Impact of Asthma Medications During Pregnancy on Asthma Exacerbation, Maternal, and Neonatal Outcomes.

BACKGROUND: Asthma affects 5% to 13% of pregnant women, and many require daily pharmacotherapy to achieve asthma control; however, adherence to medication during pregnancy often decreases. OBJECTIVE: To understand the association between the use of or adherence to asthma medication with asthma exacerbation and maternal/neonatal outcomes. METHODS: Using linked population-based administrative databases from Alberta, Canada (2012-2018), pregnant women with asthma were categorized based on asthma medication use 1 year before pregnancy: short-acting ß-agonists (SABA), inhaled corticosteroids (ICS), and ICS with long-acting ß-agonists (ICS+LABA). Women on ICS+LABA were grouped by trajectory of adherence during pregnancy using group-based trajectory modeling. Logistic regressions were used to estimate the associations between the use of or trajectories of adherence to asthma medication during pregnancy with asthma exacerbation and maternal/neonatal outcomes. RESULTS: Overall, 13,509 of 238,751 (5.7%) pregnant women had asthma before pregnancy (SABA: 24.7%; ICS: 12.5%; ICS+LABA: 25.1%; none: 36.1%). The use of SABA (adjusted odds ratio [aOR]: 1.79, 95% confidence interval [CI]: 1.21, 2.64), ICS (aOR: 3.37, 95% CI: 2.10, 5.39), and ICS+LABA (aOR: 3.64, 95% CI: 2.57, 5.17) had greater odds of disease exacerbation than no asthma medication during pregnancy. ICS+LABA adherence groups during pregnancy included low (79.8%), moderate-to-decreasing (14.0%), and moderate-to-increasing (6.2%). The moderate-to-decreasing (aOR: 1.45, 95% CI: 1.14, 1.84) and moderate-to-increasing (aOR: 2.06, 95% CI: 1.50, 2.83) adherence groups had greater odds of disease exacerbation than the low adherence group. ICS use during pregnancy decreased odds of preterm birth (aOR: 0.62; 95% CI: 0.39, 0.99) and neonatal intensive care unit admission (aOR: 0.66; 95% CI: 0.45, 0.97). Other group comparisons were not statistically significant. CONCLUSIONS: Our study shows the importance of continuing asthma maintenance medication during pregnancy to improve outcomes. Future research should study the postpartum and long-term outcomes with asthma medication during pregnancy.

Prolonged venous transit on perfusion imaging is associated with higher odds of mortality in successfully reperfused patients with large vessel occlusion stroke.

BACKGROUND: Poor venous outflow (VO) profiles are associated with unfavorable outcomes in patients with acute ischemic stroke caused by large vessel occlusion (AIS-LVO), despite achieving successful reperfusion. The objective of this study is to assess the association between mortality and prolonged venous transit (PVT), a novel visual qualitative VO marker on CT perfusion (CTP) time to maximum (Tmax) maps. METHODS: We performed a retrospective analysis of prospectively collected data from consecutive adult patients with AIS-LVO with successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b/2c/3). PVT+ was defined as Tmax ≥10 s timing on CTP Tmax maps in at least one of the following: superior sagittal sinus (proximal venous drainage) and/or torcula (deep venous drainage). PVT- was defined as lacking this in both regions. The primary outcome was mortality at 90 days. In a 1:1 propensity score-matched cohort, regressions were performed to determine the effect of PVT on 90-day mortality. RESULTS: In 127 patients of median (IQR) age 71 (64-81) years, mortality occurred in a significantly greater proportion of PVT+ patients than PVT- patients (32.5% vs 12.6%, P=0.01). This significant difference persisted after matching (P=0.03). PVT+ was associated with a significantly increased likelihood of 90-day mortality (OR 1.22 (95% CI 1.02 to 1.46), P=0.03) in the matched cohort. CONCLUSIONS: PVT+ was significantly associated with 90-day mortality despite successful reperfusion therapy in patients with AIS-LVO. PVT is a simple VO profile marker with potential as an adjunctive metric during acute evaluation of AIS-LVO patients. Future studies will expand our understanding of using PVT in the evaluation of patients with AIS-LVO.

