebral artery bifurcation (27/182, 14.8%). Stents were placed in the anticipated anatomic location in all patients. The study met both primary safety and efficacy end points. The composite primary efficacy end point of complete aneurysm occlusion (Raymond-Roy 1) without parent artery stenosis or aneurysm retreatment was achieved in 84.7% (95% CI, 78.6%-90.9%) of patients. Overall, 4.4% (8/182, 95% CI, 1.9%-8.5%) of patients experienced a primary safety end point of major ipsilateral stroke or neurological death. CONCLUSIONS: In the ATLAS IDE anterior circulation aneurysm cohort premarket approval study, the Neuroform Atlas stent with adjunctive coiling met the primary end points and demonstrated high rates of long-term complete aneurysm occlusion at 12 months, with 100% technical success and <5% morbidity. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02340585.

Helicobacter pylori Infections in the Bronx, New York: Surveying Antibiotic Susceptibility and Strain Lineage by Whole-Genome Sequencing.

The emergence of drug resistance in Helicobacter pylori has resulted in a greater need for susceptibility-guided treatment. While the alleles associated with resistance to clarithromycin and levofloxacin have been defined, there are limited data regarding the molecular mechanisms underlying resistance to other antimicrobials. Using H. pylori isolates from 42 clinical specimens, we compared phenotypic and whole-genome sequencing (WGS)-based detection of resistance. Phenotypic resistance correlated with the presence of alleles of 23S rRNA (A2142G/A2143G) for clarithromycin (kappa coefficient, 0.84; 95% confidence interval [CI], 0.67 to 1.0) and gyrA (N87I/N87K/D91Y/D91N/D91G/D99N) for levofloxacin (kappa coefficient, 0.90; 95% CI, 0.77 to 1.0). Phenotypic resistance to amoxicillin in three isolates correlated with mutations in pbp1, pbp2, and/or pbp3 within coding regions near known amoxicillin binding motifs. All isolates were phenotypically susceptible to tetracycline, although four bore a mutation in 16S rRNA (A926G). For metronidazole, nonsense mutations and R16H substitutions in rdxA correlated with phenotypic resistance (kappa coefficient, 0.76; 95% CI, 0.56 to 0.96). Previously identified mutations in the rpoB rifampin resistance-determining region (RRDR) were not present, but 14 novel mutations outside the RRDR were found in rifampin-resistant isolates. WGS also allowed for strain lineage determination, which may be important for future studies in associating precise MICs with specific resistance alleles. In summary, WGS allows for broad analyses of H. pylori isolates, and our findings support the use of WGS for the detection of clarithromycin and levofloxacin resistance. Additional studies are warranted to better define mutations conferring resistance to amoxicillin, tetracycline, and rifampin, but combinatorial analyses for rdxA gene truncations and R16H mutations have utility for determining metronidazole resistance.

Next-Generation-Sequencing-Based Hospital Outbreak Investigation Yields Insight into Klebsiella aerogenes Population Structure and Determinants of Carbapenem Resistance and Pathogenicity.

Klebsiella aerogenes is a nosocomial pathogen associated with drug resistance and outbreaks in intensive care units. In a 5-month period in 2017, we experienced an increased incidence of cultures for carbapenem-resistant K. aerogenes (CR-KA) from an adult cardiothoracic intensive care unit (CICU) involving 15 patients. Phylogenomic analysis following whole-genome sequencing (WGS) identified the outbreak CR-KA isolates to group together as a tight monoclonal cluster (with no more than six single nucleotide polymorphisms [SNPs]), suggestive of a protracted intraward transmission event. No clonal relationships were identified between the CICU CR-KA strains and additional hospital CR-KA patient isolates from different wards and/or previous years. Carbapenemase-encoding genes and drug-resistant plasmids were absent in the outbreak strains, and carbapenem resistance was attributed to mutations impacting AmpD activity and membrane permeability. The CICU outbreak strains harbored an integrative conjugative element (ICE) which has been associated with pathogenic Klebsiella pneumoniae lineages (ICEKp10). Comparative genomics with global K. aerogenes genomes showed our outbreak strains to group closely with global sequence type 4 (ST4) strains, which, along with ST93, likely represent dominant K. aerogenes lineages associated with human infections. For poorly characterized pathogens, scaling analyses to include sequenced genomes from public databases offer the opportunity to identify emerging trends and dominant clones associated with specific attributes, syndromes, and geographical locations.

