Evaluation of flow diverters for cerebral aneurysm therapy: recommendations for imaging analyses in clinical studies, endorsed by ESMINT, ESNR, OCIN, SILAN, SNIS, and WFITN.

BACKGROUND: Multiple studies and meta-analyses have described the technical and clinical outcomes in large cohorts of aneurysm patients treated with flow diverters (FDs). Variations in evaluation methodology complicate making comparisons among studies, hinder understanding of the device behavior, and pose an obstacle in the assessment of further advances in FD therapy. METHODS: A multidisciplinary panel of neurointerventionalists, imaging experts, and neuroradiologists convened with the goal of establishing consensus recommendations for the standardization of image analyses in FD studies. RESULTS: A standardized methodology is proposed for evaluating and reporting radiological outcomes of FD treatment of intracranial aneurysms. The recommendations include general imaging considerations for clinical studies and evaluations of longitudinal changes, such as neointimal lining and stenosis. They cover standards for classification of aneurysm location, morphology, measurements, as well as the assessment of aneurysm occlusion, wall apposition, and neck coverage. These reporting standards further define four specific braid deformation patterns: foreshortening, fish-mouthing, braid bump deformation, and braid collapse, collectively termed 'F2B2'. CONCLUSIONS: When widely applied, standardization of methods of measuring and reporting outcomes will help to harmonize the assessment of treatment outcomes in clinical studies, help facilitate communication of results among specialists, and help enable research and development to focus on specific aspects of FD techniques and technology.

Volumetric microscopy of cerebral arteries with a miniaturized optical coherence tomography imaging probe.

Endovascular interventions are increasingly becoming the preferred approach for treating strokes and cerebral artery diseases. These procedures rely on sophisticated angiographical imaging guidance, which encounters challenges because of limited contrast and spatial resolution. Achieving a more precise visualization of the underlying arterial pathology and neurovascular implants is crucial for accurate procedural decision-making. In a human study involving 32 patients, we introduced the clinical application of a miniaturized endovascular neuro optical coherence tomography (nOCT) imaging probe. This technology was designed to navigate the tortuous paths of the cerebrovascular circulation and to offer high-resolution imaging in situ. The nOCT probe is compatible with standard neurovascular microcatheters, integrating with the procedural workflow used in clinical routine. Equipped with a miniaturized optical fiber and a distal lens, the probe illuminates the tissue and collects the backscattered, near-infrared light. While rotating the fiber and the lens at high speed, the probe is rapidly retracted, creating a spiral-shaped light pattern to comprehensively capture the arterial wall and implanted devices. Using nOCT, we demonstrated volumetric microscopy of cerebral arteries in patients undergoing endovascular procedures. We imaged the anterior and posterior circulation of the brain, including distal segments of the internal carotid and middle-cerebral arteries, as well as the vertebral, basilar, and posterior cerebral arteries. We captured a broad spectrum of neurovascular pathologies, such as brain aneurysms, ischemic stroke, arterial stenoses, dissections, and intracranial atherosclerotic disease. nOCT offered artifact-free, high-resolution visualizations of intracranial artery pathology and neurovascular devices.

Telestroke network to robotic telestroke network: How to upgrade regional stroke care to include remote robotics?

Objective: Selected patients with large vessel occlusion (LVO) strokes can benefit from endovascular therapy (EVT). However, the effectiveness of EVT is largely dependent on how quickly the patient receives treatment. Recent technological developments have led to the first neurointerventional treatments using robotic assistance, opening up the possibility of performing remote stroke interventions. Existing telestroke networks provide acute stroke care, including remote administration of intravenous thrombolysis (IVT). Therefore, the introduction of remote EVT in distant stroke centers requires an adaptation of the existing telestroke networks. The aim of this work was to propose a framework for centers that are potential candidates for telerobotics according to the resources currently available in these centers. Methods: In this paper, we highlight the future challenges for including remote robotics in telestroke networks. A literature review provides potential solutions. Results: Existing telestroke networks need to determine which centers to prioritize for remote robotic technologies based on objective criteria and cost-effectiveness analysis. Organizational challenges include regional coordination and specific protocols. Technological challenges mainly concern telecommunication networks. Conclusions: Specific adaptations will be necessary if regional telestroke networks are to include remote robotics. Some of these can already be put in place, which could greatly help the future implementation of the technology.