Redefining CT perfusion-based ischemic core estimates for the ghost core in early time window stroke.

BACKGROUND AND PURPOSE: In large vessel occlusion (LVO) stroke patients, relative cerebral blood flow (rCBF)<30% volume thresholds are commonly used in treatment decisions. In the early time window, nearly infarcted but salvageable tissue volumes may lead to pretreatment overestimates of infarct volume, and thus potentially exclude patients who may otherwise benefit from intervention. Our multisite analysis aims to explore the strength of relationships between widely used pretreatment CT parameters and clinical outcomes for early window stroke patients. METHODS: Patients from two sites in a prospective registry were analyzed. Patients with LVOs, presenting within 3 hours of last known well, and who were successfully reperfused were included. Primary short-term neurological outcome was percent National Institutes of Health Stroke Scale (NIHSS) change from admission to discharge. Secondary long-term outcome was 90-day modified Rankin score. Spearman's correlations were performed. Significance was attributed to p-value ≤.05. RESULTS: Among 73 patients, median age was 66 (interquartile range 54-76) years. Among all pretreatment imaging parameters, rCBF<30%, rCBF<34%, and rCBF<38% volumes were significantly, inversely correlated with percentage NIHSS change (p<.048). No other parameters significantly correlated with outcomes. CONCLUSIONS: Our multisite analysis shows that favorable short-term neurological recovery was significantly correlated with rCBF volumes in the early time window. However, modest strength of correlations provides supportive evidence that the applicability of general ischemic core estimate thresholds in this subpopulation is limited. Our results support future larger-scale efforts to liberalize or reevaluate current rCBF parameter thresholds guiding treatment decisions for early time window stroke patients.

Pretreatment parameters associated with hemorrhagic transformation among successfully recanalized medium vessel occlusions.

Although pretreatment radiographic biomarkers are well established for hemorrhagic transformation (HT) following successful mechanical thrombectomy (MT) in large vessel occlusion (LVO) strokes, they are yet to be explored for medium vessel occlusion (MeVO) acute ischemic strokes. We aim to investigate pretreatment imaging biomarkers representative of collateral status, namely the hypoperfusion intensity ratio (HIR) and cerebral blood volume (CBV) index, and their association with HT in successfully recanalized MeVOs. A prospectively collected registry of acute ischemic stroke patients with MeVOs successfully recanalized with MT between 2019 and 2023 was retrospectively reviewed. A multivariate logistic regression for HT of any subtype was derived by combining significant univariate predictors into a forward stepwise regression with minimization of Akaike information criterion. Of 60 MeVO patients successfully recanalized with MT, HT occurred in 28.3% of patients. Independent factors for HT included: diabetes mellitus history (p = 0.0005), CBV index (p = 0.0071), and proximal versus distal occlusion location (p = 0.0062). A multivariate model with these factors had strong diagnostic performance for predicting HT (area under curve [AUC] 0.93, p < 0.001). Lower CBV indexes, distal occlusion location, and diabetes history are significantly associated with HT in MeVOs successfully recanalized with MT. Of note, HIR was not found to be significantly associated with HT.

Pretreatment CTP Collateral Parameters Predict Good Outcomes in Successfully Recanalized Middle Cerebral Artery Distal Medium Vessel Occlusions.