Enhanced control of Mycobacterium tuberculosis extrapulmonary dissemination in mice by an arabinomannan-protein conjugate vaccine.

Currently there are a dozen or so of new vaccine candidates in clinical trials for prevention of tuberculosis (TB) and each formulation attempts to elicit protection by enhancement of cell-mediated immunity (CMI). In contrast, most approved vaccines against other bacterial pathogens are believed to mediate protection by eliciting antibody responses. However, it has been difficult to apply this formula to TB because of the difficulty in reliably eliciting protective antibodies. Here, we developed capsular polysaccharide conjugates by linking mycobacterial capsular arabinomannan (AM) to either Mtb Ag85b or B. anthracis protective antigen (PA). Further, we studied their immunogenicity by ELISA and AM glycan microarrays and protection efficacy in mice. Immunization with either Abg85b-AM or PA-AM conjugates elicited an AM-specific antibody response in mice. AM binding antibodies stimulated transcriptional changes in Mtb. Sera from AM conjugate immunized mice reacted against a broad spectrum of AM structural variants and specifically recognized arabinan fragments. Conjugate vaccine immunized mice infected with Mtb had lower bacterial numbers in lungs and spleen, and lived longer than control mice. These findings provide additional evidence that humoral immunity can contribute to protection against Mtb.

CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection.

The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4(+) T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4(+) T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8(+) memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.

Post-translational Acetylation of MbtA Modulates Mycobacterial Siderophore Biosynthesis.

Iron is an essential element for life, but its soluble form is scarce in the environment and is rarer in the human body. Mtb (Mycobacterium tuberculosis) produces two aryl-capped siderophores, mycobactin (MBT) and carboxymycobactin (cMBT), to chelate intracellular iron. The adenylating enzyme MbtA catalyzes the first step of mycobactin biosynthesis in two half-reactions: activation of the salicylic acid as an acyl-adenylate and ligation onto the acyl carrier protein (ACP) domain of MbtB to form covalently salicylated MbtB-ACP. We report the first apo-MbtA structure from Mycobacterium smegmatis at 2.3 Å. We demonstrate here that MbtA activity can be reversibly, post-translationally regulated by acetylation. Indeed the mycobacterial Pat (protein lysine acetyltransferase), Rv0998, specifically acetylates MbtA on lysine 546, in a cAMP-dependent manner, leading to enzyme inhibition. MbtA acetylation can be reversed by the NAD+-dependent DAc (deacetyltransferase), Rv1151c. Deletion of Pat and DAc genes in Mtb revealed distinct phenotypes for strains lacking one or the other gene at low pH and limiting iron conditions. This study establishes a direct connection between the reversible acetylation system Pat/DAc and the ability of Mtb to adapt in limited iron conditions, which is critical for mycobacterial infection.

Flow Diverter Therapy With the Pipeline Embolization Device Is Associated With an Elevated Rate of Delayed Fluid-Attenuated Inversion Recovery Lesions.

BACKGROUND AND PURPOSE: Flow diversion using the Pipeline Embolization Device is reported as a safe treatment of aneurysms. Complete aneurysm occlusion, however, occurs in a delayed fashion with initial persistent filling of the aneurysm dome. We hypothesized that this transflow across metallic struts may be associated with thromboembolic events. METHODS: Forty-one consecutive patients undergoing aneurysm treatment with the Pipeline Embolization Device and a comparison group of 78 Neuroform stent-mediated embolizations were studied. Patients' charts, procedure notes, platelet function, and anticoagulation state were analyzed. Serial magnetic resonance images were assessed for the presence of newly occurring diffusion-weighted imaging and fluid-attenuated inversion recovery (FLAIR) lesions at multiple postprocedure time ranges (average days post procedure [Pipeline Embolization Device/Neuroform]: T1=1, T2=73/107, T3=174, T4=277/335, and T5=409). In addition, diffusion-weighted imaging or FLAIR burden was estimated by lesional diameter summation. RESULTS: Pipeline patients were more likely to have new ipsilateral FLAIR lesions at all time points studied (30.6% versus 7.2% of patients at T=2 and 34.5% versus 6.2% at T=4). The mean FLAIR burden was significantly increased for Pipeline patients (10.1 versus 0.7 mm at T=2 and 8.8 versus 1.9 mm at T=4). Overall 34% (14/41) of Pipeline patients experienced a new FLAIR lesion at anytime when compared with 10% (8/78) of Neuroform stent-coil patients. Postprocedural diffusion-weighted imaging did not predict future FLAIR lesions suggesting a nonprocedural cause. CONCLUSIONS: The Pipeline Embolization Device is associated with increased rate of de novo FLAIR lesions occurring in a delayed fashion and distinct from perioperative diffusion-weighted imaging lesions. The cause and clinical effect of these lesions are unknown and suggest the need for prudent follow-up and evaluation.

IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer.

IL-15 has pivotal roles in the control of CD8(+) memory T cells and has been investigated as a therapeutic option in cancer therapy. Although IL-15 and IL-2 share many functions together, including the stimulation of CD8 T cell proliferation and IFN-γ production, the different in vivo roles of IL-15 and IL-2 have been increasingly recognized. Here, we explored the different effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells from resected breast tumors. We found that neither IL-2 nor IL-15 induced intratumoral CD8 T cell proliferation by itself, but after CD3/CD28-stimulation, IL-15 induced significantly higher proliferation than IL-2 during early time points, at day 2, day 3 and day 6. However, the IL-15-induced proliferation leveled off at day 9 and day 12, whereas IL-2 induced lower but progressive proliferation at each time point. Furthermore, IL-15 caused an early and robust increase of IFN-γ in the supernatant of TI cell cultures, which diminished at later time points, while the IL-2-induced IFN-γ production remained constant over time. In addition, the IL-15-costimulated CD8 T cells presented higher frequencies of apoptotic cells. The diminishing IL-15-induced response was possibly due to regulatory and/or exhaustion mechanisms. We did not observe increased IL-10 or PD-1 upregulation, but we have found an increase of Tim-3 upregulation on IL-15-, but not IL-2-stimulated cells. Blocking Tim-3 function using anti-Tim-3 antibodies resulted in increased IL-15-induced proliferation and IFN-γ production for a prolonged period of time, whereas adding Tim-3 ligand galectin 9 led to reduced proliferation and IFN-γ production. Our results suggest that IL-15 in combination of Tim-3 blocking antibodies could potentially act as an IL-2 alternative in tumor CD8 T cell expansion in vitro, a crucial step in adoptive T cell therapy.

Widening and high inclination of the middle cerebral artery bifurcation are associated with presence of aneurysms.

BACKGROUND AND PURPOSE: The middle cerebral artery (MCA) bifurcation is a preferred site for aneurysm formation. Wider bifurcation angles have been correlated with increased risk of aneurysm formation. We hypothesized a link between the presence of MCA aneurysms and the angle morphology of the bifurcation. METHODS: Three-dimensional rotational angiography volumes of 146 MCA bifurcations (62 aneurysmal) were evaluated for angle morphology: parent-daughter angles (larger daughter Ф1, smaller daughter Ф2), bifurcation angle (Ф1+Ф2), and inclination angle (γ) between the parent vessel axis and the plane determined by daughter vessel axes. Statistics were evaluated using Wilcoxon rank-sum analysis and area under the receiver operator characteristic curve. RESULTS: Aneurysmal bifurcations had wider inclination angle γ (median 57.8° versus 15.4°; P<0.0001). Seventy-five percent of aneurysmal MCAs had γ >10°, compared with 25% nonaneurysmal. Ф1 and Ф2, but especially Ф1+Ф2, were significantly larger in aneurysmal bifurcations (median 171.3° versus 98.1°; P<0.0001). Sixty-seven percent of aneurysmal bifurcations had Ф1+Ф2 >161°, compared with 0% nonaneurysmal MCAs. An optimal threshold of 140° was established for Ф1+Ф2 (area under the curve, 0.98). Sixty-eight percent of aneurysms originated off the daughter branches. Seventy-six percent of them originated off the branch with the largest branching angle, specifically if this was the smaller daughter branch. Wider Ф1+Ф2 correlated with aneurysm neck width, but not dome size. CONCLUSIONS: MCA bifurcations harboring aneurysms have significantly larger branching angles and more often originate off the branch with the largest angle. Wider inclination angle is strongly correlated with aneurysm presence, a novel finding. The results point to altered wall shear stress regulation as a possible factor in aneurysm development and progression.