Novel, braided, self-expandable stent designed for the treatment of pulsatile tinnitus caused by intracranial venous stenosis: first-in-human experience and long-term outcomes.

BACKGROUND: Pulsatile tinnitus (PT) can be a disabling clinical condition, which may be caused by a sigmoid/transverse sinus stenosis (STSS). Intracranial venous stenting with off-label carotid or peripheral venous stents has been used successfully to treat this condition. We present the results of a cohort of patients presenting with PT treated with a novel, dedicated, braided stent for the endovascular treatment of STSS. METHODS: Twelve patients presenting with PT and associated STSS were treated at our institution (December 2022-June 2023). All clinical and procedural variables were prospectively collected. We used the Tinnitus Function Index (TFI) and the Tinnitus Handicap Inventory (THI) scores to assess the impact of PT on quality of life before and after the treatment (mean follow-up: 10.3 months). RESULTS: Twelve women (mean age: 44±16.5 years) presenting with PT and STSS were treated. Mean pretreatment TFI/THI scores were 78.8/77. The BosStent was successfully deployed in all patients. We experienced no intraprocedural/postoperative complications. Intra-stent angioplasty was performed in three cases. All patients reported a complete resolution of PT symptoms within 1 month and remained stable and PT-free at the last follow-up (mean posttreatment TFI/THI score: 7.1/5, p<0001). CONCLUSIONS: The BosStent was successfully used in a cohort of patients with PT without any intraprocedural complications. All the patients experienced a complete resolution of PT symptoms after 1 month, which was stable during the follow-up period. Further studies with larger populations will be necessary to investigate the safety and effectiveness of this novel stent for the treatment of PT with STSS.

Risk of adjacent level fracture after percutaneous vertebroplasty and kyphoplasty vs natural history for the management of osteoporotic vertebral compression fractures: a network meta-analysis of randomized controlled trials.

OBJECTIVES: Percutaneous vertebroplasty and kyphoplasty are common interventions for osteoporotic vertebral compression fractures. However, there is concern about an increased risk of adjacent-level fractures after treatment. This study aimed to compare the risk of adjacent-level fractures after vertebroplasty and kyphoplasty with the natural history after osteoporotic vertebral compression fractures. MATERIALS AND METHODS: A network meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the risk of adjacent-level fractures after vertebroplasty and kyphoplasty compared to the natural history after osteoporotic vertebral compression fractures. Frequentist network meta-analysis was conducted using the "netmeta" package, and heterogeneity was assessed using Q statistics. The pooled risk ratio (RR) and 95% confidence intervals (CI) were calculated using random effects. RESULTS: Twenty-three RCTs with a total of 2838 patients were included in the analysis. The network meta-analysis showed comparable risks of adjacent-level fractures between vertebroplasty, kyphoplasty, and natural history after osteoporotic vertebral compression fractures with a mean follow-up of 21.2 (range: 3-49.4 months). The pooled RR for adjacent-level fractures after kyphoplasty compared to natural history was 1.35 (95% CI, 0.78-2.34, p = 0.23) and for vertebroplasty compared to natural history was 1.16 (95% CI, 0.62-2.14) p = 0.51. The risk of bias assessment showed a low to moderate risk of bias among included RCTs. CONCLUSION: There was no difference in the risk of adjacent-level fractures after vertebroplasty and kyphoplasty compared to natural history after osteoporotic vertebral compression fractures. The inclusion of a large patient number and network meta-analysis of RCTs serve evidence-based clinical practice. CLINICAL RELEVANCE STATEMENT: The risk of adjacent-level fracture following percutaneous vertebroplasty or kyphoplasty is similar to that observed in the natural history after osteoporotic vertebral compression fractures. KEY POINTS: RCTs have examined the risk of adjacent-level fracture after intervention for osteoporotic vertebral compression fractures. There was no difference between vertebroplasty and kyphoplasty patients compared to the natural disease history for adjacent compression fractures. This is strong evidence that interventional treatments for these fractures do not increase the risk of adjacent fractures.