BACKGROUND/PURPOSE: Distal medium vessel occlusions (DMVOs) account for a large percentage of vessel occlusions resulting in acute ischemic stroke (AIS) with disabling symptoms. We aim to assess whether pretreatment quantitative CTP collateral status (CS) parameters can serve as imaging biomarkers for good clinical outcomes prediction in successfully recanalized middle cerebral artery (MCA) DMVOs. METHODS: We performed a retrospective analysis of consecutive patients with AIS secondary to primary MCA-DMVOs who were successfully recanalized by mechanical thrombectomy (MT) defined as modified thrombolysis in cerebral infarction (mTICI) 2b, 2c, or 3. We evaluated the association between the CBV index and HIR independently with good clinical outcomes (modified Rankin score 0-2) using Spearman rank correlation, logistic regression, and ROC analyses. RESULTS: From 22 August 2018 to 18 October 2022 8/22/2018 to 10/18/2022, 60 consecutive patients met our inclusion criteria (mean age 71.2 ± 13.9 years old [mean ± SD], 35 female). The CBV index (r = -0.693, p < 0.001) and HIR (0.687, p < 0.001) strongly correlated with 90-day mRS. A CBV index ≥ 0.7 (odds ratio, OR, 2.27, range 6.94-21.23 [OR] 2.27 [6.94-21.23], p = 0.001)) and lower likelihood of prior stroke (0.13 [0.33-0.86]), p = 0.024)) were independently associated with good outcomes. The ROC analysis demonstrated good performance of the CBV index in predicting good 90-day mRS (AUC 0.73, p = 0.003) with a threshold of 0.7 for optimal sensitivity (71% [52.0-85.8%]) and specificity (76% [54.9-90.6%]). The HIR also demonstrated adequate performance in predicting good 90-day mRS (AUC 0.77, p = 0.001) with a threshold of 0.3 for optimal sensitivity (64.5% [45.4-80.8%]) and specificity (76.0% [54.9-90.6%]). CONCLUSION: A CBV index ≥ 0.7 may be independently associated with good clinical outcomes in our cohort of AIS caused by MCA-DMVOs that were successfully treated with MT. Furthermore, a HIR < 0.3 is also associated with good clinical outcomes. This is the first study of which we are aware to identify a CBV index threshold for MCA-DMVOs.

Diffusion tensor free water MRI predicts progression of FLAIR white matter hyperintensities after ischemic stroke.

Background: The progression of FLAIR white matter hyperintensities (WMHs) on MRI heralds vascular-mediated cognitive decline. Even before FLAIR WMH progression, adjacent normal appearing white matter (NAWM) already demonstrates microstructural deterioration on diffusion tensor imaging (DTI). We hypothesized that elevated DTI free water (FW) would precede FLAIR WMH progression, implicating interstitial fluid accumulation as a key pathological step in the progression of cerebral small vessel disease. Methods: Participants at least 3 months after an ischemic stroke or TIA with WMH on MRI underwent serial brain MRIs every 3 months over the subsequent year. For each participant, the WMHs were automatically segmented, serial MRIs were aligned, and a region of WMH penumbra tissue at risk was defined by dilating lesions at any time point and subtracting baseline lesions. Penumbra voxels were classified as either stable or progressing to WMH if they were segmented as new lesions and demonstrated increasing FLAIR intensity over time. Aligned DTI images included FW and FW-corrected fractional anisotropy (FATissue) and mean diffusivity (MDTissue). Logistic regression and area under the receiver-operator characteristic curve (AUC) were used to test whether baseline DTI predicted voxel-wise classification of stable penumbra or progression to WMH while covarying for clinical risk factors. Results: In the included participants (n = 26, mean age 71 ± 9 years, 31% female), we detected a median annual voxel-wise WMH growth of 2.9 ± 2.6 ml. Each baseline DTI metric was associated with lesion progression in the penumbra, but FW had the greatest AUC of 0.732 (0.730 - 0.733) for predicting voxel-wise WMH progression pooled across participants. Discussion: Baseline increased interstitial fluid, estimated as FW on DTI, predicted the progression of NAWM to WMH over the following year. These results implicate the presence of FW in the pathogenesis of cerebral small vessel disease progression.