Endovascular Shunting for Communicating Hydrocephalus Using a Biologically Inspired Transdural Cerebrospinal Fluid Valved eShunt® Implant.

Cerebrospinal fluid (CSF) bathing the central nervous system is produced by brain and choroid plexus within the ventricles for re-absorption into the venous circulation through arachnoid granulations (AG). Communicating hydrocephalus results from disruption of the absorptive process, necessitating surgical catheter-based shunt placement to relieve excess pressure from CSF buildup. Adjustable valve designs and antibiotic impregnation have minimally impacted persistent failure rates and postoperative complications. To confront this challenge, we have developed an innovative endovascular shunt implant biologically inspired from AG function to restore the natural dynamics of CSF drainage while concurrently addressing the predominant factors contributing to conventional shunt malfunction.

Open Surgical Obliteration of Three Indirect Carotid-Cavernous Fistulas.

BACKGROUND AND IMPORTANCE: Carotid-cavernous fistulas (CCFs) are abnormal connections between the carotid artery and the cavernous sinus (CS). CCFs are primarily treated by an endovascular route, but there are situations in which a lesion is not amenable to endovascular or transorbital treatment, necessitating a transcranial approach. In this select group of patients, the use of crushed temporalis muscle to pack the CS fistula site was found to be an effective method for treatment of CCFs. CLINICAL PRESENTATION: In this case series, we present 3 patients with CCFs in which endovascular treatment was not possible because of occlusion of the petrosal sinuses or stenosis of the superior ophthalmic vein at the superior orbital fissure, rendering the lesion inaccessible by a transvenous or transorbital route. Each patient was treated with a variation of temporalis muscle packing through a skull base triangle; one was treated through the anteromedial triangle, one through the supratrochlear triangle, and the third through the Parkinson triangle. The fistulas were cured in each case. CONCLUSION: Cavernous-carotid fistulas that are not amenable to endovascular or transorbital treatment can be successfully treated by packing the CS fistula site with crushed temporalis muscle. To cure these patients' symptoms and enhance their quality of life, it is crucial to weigh the advantages and disadvantages of each therapy option.

Extradural internal carotid artery caliber dysregulation is associated with cerebral aneurysms.

BACKGROUND AND PURPOSE: Flow-induced hemodynamic forces are critical in extra- and intracranial arterial caliber regulation and have been proposed to mediate intracranial aneurysm (IA) formation and rupture. We hypothesized that vascular structural control may be impaired in patients harboring brain aneurysms and sought to examine any differences in extradural internal carotid artery (ICA) caliber profiles. METHODS: Ninety-six catheter 2-dimensional angiograms were divided into 3 subgroups: (1) ICA leading to IA (n=38), (2) matched contralateral ICA (n=25), and (3) ICA from nonaneurysmal controls (n=33). ICA diameter was measured proximally beyond the bulb (DProx) and distally at the extradural point of maximal dilation (DMaxDist), yielding maximal distal-to-proximal ratio (RMdp). RESULTS: Unlike non-IA controls that tapered smoothly, ICAs leading to IA consistently demonstrated focal sites of abnormal dilation in the distal cervical or petrous extradural segments. RMdp was greater in ICAs leading to IA compared with non-IA controls (1.17±0.1 versus 1.0±0.08; P<0.0001). Matched-pair analysis showed RMdp to be higher in ICAs leading to IA than the corresponding contralateral ICAs (1.19±0.1 versus 1.07±0.11; P=0.001); RMdp from contralateral ICAs was greater than non-IA controls (P=0.005). Among ICAs leading to IA, women showed higher RMdp (1.11±0.12 versus 1.05±0.11; P=0.02) with no relationship to intradural IA location. CONCLUSIONS: Measurements of the extradural ICA in patients harboring intradural IA suggest an association with a remote upstream abnormal vascular caliber control consistent with a diffuse flow-mediated structural dysregulation showing laterality and sex dependence.