The Impact of Preprocedural Platelet Function Testing on Periprocedural Complication Rates Associated With Pipeline Flow Diversion: An International Multicenter Study.

BACKGROUND AND OBJECTIVES: Dual antiplatelet therapy (DAPT) is necessary to minimize the risk of periprocedural thromboembolic complications associated with aneurysm embolization using pipeline embolization device (PED). We aimed to assess the impact of platelet function testing (PFT) on reducing periprocedural thromboembolic complications associated with PED flow diversion in patients receiving aspirin and clopidogrel. METHODS: Patients with unruptured intracranial aneurysms requiring PED flow diversion were identified from 13 centers for retrospective evaluation. Clinical variables including the results of PFT before treatment, periprocedural DAPT regimen, and intracranial complications occurring within 72 h of embolization were identified. Complication rates were compared between PFT and non-PFT groups. Differences between groups were tested for statistical significance using the Wilcoxon rank sum, Fisher exact, or χ 2 tests. A P -value <.05 was statistically significant. RESULTS: 580 patients underwent PED embolization with 262 patients dichotomized to the PFT group and 318 patients to the non-PFT group. 13.7% of PFT group patients were clopidogrel nonresponders requiring changes in their pre-embolization DAPT regimen. Five percentage of PFT group [2.8%, 8.5%] patients experienced thromboembolic complications vs 1.6% of patients in the non-PFT group [0.6%, 3.8%] ( P = .019). Two (15.4%) PFT group patients with thromboembolic complications experienced permanent neurological disability vs 4 (80%) non-PFT group patients. 3.7% of PFT group patients [1.5%, 8.2%] and 3.5% [1.8%, 6.3%] of non-PFT group patients experienced hemorrhagic intracranial complications ( P > .9). CONCLUSION: Preprocedural PFT before PED treatment of intracranial aneurysms in patients premedicated with an aspirin and clopidogrel DAPT regimen may not be necessary to significantly reduce the risk of procedure-related intracranial complications.

Can micro-guidewire advancement forces predict clot consistency and location to assist the first-line technique for mechanical thrombectomy?

BACKGROUND: The identification of specific clot characteristics before mechanical thrombectomy (MTB) might allow the selection of the most effective first-line technique, thus potentially improving the procedural outcome. We aimed to evaluate if the microwire push forces could extrapolate information on clot consistency and extension before MTB, based on clot mechanical properties. METHODS: We measured in vitro the forces exerted on the proximal extremity of the guidewire during the advancement and retrieval of the guidewire through clot analogs of different compositions. In addition, we analyzed the forces exerted on the guidewire to extrapolate information about the location of the proximal and distal extremities of the clot analogs. RESULTS: The maximum forces recorded during the whole penetration phase were significantly different for hard and soft clots (median values, 55.6 mN vs 15.4 mN, respectively; P<0.0001). The maximum slope of the force curves recorded during the advancement of the guidewire for the first 3 s of penetration also significantly differentiated soft from hard clot analogs (7.6 mN/s vs 23.9 mN/s, respectively; P<0.0001). In addition, the qualitative analysis of the shape of the force curves obtained during the advancement and retrieval of the guidewire showed a good potential for the identification of the proximal and distal edges of the clot analogs. CONCLUSION: Our results demonstrated that it was possible to differentiate between soft and hard clot analogs. Furthermore, force measurements could give important information about the location of the clot extremities. Such an approach might support the selection of the first-line MTB technique, with the potential to improve the outcome.

Long-term neuropsychiatric complications of aneurysmal subarachnoid hemorrhage: a narrative review.