Synergy between Interleukin-1ß, Interferon-γ, and Glucocorticoids to Induce TLR2 Expression Involves NF-κB, STAT1, and the Glucocorticoid Receptor.

Glucocorticoids act via the glucocorticoid receptor (GR; NR3C1) to downregulate inflammatory gene expression and are effective treatments for mild to moderate asthma. However, in severe asthma and virus-induced exacerbations, glucocorticoid therapies are less efficacious, possibly due to reduced repressive ability and/or the increased expression of proinflammatory genes. In human A549 epithelial and primary human bronchial epithelial cells, toll-like receptor (TLR)-2 mRNA and protein were supra-additively induced by interleukin-1ß (IL-1ß) plus dexamethasone (IL-1ß+Dex), interferon-γ (IFN-γ) plus dexamethasone (IFN-γ+Dex), and IL-1ß plus IFN-γ plus dexamethasone (IL-1ß+IFN-γ+Dex). Indeed, ∼34- to 2100-fold increases were apparent at 24 hours for IL-1ß+IFN-γ+Dex, and this was greater than for any single or dual treatment. Using the A549 cell model, TLR2 induction by IL-1ß+IFN-γ+Dex was antagonized by Org34517, a competitive GR antagonist. Further, when combined with IL-1ß, IFN-γ, or IL-1ß+IFN-γ, the enhancements by dexamethasone on TLR2 expression required GR. Likewise, inhibitor of κB kinase 2 inhibitors reduced IL-1ß+IFN-γ+Dex-induced TLR2 expression, and TLR2 expression induced by IL-1ß+Dex, with or without IFN-γ, required the nuclear factor (NF)-κB subunit, p65. Similarly, signal transducer and activator of transcription (STAT)-1 phosphorylation and γ-interferon-activated sequence-dependent transcription were induced by IFN-γ These, along with IL-1ß+IFN-γ+Dex-induced TLR2 expression, were inhibited by Janus kinase (JAK) inhibitors. As IL-1ß+IFN-γ+Dex-induced TLR2 expression also required STAT1, this study reveals cooperation between JAK-STAT1, NF-κB, and GR to upregulate TLR2 expression. Since TLR2 agonism elicits inflammatory responses, we propose that synergies involving TLR2 may occur within the cytokine milieu present in the immunopathology of glucocorticoid-resistant disease, and this could promote glucocorticoid resistance. SIGNIFICANCE STATEMENT: This study highlights that in human pulmonary epithelial cells, glucocorticoids, when combined with the inflammatory cytokines interleukin-1ß (IL-1ß) and interferon-γ (IFN-γ), can synergistically induce the expression of inflammatory genes, such as TLR2. This effect involved positive combinatorial interactions between NF-κB/p65, glucocorticoid receptor, and JAK-STAT1 signaling to synergistically upregulate TLR2 expression. Thus, synergies involving glucocorticoid enhancement of TLR2 expression may occur in the immunopathology of glucocorticoid-resistant inflammatory diseases, including severe asthma.

A large public dataset of annotated clinical MRIs and metadata of patients with acute stroke.

To extract meaningful and reproducible models of brain function from stroke images, for both clinical and research proposes, is a daunting task severely hindered by the great variability of lesion frequency and patterns. Large datasets are therefore imperative, as well as fully automated image post-processing tools to analyze them. The development of such tools, particularly with artificial intelligence, is highly dependent on the availability of large datasets to model training and testing. We present a public dataset of 2,888 multimodal clinical MRIs of patients with acute and early subacute stroke, with manual lesion segmentation, and metadata. The dataset provides high quality, large scale, human-supervised knowledge to feed artificial intelligence models and enable further development of tools to automate several tasks that currently rely on human labor, such as lesion segmentation, labeling, calculation of disease-relevant scores, and lesion-based studies relating function to frequency lesion maps.

Automatic comprehensive radiological reports for clinical acute stroke MRIs.