Variability of computational fluid dynamics solutions for pressure and flow in a giant aneurysm: the ASME 2012 Summer Bioengineering Conference CFD Challenge.

Stimulated by a recent controversy regarding pressure drops predicted in a giant aneurysm with a proximal stenosis, the present study sought to assess variability in the prediction of pressures and flow by a wide variety of research groups. In phase I, lumen geometry, flow rates, and fluid properties were specified, leaving each research group to choose their solver, discretization, and solution strategies. Variability was assessed by having each group interpolate their results onto a standardized mesh and centerline. For phase II, a physical model of the geometry was constructed, from which pressure and flow rates were measured. Groups repeated their simulations using a geometry reconstructed from a micro-computed tomography (CT) scan of the physical model with the measured flow rates and fluid properties. Phase I results from 25 groups demonstrated remarkable consistency in the pressure patterns, with the majority predicting peak systolic pressure drops within 8% of each other. Aneurysm sac flow patterns were more variable with only a few groups reporting peak systolic flow instabilities owing to their use of high temporal resolutions. Variability for phase II was comparable, and the median predicted pressure drops were within a few millimeters of mercury of the measured values but only after accounting for submillimeter errors in the reconstruction of the life-sized flow model from micro-CT. In summary, pressure can be predicted with consistency by CFD across a wide range of solvers and solution strategies, but this may not hold true for specific flow patterns or derived quantities. Future challenges are needed and should focus on hemodynamic quantities thought to be of clinical interest.

Topological Data Analysis and Use of Mapper for Cerebral Aneurysm Rupture Status Discrimination Based on 3-Dimensional Shape Analysis.

BACKGROUND AND OBJECTIVES: Topological data analysis (TDA), which identifies patterns in data through simplified topological signatures, has yet to be applied to aneurysm research. We investigate TDA Mapper graphs (Mapper) for aneurysm rupture discrimination. METHODS: Two hundred sixteen bifurcation aneurysms (90 ruptured) from 3-dimensional rotational angiography were segmented from vasculature and evaluated for 12 size/shape and 18 enhanced radiomics features. Using Mapper, uniformly dense aneurysm models were represented as graph structures and described by graph shape metrics. Mapper dissimilarity scores (MDS) were computed between pairs of aneurysms based on shape metrics. Lower MDS described similar shapes, whereas high MDS represented shapes that do not share common characteristics. Ruptured/unruptured average MDS scores (how "far" an aneurysm is shape-wise to ruptured/unruptured data sets, respectively) were evaluated for each aneurysm. Rupture status discrimination univariate and multivariate statistics were reported for all features. RESULTS: The average MDS for pairs of ruptured aneurysms were significantly larger compared with unruptured pairs (0.055 ± 0.027 vs 0.039 ± 0.015, P < .0001). Low MDS suggest that, in contrast to ruptured aneurysms, unruptured aneurysms have similar shape characteristics. An MDS threshold value of 0.0417 (area under the curve [AUC] = 0.73, 80% specificity, 60% sensitivity) was identified for rupture status classification. Under this predictive model, MDS scores <0.0417 would identify unruptured status. MDS statistical performance in discriminating rupture status was similar to that of nonsphericity and radiomics Flatness (AUC = 0.73), outperforming other features. Ruptured aneurysms were more elongated ( P < .0001), flatter ( P < .0001), and showed higher nonsphericity ( P < .0001) compared with unruptured. Including MDS in multivariate analysis resulted in AUC = 0.82, outperforming multivariate analysis on size/shape (AUC = 0.76) and enhanced radiomics (AUC = 0.78) alone. CONCLUSION: A novel application of Mapper TDA was proposed for aneurysm evaluation, with promising results for rupture status classification. Multivariate analysis incorporating Mapper resulted in high accuracy, which is particularly important given that bifurcation aneurysms are challenging to classify morphologically. This proof-of-concept study warrants future investigation into optimizing Mapper functionality for aneurysm research.