This review focuses on the often-neglected long-term neuropsychiatric consequences of aneurysmal subarachnoid hemorrhage (aSAH), beyond traditional randomized trial outcomes of mortality and retreatment. While current guidelines recommend screening for these sequalae, it may not be routinely practiced. This review will underscore the prevalence and management of common neuropsychiatric sequalae, including anxiety, depression, cognitive dysfunction, headaches, seizures, and sexual dysfunction, all of which can significantly impact the quality of life of survivors of aSAH. We emphasize the critical role neurointerventionalists can play by going beyond the customary practice of radiological monitoring for treated aneurysms by screening for and helping guide management of these common neuropsychiatric complications.

Stent-assisted Woven EndoBridge embolization for the treatment of pulsatile tinnitus caused by an ipsilateral high-riding jugular bulb.

PURPOSE: Pulsatile tinnitus can be caused by a high-riding jugular bulb (HRJB), characterized by the superior position of the jugular bulb in the petrous temporal bone. The anatomical position and morphology of this entity make it challenging for endovascular treatment. We report our experience with two patients successfully treated with a stent-assisted Woven EndoBridge (WEB; Microvention, Tustin, CA, USA) device. MATERIALS AND METHODS: We describe two cases of HRJB in patients presenting with disabling pulsatile tinnitus. Temporary balloon occlusion of the jugular bulb prior to the intervention reduced tinnitus intensity. Both patients were subsequently treated under general anesthesia with the WEB device deployed in the HRJB which was held by a stent deployed in the sigmoid sinus. RESULTS: Both procedures were successful with good positioning of the WEB device and no procedural complications. Both patients had complete resolution of pulsatile tinnitus immediately after the procedure. Follow-up imaging showed successful occlusion of the venous cavity with a widely patent stent. CONCLUSION: Among patients with pulsatile tinnitus caused by an ipsilateral HRJB, a stent-assisted WEB device seems to be a viable endovascular option with angiographic and clinical success.

Outcomes with General Anesthesia Compared to Conscious Sedation for Endovascular Treatment of Medium Vessel Occlusions: Results of an International Multicentric Study.

BACKGROUND: Optimal anesthetic strategy for the endovascular treatment of stroke is still under debate. Despite scarce data concerning anesthetic management for medium and distal vessel occlusions (MeVOs) some centers empirically support a general anesthesia (GA) strategy in these patients. METHODS: We conducted an international retrospective study of MeVO cases. A propensity score matching algorithm was used to mitigate potential differences across patients undergoing GA and conscious sedation (CS). Comparisons in clinical and safety outcomes were performed between the two study groups GA and CS. The favourable outcome was defined as a modified Rankin Scale (mRS) 0-2 at 90 days. Safety outcomes were 90-days mortality and symptomatic intracranial hemorrhage (sICH). Predictors of a favourable outcome and sICH were evaluated with backward logistic regression. RESULTS: After propensity score matching 668 patients were included in the CS and 264 patients in the GA group. In the matched cohort, either strategy CS or GA resulted in similar rates of good functional outcomes (50.1% vs. 48.4%), and successful recanalization (89.4% vs. 90.2%). The GA group had higher rates of 90-day mortality (22.6% vs. 16.5%, p < 0.041) and sICH (4.2% vs. 0.9%, p = 0.001) compared to the CS group. Backward logistic regression did not identify GA vs CS as a predictor of good functional outcome (OR for GA vs CS = 0.95 (0.67-1.35)), but GA remained a significant predictor of sICH (OR = 5.32, 95% CI 1.92-14.72). CONCLUSION: Anaesthetic strategy in MeVOs does not influence favorable outcomes or final successful recanalization rates, however, GA may be associated with an increased risk of sICH and mortality.

Safety and effectiveness assessment of the surpass evolve (SEASE): a post-market international multicenter study.