BACKGROUND: Although artificial intelligence systems that diagnosis among different conditions from medical images are long term aims, specific goals for automation of human-labor, time-consuming tasks are not only feasible but equally important. Acute conditions that require quantitative metrics, such as acute ischemic strokes, can greatly benefit by the consistency, objectiveness, and accessibility of automated radiological reports. METHODS: We used 1,878 annotated brain MRIs to generate a fully automated system that outputs radiological reports in addition to the infarct volume, 3D digital infarct mask, and the feature vector of anatomical regions affected by the acute infarct. This system is associated to a deep-learning algorithm for segmentation of the ischemic core and to parcellation schemes defining arterial territories and classically-identified anatomical brain structures. RESULTS: Here we show that the performance of our system to generate radiological reports was comparable to that of an expert evaluator. The weight of the components of the feature vectors that supported the prediction of the reports, as well as the prediction probabilities are outputted, making the pre-trained models behind our system interpretable. The system is publicly available, runs in real time, in local computers, with minimal computational requirements, and it is readily useful for non-expert users. It supports large-scale processing of new and legacy data, enabling clinical and translational research. CONCLUSION: The generation of reports indicates that our fully automated system is able to extract quantitative, objective, structured, and personalized information from stroke MRIs.

Artificial intelligence (AI) uses computer software to solve problems that normally require human input. It is likely that AI will take over, or help with, certain tasks in medical imaging, particularly where these tasks are time-consuming and laborious for clinicians. Here, we demonstrate the possibility of using AI to generate radiological reports for brain scans from patients who have had a stroke. These reports provide a summary of what is shown in the scans, and are normally written by clinicians. Our system performs similarly to human experts, is fast, publicly available, and runs on normal computers with minimal computational requirements, meaning that it might be a useful tool for researchers and clinicians to use when assessing and treating patients with stroke.

Differential regulation of BIRC2 and BIRC3 expression by inflammatory cytokines and glucocorticoids in pulmonary epithelial cells.

Roles for the baculoviral inhibitor of apoptosis repeat-containing (BIRC) genes, BIRC2 and BIRC3, may include signaling to the inflammatory transcription factor, nuclear factor-κB (NF-κB) and protection from cell death. However, distinct functions for each BIRC are not well-delineated. Given roles for the epithelium in barrier function and host defence, BIRC2 and BIRC3 expression was characterized in pulmonary epithelial cell lines and primary human bronchial epithelial cells (pHBECs) grown as undifferentiated cells in submersion culture (SC) or as highly differentiated cells at air-liquid interface (ALI). In A549 cells, interleukin-1ß (IL1B) and tumor necrosis factor α (TNF) induced BIRC3 mRNA (~20-50-fold), with maximal protein expression from 6-24 h. Similar effects occurred in BEAS-2B and Calu-3 cells, as well as SC and ALI pHBECs. BIRC2 protein was readily detected in unstimulated cells, but was not markedly modulated by IL1B or TNF. Glucocorticoids (dexamethasone, budesonide) modestly increased BIRC3 mRNA and protein, but showed little effect on BIRC2 expression. In A549 cells, BIRC3 mRNA induced by IL1B was unchanged by glucocorticoids and showed supra-additivity with TNF-plus-glucocorticoid. Supra-additivity was also evident for IL1B-plus-budesonide induced-BIRC3 in SC and ALI pHBECs. Using A549 cells, IL1B- and TNF-induced BIRC3 expression, and to a lesser extent, BIRC2, was prevented by NF-κB inhibition. Glucocorticoid-induced BIRC3 expression was prevented by silencing and antagonism of the glucocorticoid receptor. Whereas TNF, but not IL1B, induced degradation of basal BIRC2 and BIRC3 protein, IL1B- and TNF-induced BIRC3 protein remained stable. Differential regulation by cytokines and glucocorticoids shows BIRC2 protein expression to be consistent with roles in rapid signaling events, whereas cytokine-induced BIRC3 may be more important in later effects. While TNF-induced degradation of both BIRCs may restrict their activity, cytokine-enhanced BIRC3 expression could prime for its function. Finally, shielding from glucocorticoid repression, or further enhancement by glucocorticoid, may indicate a key protective role for BIRC3.

Role of Brain Imaging in the Prediction of Intracerebral Hemorrhage Following Endovascular Therapy for Acute Stroke.

Currently most acute ischemic stroke patients presenting with a large vessel occlusion are treated with endovascular therapy (EVT), which results in high rates of successful recanalization. Despite this success, more than half of EVT-treated patients are significantly disabled 3 months later partly due to the occurrence of post-EVT intracerebral hemorrhage. Predicting post-EVT intracerebral hemorrhage is important for individualizing treatment strategies in clinical practice (eg, safe initiation of early antithrombotic therapies), as well as in selecting the optimal candidates for clinical trials that aim to reduce this deleterious outcome. Emerging data suggest that brain and vascular imaging biomarkers may be particularly relevant since they provide insights into the ongoing acute stroke pathophysiology. In this review/perspective, we summarize the accumulating literature on the role of cerebrovascular imaging biomarkers in predicting post-EVT-associated intracerebral hemorrhage. We focus on imaging acquired before EVT, during the EVT procedure, and in the early post-EVT time frames when new therapeutic therapies could be tested. Accounting for the complex pathophysiology of post-EVT-associated intracerebral hemorrhage, this review may provide some guidance for future prospective observational or therapeutic studies.

Canadian multidisciplinary expert consensus on the use of biologics in upper airways: a Delphi study.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) often coexists with lower airway disease. With the overlap between upper and lower airway disease, optimal management of the upper airways is undertaken in conjunction with that of the lower airways. Biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of both upper and lower airway diseases. Knowledge gaps nevertheless exist in how best to approach patient care as a whole. There have been sixteen randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL- 5R, IL-33, and immunoglobulin (Ig)E. This white paper considers the perspectives of experts in various disciplines such as rhinology, allergy, and respirology across Canada, all of whom have unique and valuable insights to contribute on how to best approach patients with upper airway disease from a multidisciplinary perspective. METHODS: A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. A national multidisciplinary expert panel of 34 certified specialists was created, composed of 16 rhinologists, 7 allergists, and 11 respirologists who evaluated the 20 original statements on a scale of 1-9 and provided comments. All ratings were quantitively reviewed by mean, median, mode, range, standard deviation and inter-rater reliability. Consensus was defined by relative interrater reliability measures-kappa coefficient ([Formula: see text]) value > 0.61. RESULTS: After three rounds, a total of 22 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with upper airway disease. CONCLUSION: This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of upper airway disease from a multidisciplinary perspective, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years.

Cost Analysis of a Transition Care Bundle Compared with Usual Care for COPD Patients Being Discharged from Hospital: Evaluation of a Randomized Controlled Trial.