BACKGROUND: Flow diverters are the first-line treatment for specific intracranial aneurysms (iA). Surpass Evolve (SE) is a new-generation 64-wire flow diverter with a high braid angle. Current literature on the SE is limited. We aimed to report the first international real-world experience evaluating the safety and effectiveness of the SE. METHODS: The Safety and Effectiveness Assessment of the Surpass Evolve (SEASE) was a multicenter retrospective international post-marketing cohort study including consecutive patients treated with SE for iAs between 2020 and 2022. Demographic, clinical, and angiographic data were collected. Primary effectiveness was independent core lab adjudicated complete occlusion rates (Raymond-Roy Class 1) at last follow-up. Primary safety were major ischemic/hemorrhagic events and mortality. RESULTS: In total, 305 patients with 332 aneurysms underwent SE implantation. The patients had a median age of 59 [50-67] years, and 256 (83.9%) were female. The baseline modified Rankin scale score was 0-2 in 291 patients (96.7%). Most aneurysms were unruptured (285, 93.4%) and saccular (309, 93.1%). Previous treatment was present in 76 (22.9%) patients. The median aneurysm size was 5.1 [3.4-9.0] mm, and the median neck width was 3.6 [2.7-5.1] mm. Most aneurysms were in the internal carotid artery C6 ophthalmic segment (126, 38.0%), followed by the communicating segment (58, 17.5%). At median 10.2 [6.4-12.9] months follow-up, 233 (73.0%) aneurysms achieved complete occlusion. After adjusting for confounders, complete occlusion remained consistent. Major stroke and procedure-related mortality were reported in 6 (2%) and 2 (0.7%) cases, respectively. CONCLUSION: These results demonstrate that SE has a consistently high effectiveness and favorable safety for the treatment of iAs.

ARISE I Consensus Statement on the Management of Chronic Subdural Hematoma.

ARISE (Aneurysm/AVM/cSDH Roundtable Discussion With Industry and Stroke Experts) organized a one-and-a-half day meeting and workshop and brought together representatives from academia, industry, and government to discuss the most promising approaches to improve outcomes for patients with chronic subdural hematoma (cSDH). The emerging role of middle meningeal artery embolization in clinical practice and the design of current and potential future trials were the primary focuses of discussion. Existing evidence for imaging, indications, agents, and techniques was reviewed, and areas of priority for study and key questions surrounding the development of new and existing treatments for cSDH were identified. Multiple randomized, controlled trials have met their primary efficacy end points, providing high-level evidence that middle meningeal artery embolization is a potent adjunctive therapy to the standard (surgical and nonsurgical) management of neurologically stable cSDH patients in terms of reducing rates of disease recurrence. Pooled data analyses following the formal conclusion and publication of these trials will form a robust foundation upon which guidelines can be strengthened for cSDH treatment modalities and optimal patient selection, as well as delineate future lines of investigation.

The feasibility of mechanical thrombectomy versus medical management for acute stroke with a large ischemic territory.

BACKGROUND: Mechanical thrombectomy (MT) for acute ischemic stroke is generally avoided when the expected infarction is large (defined as an Alberta Stroke Program Early CT Score of <6). OBJECTIVE: To perform a meta-analysis of recent trials comparing MT with best medical management (BMM) for treatment of acute ischemic stroke with large infarction territory, and then to determine the cost-effectiveness associated with those treatments. METHODS: A meta-analysis of the RESCUE-Japan, SELECT2, and ANGEL-ASPECT trials was conducted using R Studio. Statistical analysis employed the weighted average normal method for calculating mean differences from medians in continuous variables and the risk ratio for categorical variables. TreeAge software was used to construct a cost-effectiveness analysis model comparing MT with BMM in the treatment of ischemic stroke with large infarction territory. RESULTS: The meta-analysis showed significantly better functional outcomes, with higher rates of patients achieving a modified Rankin Scale score of 0-3 at 90 days with MT as compared with BMM. In the base-case analysis using a lifetime horizon, MT led to a greater gain in quality-adjusted life-years (QALYs) of 3.46 at a lower cost of US$339 202 in comparison with BMM, which led to the gain of 2.41 QALYs at a cost of US$361 896. The incremental cost-effectiveness ratio was US$-21 660, indicating that MT was the dominant treatment at a willingness-to-pay of US$70 000. CONCLUSIONS: This study shows that, besides having a better functional outcome at 90-days' follow-up, MT was more cost-effective than BMM, when accounting for healthcare cost associated with treatment outcome.