BACKGROUND: Appropriate management of chronic obstructive pulmonary disease (COPD) patients following acute exacerbations can reduce the risk of future exacerbations, improve health status, and lower care costs. While a transition care bundle (TCB) was associated with lower readmissions to hospitals than usual care (UC), it remains unclear whether the TCB was associated with cost savings. OBJECTIVE: The aim of this study was to evaluate how this TCB was associated with future Emergency Department (ED)/outpatient visits, hospital readmissions, and costs in Alberta, Canada. METHODS: Patients who were aged 35 years or older, who were admitted to hospital for a COPD exacerbation, and had not been treated with a care bundle received either TCB or UC. Those who received the TCB were then randomized to either TCB alone or TCB enhanced with a care coordinator. Data collected were ED/outpatient visits, hospital admissions and associated resources used for index admissions, and 7-, 30- and 90-day post-index discharge. A decision model with a 90-day time horizon was developed to estimate the cost. A generalized linear regression was conducted to adjust for imbalance in patient characteristics and comorbidities, and a sensitivity analysis was conducted on the proportion of patients' combined ED/outpatient visits and inpatient admissions as well as the use of a care coordinator. RESULTS: Differences in length of stay (LOS) and costs between groups were statistically significant, although with some exceptions. Inpatient LOS and costs were 7.1 days (95% confidence interval [CI] 6.9-7.3) and Canadian dollars (CAN$) 13,131 (95% CI CAN$12,969-CAN$13,294) in UC, 6.1 days (95% CI 5.8-6.5) and CAN$7634 (95% CI CAN$7546-CAN$7722) in TCB with a coordinator, and 5.9 days (95% CI 5.6-6.2) and CAN$8080 (95% CI CAN$7975-CAN$8184) in TCB without a coordinator. Decision modelling indicated TCB was less costly than UC, with a mean (standard deviation [SD]) of CAN$10,172 (40) versus CAN$15,588 (85), and TCB with a coordinator was slightly less costly than without a coordinator (CAN$10,109 [49] versus CAN$10,244 [57]). CONCLUSION: This study suggests that the use of the TCB, with or without a care coordinator, appears to be an economically attractive intervention compared with UC.

Post-ischemic hyperemia following endovascular therapy for acute stroke is associated with lesion growth.

A substantial proportion of acute stroke patients fail to recover following successful endovascular therapy (EVT) and injury to the brain and vasculature secondary to reperfusion may be a contributor. Acute stroke patients were included with: i) large vessel occlusion of the anterior circulation, ii) successful recanalization, and iii) evaluable MRI early after EVT. Presence of hyperemia on MRI perfusion was assessed by consensus using a modified ASPECTS. Three different approaches were used to quantify relative cerebral blood flow (rCBF). Sixty-seven patients with median age of 66 [59-76], 57% female, met inclusion criteria. Hyperemia was present in 35/67 (52%) patients early post-EVT, in 32/65 (49%) patients at 24 hours, and in 19/48 (40%) patients at 5 days. There were no differences in incomplete reperfusion, HT, PH-2, HARM, severe HARM or symptomatic ICH rates between those with and without early post-EVT hyperemia. A strong association (R2 = 0.81, p < 0.001) was found between early post-EVT hyperemia (p = 0.027) and DWI volume at 24 hours after adjusting for DWI volume at 2 hours (p < 0.001) and incomplete reperfusion at 24 hours (p = 0.001). Early hyperemia is a potential marker for cerebrovascular injury and may help select patients for adjunctive therapy to prevent edema, reperfusion injury, and lesion growth.

Neuroimaging is the new "spatial omic": multi-omic approaches to neuro-inflammation and immuno-thrombosis in acute ischemic stroke.

Ischemic stroke (IS) is the leading cause of acquired disability and the second leading cause of dementia and mortality. Current treatments for IS are primarily focused on revascularization of the occluded artery. However, only 10% of patients are eligible for revascularization and 50% of revascularized patients remain disabled at 3 months. Accumulating evidence highlight the prognostic significance of the neuro- and thrombo-inflammatory response after IS. However, several randomized trials of promising immunosuppressive or immunomodulatory drugs failed to show positive results. Insufficient understanding of inter-patient variability in the cellular, functional, and spatial organization of the inflammatory response to IS likely contributed to the failure to translate preclinical findings into successful clinical trials. The inflammatory response to IS involves complex interactions between neuronal, glial, and immune cell subsets across multiple immunological compartments, including the blood-brain barrier, the meningeal lymphatic vessels, the choroid plexus, and the skull bone marrow. Here, we review the neuro- and thrombo-inflammatory responses to IS. We discuss how clinical imaging and single-cell omic technologies have refined our understanding of the spatial organization of pathobiological processes driving clinical outcomes in patients with an IS. We also introduce recent developments in machine learning statistical methods for the integration of multi-omic data (biological and radiological) to identify patient-specific inflammatory states predictive of IS clinical outcomes.

Inhaled anti-TSLP antibody fragment, ecleralimab, blocks responses to allergen in mild asthma.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma. METHODS: This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18-60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3-7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (F ENO) were secondary and exploratory end-points. RESULTS: 28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC3-7h by 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0-2h (p=0.097) and EAR% (p=0.105). F ENO levels were significantly reduced from baseline throughout the study (p<0.05), except at 24 h post-allergen (day 43 and day 85). Overall, ecleralimab was safe and well tolerated. CONCLUSION: Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.

Sounding the alarmins-The role of alarmin cytokines in asthma.

The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 are epithelial cell-derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen-induced responses including bronchoconstriction, airway hyperresponsiveness, and inflammation, and subsequent clinical trials of an anti-TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2-high and with T2-low asthma. Clinical trials blocking IL-33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates; however, the impact of blocking the IL-33/ST2 axis in T2-high versus T2-low asthma is unclear. To date, there is no evidence that IL-25 blockade is beneficial in asthma. Despite the considerable overlap in the cellular functions of IL-25, IL-33, and TSLP, they appear to have distinct roles in the immunopathology of asthma.

Amide proton transfer imaging in stroke.

Amide proton transfer (APT) imaging, a variant of chemical exchange saturation transfer MRI, has shown promise in detecting ischemic tissue acidosis following impaired aerobic metabolism in animal models and in human stroke patients due to the sensitivity of the amide proton exchange rate to changes in pH within the physiological range. Recent studies have demonstrated the possibility of using APT-MRI to detect acidosis of the ischemic penumbra, enabling the assessment of stroke severity and risk of progression, monitoring of treatment progress, and prognostication of clinical outcome. This paper reviews current APT imaging methods actively used in ischemic stroke research and explores the clinical aspects of ischemic stroke and future applications for these methods.

Excellent Recanalization and Small Core Volumes Are Associated With Favorable AM-PAC Score in Patients With Acute Ischemic Stroke Secondary to Large Vessel Occlusion.

Objective: To assess pretreatment and interventional parameters as predictors of favorable Activity Measure for Post-Acute Care (AM-PAC) scores for optimal discharge planning. Design: In this prospectively collected, retrospectively reviewed multicenter study from 9/1/2017 to 9/22/2022, patients were dichotomized into favorable and unfavorable AM-PAC. Multivariate logistic regression and receiver operator characteristics analyses were performed for the identified significant variables. A P value of ≤.05 was significant. Setting: Hospitalized care. Participants: In total, 229 patients (mean ±SD 70.65 ±15.2 [55.9% women]) met our inclusion criteria. Inclusion criteria were (a) computed tomography (CT) angiography confirmed LVO from 9/1/2017 to 9/22/2022; (b) diagnostic CT perfusion; and (c) available AM-PAC scores. Interventions: None. Main Outcome Measures: Favorable AM-PAC, defined as a daily activity score ≥19 and basic mobility score of ≥17. Results: Patients with favorable AM-PAC were younger (61.3 vs 70.7, P<.001), had lower admission glucose (mean, 124 vs 136, P=.042), lower blood urea nitrogen (mean, 15.59 vs 19.11, P<.001), and lower admission National Institutes of Health Stroke Scale (NIHSS) (mean, 10.58 vs 16.15, P<.001). No differences in sex were noted. Multivariate regression analyses revealed age, admission NIHSS, relative cerebral blood flow (rCBF) <30% volume, and modified thrombolysis in cerebral infarction (mTICI) score to be independent predictors of favorable AM-PAC (P<.047 for all predictors). The combined model revealed an area under the curve (AUC) of 0.83 (IQR 0.75-0.86). Conclusion: Excellent recanalization, smaller core volumes, younger age, and lower stroke severity independently predict favorable outcomes as measured by AM-PAC.