Clinical relevance of intracranial hemorrhage after thrombectomy versus medical management for large core infarct: a secondary analysis of the SELECT2 randomized trial.

BACKGROUND: The incidence of intracerebral hemorrhage (ICH) and its effect on the outcomes after endovascular thrombectomy (EVT) for patients with large core infarcts have not been well-characterized. METHODS: SELECT2 trial follow-up imaging was evaluated using the Heidelberg Bleeding Classification (HBC) to define hemorrhage grade. The association of ICH with clinical outcomes and treatment effect was examined. RESULTS: Of 351 included patients, 194 (55%) and 189 (54%) demonstrated intracranial and intracerebral hemorrhage, respectively, with a higher incidence in EVT (134 (75%) and 130 (73%)) versus medical management (MM) (60 (35%) and 59 (34%), both P<0.001). Hemorrhagic infarction type 1 (HBC=1a) and type 2 (HBC=1b) accounted for 93% of all hemorrhages. Parenchymal hematoma (PH) type 1 (HBC=1c) and type 2 (HBC=2) were observed in 1 (0.6%) EVT-treated and 4 (2.2%) MM patients. Symptomatic ICH (sICH) (SITS-MOST definition) was seen in 0.6% EVT patients and 1.2% MM patients. No trend for ICH with core volumes (P=0.10) or Alberta Stroke Program Early CT Score (ASPECTS) (P=0.74) was observed. Among EVT patients, the presence of any ICH did not worsen clinical outcome (modified Rankin Scale (mRS) at 90 days: 4 (3-6) vs 4 (3-6); adjusted generalized OR 1.00, 95% CI 0.68 to 1.47, P>0.99) or modify EVT treatment effect (Pinteraction=0.77). CONCLUSIONS: ICH was present in 75% of the EVT population, but PH or sICH were infrequent. The presence of any ICH did not worsen functional outcomes or modify EVT treatment effect at 90-day follow-up. The high rate of hemorrhages overall still represents an opportunity for adjunctive therapies in EVT patients with a large ischemic core.

Clinical uncertainty in large vessel occlusion ischemic stroke: does automated perfusion imaging make a difference? An intra-rater and inter-rater agreement study.

BACKGROUND: Limited research exists regarding the impact of neuroimaging on endovascular thrombectomy (EVT) decisions for late-window cases of large vessel occlusion (LVO) stroke. OBJECTIVE: T0 assess whether perfusion CT imaging: (1) alters the proportion of recommendations for EVT, and (2) enhances the reliability of EVT decision-making compared with non-contrast CT and CT angiography. METHODS: We conducted a survey using 30 patients drawn from an institutional database of 3144 acute stroke cases. These were presented to 29 Canadian physicians with and without perfusion imaging. We used non-overlapping 95% confidence intervals and difference in agreement classification as criteria to suggest a difference between the Gwet AC1 statistics (κG). RESULTS: The percentage of EVT recommendations differed by 1.1% with or without perfusion imaging. Individual decisions changed in 21.4% of cases (11.3% against EVT and 10.1% in favor). Inter-rater agreement (κG) among the 29 raters was similar between non-perfusion and perfusion CT neuroimaging (κG=0.487; 95% CI 0.327 to 0.647 and κG=0.552; 95% CI 0.430 to 0.675). The 95% CIs overlapped with moderate agreement in both. Intra-rater agreement exhibited overlapping 95% CIs for all 28 raters. κG was either substantial or excellent (0.81-1) for 71.4% (20/28) of raters in both groups. CONCLUSIONS: Despite the minimal difference in overall EVT recommendations with either neuroimaging protocol one in five decisions changed with perfusion imaging. Regarding agreement we found that the use of automated CT perfusion images does not significantly impact the reliability of EVT decisions for patients with late-window LVO.

Early versus late cardiac magnetic resonance in the diagnosis of MINOCA.

INTRODUCTION AND OBJECTIVES: Myocardial infarction with non-obstructive coronary arteries (MINOCA) is responsible for about 10% of all acute myocardial infarctions (AMI). Therapeutic strategies and prognosis depend on the underlying etiology, and a multimodal approach is essential. Characterize the group of patients diagnosed with MINOCA. Evaluate the diagnostic yield of cardiovascular magnetic resonance (CMR). METHODS: This was a retrospective, observational, and analytical study, including 516 patients admitted for a non-ST-elevation MI and with no significant coronary disease on coronary angiography between January 2016 and September 2021. RESULTS: After the inclusion criteria, 163 patients remained of the 516 admitted to the study. They were divided into four groups based on the CMR results: MINOCA (n=51), Takotsubo syndrome (n=37), myocarditis (n=33), and without diagnosis (n=42). Most patients diagnosed with MINOCA were female with a mean age of 61.06±13.83 years. CMR identified the diagnosis in 74.2% of patients admitted for suspected acute MI, in which coronary angiography showed the absence of significant obstructions. The median time between hospital admission and CMR was significantly shorter in the groups that had a diagnosis compared with the group with no diagnosis (p=0.038), with a significant increase in diagnostic profitability if CMR was performed up to 14 days after admission (p=0.022). There were no deaths of cardiovascular etiology during the follow-up period. CONCLUSIONS: CMR was fundamental as it identified the diagnosis in three out of four patients; it should be performed in the first 14 days.

Reconstruction of cell-specific models capturing the influence of metabolism on DNA methylation in cancer.

The imbalance of epigenetic regulatory mechanisms such as DNA methylation, which can promote aberrant gene expression profiles without affecting the DNA sequence, may cause the deregulation of signaling, regulatory, and metabolic processes, contributing to a cancerous phenotype. Since some metabolites are substrates and cofactors of epigenetic regulators, their availability can be affected by characteristic cancer cell metabolic shifts, feeding cancer onset and progression through epigenetic deregulation. Hence, there is a need to study the influence of cancer metabolic reprogramming in DNA methylation to design new effective treatments. In this study, a generic Genome-Scale Metabolic Model (GSMM) of a human cell, integrating DNA methylation or demethylation reactions, was obtained and used for the reconstruction of Genome-Scale Metabolic Models enhanced with Enzymatic Constraints using Kinetic and Omics data (GECKOs) of 31 cancer cell lines. Furthermore, cell-line-specific DNA methylation levels were included in the models, as coefficients of a DNA composition pseudo-reaction, to depict the influence of metabolism over global DNA methylation in each of the cancer cell lines. Flux simulations demonstrated the ability of these models to provide simulated fluxes of exchange reactions similar to the equivalent experimentally measured uptake/secretion rates and to make good functional predictions. In addition, simulations found metabolic pathways, reactions and enzymes directly or inversely associated with the gene promoter methylation. Two potential candidates for targeted cancer epigenetic therapy were identified.

Enterobacteria in anaerobic digestion of dairy cattle wastewater: Assessing virulence and resistance for one health security.

Samples from a dairy cattle waste-fed anaerobic digester were collected across seasons to assess sanitary safety for biofertilizer use. Isolated enterobacteria (suggestive of Escherichia coli) were tested for susceptibility to biocides, antimicrobials, and biofilm-forming capability. Results revealed a decrease in total bacteria, coliforms, and enterobacteria in biofertilizer compared to the effluent. Among 488 isolates, 98.12 % exhibited high biofilm formation. Biofertilizer isolates exhibited a similar biofilm formation capability as effluent isolates in summer, but greater propensity in winter. Resistance to biocides and antimicrobials varied, with tetracycline resistance reaching 19 %. Of the isolates, 25 were multidrug-resistant (MDR), with 64 % resistant to three drugs. Positive correlations were observed between MDR and increased biofilm formation capacity in both samples, while there was negative correlation between MDR and increased biocide resistance. A higher number of MDR bacteria were found in biofertilizer compared to the effluent, revealing the persistence of E. coli resistance, posing challenges to food safety and public health.

Endovascular thrombectomy plus medical care versus medical care alone for large ischaemic stroke: 1-year outcomes of the SELECT2 trial.

BACKGROUND: Multiple randomised trials have shown efficacy and safety of endovascular thrombectomy in patients with large ischaemic stroke. The aim of this study was to evaluate long-term (ie, at 1 year) evidence of benefit of thrombectomy for these patients. METHODS: SELECT2 was a phase 3, open-label, international, randomised controlled trial with blinded endpoint assessment, conducted at 31 hospitals in the USA, Canada, Spain, Switzerland, Australia, and New Zealand. Patients aged 18-85 years with ischaemic stroke due to proximal occlusion of the internal carotid artery or of the first segment of the middle cerebral artery, showing large ischaemic core on non-contrast CT (Alberta Stroke Program Early Computed Tomographic Score of 3-5 [range 0-10, with lower values indicating larger infarctions]) or measuring 50 mL or more on CT perfusion and MRI, were randomly assigned, within 24 h of ischaemic stroke onset, to thrombectomy plus medical care or to medical care alone. The primary outcome for this analysis was the ordinal modified Rankin Scale (range 0-6, with higher scores indicating greater disability) at 1-year follow-up in an intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT03876457) and is completed. FINDINGS: The trial was terminated early for efficacy at the 90-day follow-up after 352 patients had been randomly assigned (178 to thrombectomy and 174 to medical care only) between Oct 11, 2019, and Sept 9, 2022. Thrombectomy significantly improved the 1-year modified Rankin Scale score distribution versus medical care alone (Wilcoxon-Mann-Whitney probability of superiority 0·59 [95% CI 0·53-0·64]; p=0·0019; generalised odds ratio 1·43 [95% CI 1·14-1·78]). At the 1-year follow-up, 77 (45%) of 170 patients receiving thrombectomy had died, compared with 83 (52%) of 159 patients receiving medical care only (1-year mortality relative risk 0·89 [95% CI 0·71-1·11]). INTERPRETATION: In patients with ischaemic stroke due to a proximal occlusion and large core, thrombectomy plus medical care provided a significant functional outcome benefit compared with medical care alone at 1-year follow-up. FUNDING: Stryker Neurovascular.

Cost-Effectiveness of Late Endovascular Thrombectomy vs. Best Medical Management in a Clinical Trial Setting and Real-World Setting.

BACKGROUND AND PURPOSE: To assess cost-effectiveness of late time-window endovascular treatment (EVT) in a clinical trial setting and a "real-world" setting. METHODS: Data are from the randomized ESCAPE trial and a prospective cohort study (ESCAPE-LATE). Anterior circulation large vessel occlusion patients presenting > 6 hours from last-known-well were included, whereby collateral status was an inclusion criterion for ESCAPE but not ESCAPE-LATE. A Markov state transition model was built to estimate lifetime costs and quality-adjusted life-years (QALYs) for EVT in addition to best medical care vs. best medical care only in a clinical trial setting (comparing ESCAPE-EVT to ESCAPE control arm patients) and a "real-world" setting (comparing ESCAPE-LATE to ESCAPE control arm patients). We performed an unadjusted analysis, using 90-day modified Rankin Scale(mRS) scores as model input and analysis adjusted for baseline factors. Acceptability of EVT was calculated using upper/lower willingness-to-pay thresholds of 100,000 USD/50,000 USD/QALY. RESULTS: Two-hundred and forty-nine patients were included (ESCAPE-LATE:n = 200, ESCAPE EVT-arm:n = 29, ESCAPE control-arm:n = 20). Late EVT in addition to best medical care was cost effective in the unadjusted analysis both in the clinical trial and real-world setting, with acceptability 96.6%-99.0%. After adjusting for differences in baseline variables between the groups, late EVT was marginally cost effective in the clinical trial setting (acceptability:49.9%-61.6%), but not the "real-world" setting (acceptability:32.9%-42.6%). CONCLUSION: EVT for LVO-patients presenting beyond 6 hours was cost effective in the clinical trial setting and "real-world" setting, although this was largely related to baseline patient differences favoring the "real-world" EVT group. After adjusting for these, EVT benefit was reduced in the trial setting, and absent in the real-world setting.