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Stroke is a leading cause of morbidity and mortality. The advent of mechanical thrombectomy has largely improved patient outcomes. This article reviews the features and outcomes associated with aspiration, stent retrievers, and combination catheters used in current practice. There is also a discussion on clinical considerations based on anatomical features and clot composition. The reperfusion grading scale and outcome metrics commonly used following thrombectomy when a patient is still in the hospital are reviewed. Lastly, there are proposed discharge and outpatient follow-up goals in caring for patients hospitalized for a stroke.

Background: It is unclear whether peripheral arterial cannulation is superior to central arterial cannulation for postcardiotomy veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Methods: A systematic review was conducted using PubMed, Scopus, and Google Scholar to identify studies on postcardiotomy VA-ECMO for the present individual patient data (IPD) meta-analysis. Analysis was performed according to the intention-to-treat principle. Results: The investigators of 10 studies agreed to participate in the present IPD meta-analysis. Overall, 1269 patients were included in the analysis. Crude rates of in-hospital mortality after central versus peripheral arterial cannulation for VA-ECMO were 70.7% vs. 63.7%, respectively (adjusted OR 1.38, 95% CI 1.08–1.75). Propensity score matching yielded 538 pairs of patients with balanced baseline characteristics and operative variables. Among these matched cohorts, central arterial cannulation VA-ECMO was associated with significantly higher in-hospital mortality compared to peripheral arterial cannulation VA-ECMO (64.5% vs. 70.8%, p = 0.027). These findings were confirmed by aggregate data meta-analysis, which showed that central arterial cannulation was associated with an increased risk of in-hospital mortality compared to peripheral arterial cannulation (OR 1.35, 95% CI 1.04–1.76, I2 21%). Conclusions: Among patients requiring postcardiotomy VA-ECMO, central arterial cannulation was associated with an increased risk of in-hospital mortality compared to peripheral arterial cannulation. This increased risk is of limited magnitude, and further studies are needed to confirm the present findings and to identify the mechanisms underlying the potential beneficial effects of peripheral VA-ECMO.

ImportanceLate-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm.ObjectiveTo report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months’ corrected age.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks’ gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers.ExposuresCulture-confirmed LOM.Main Outcomes and MeasuresIncidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021).ResultsAmong 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P < .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P < .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P < .001) and among those with culture-confirmed LOS (23%-79%, P < .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection.Conclusions and RelevanceIn this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.

Hexanucleotide G 4 C 2 repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G 4 C 2 repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged C9orf72 450 mice. However, chronic administration of anti-GA antibodies in AAV-(G 4 C 2 ) 149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.

Abstract Enteroendocrine cells (EECs) are specialized sensors of luminal forces and chemicals in the gastrointestinal (GI) epithelium that respond to stimulation with a release of signalling molecules such as serotonin (5‐HT). For mechanosensitive EECs, force activates Piezo2 channels, which generate a very rapidly activating and inactivating (∼10 ms) cationic (Na + , K + , Ca 2+ ) receptor current. Piezo2 receptor currents lead to a large and persistent increase in intracellular calcium (Ca 2+ ) that lasts many seconds to sometimes minutes, suggesting signal amplification. However, intracellular calcium dynamics in EEC mechanotransduction remain poorly understood. The aim of this study was to determine the role of Ca 2+ stores in EEC mechanotransduction. Mechanical stimulation of a human EEC cell model (QGP‐1) resulted in a rapid increase in cytoplasmic Ca 2+ and a slower decrease in ER stores Ca 2+ , suggesting the involvement of intracellular Ca 2+ stores. Comparing murine primary colonic EECs with colonocytes showed expression of intercellular Ca 2+ store receptors, a similar expression of IP 3 receptors, but a >30‐fold enriched expression of Ryr3 in EECs. In mechanically stimulated primary EECs, Ca 2+ responses decreased dramatically by emptying stores and pharmacologically blocking IP 3 and RyR1/3 receptors. RyR3 genetic knockdown by siRNA led to a significant decrease in mechanosensitive Ca 2+ responses and 5‐HT release. In tissue, pressure‐induced increase in the Ussing short circuit current was significantly decreased by ryanodine receptor blockade. Our data show that mechanosensitive EECs use intracellular Ca 2+ stores to amplify mechanically induced Ca 2+ entry, with RyR3 receptors selectively expressed in EECs and involved in Ca 2+ signalling, 5‐HT release and epithelial secretion. image Key points A population of enteroendocrine cells (EECs) are specialized mechanosensors of the gastrointestinal (GI) epithelium that respond to mechanical stimulation with the release of important signalling molecules such as serotonin. Mechanical activation of these EECs leads to an increase in intracellular calcium (Ca 2+ ) with a longer duration than the stimulus, suggesting intracellular Ca 2+ signal amplification. In this study, we profiled the expression of intracellular Ca 2+ store receptors and found an enriched expression of the intracellular Ca 2+ receptor Ryr3, which contributed to the mechanically evoked increases in intracellular calcium, 5‐HT release and epithelial secretion. Our data suggest that mechanosensitive EECs rely on intracellular Ca 2+ stores and are selective in their use of Ryr3 for amplification of intracellular Ca 2+ . This work advances our understanding of EEC mechanotransduction and may provide novel diagnostic and therapeutic targets for GI motility disorders.

Abstract INTRODUCTION Glioblastomas (GBMs) are highly aggressive tumors. A common clinical challenge after standard of care treatment is differentiating tumor progression from treatment-related changes, also known as pseudoprogression (PsP). Usually, PsP resolves or stabilizes without further treatment or a course of steroids, whereas true progression (TP) requires more aggressive management. Differentiating PsP from TP will affect the patient's outcome. This study investigated using deep learning to distinguish PsP MRI features from progressive disease. METHOD We included newly diagnosed GBM patients who met the inclusion criteria, including a new or increasing enhancing lesion size within the original radiation field and who had clinical, medication, and any histopathology available. The interpretation of the MR images at the image inclusion time point had to be indeterminate. We labeled those who subsequently were stable or improved on imaging and clinically as PSP and those with clinical and imaging deterioration as TP. A subset of subjects underwent a second resection. We labeled these subjects as PSP or TP based on the histological diagnosis. We performed skull stripping, coregistered contrast-enhanced T1 MRIs with T2-weighted images for each patient and used them as input to a 3-D Densenet121 model. We used several augmentation techniques and five-fold cross-validation to achieve more robust predictions. RESULT We included 124 patients who met the criteria, and of those, 63 were PsP and 61 were TP. We trained a deep learning model that achieved 76.4% (ranged 70%-84%, SD 5.122) mean accuracy over the 5 folds, 0.7560(ranged 0.6553-0.8535, SD 0.069) mean AUROCC, 88.72% (SD 6.86) mean sensitivity, and 62.05%(SD 9.11) mean specificity. CONCLUSION We report the development of a deep learning model that distinguishes PsP from TP in GBM patients treated per the Stupp protocol. Further refinement and external validation are required prior to widespread adoption in clinical practice.

Abstract PURPOSE Though patients with glioblastoma generally have poor overall survival (OS), OS estimates range significantly. We sought to develop a radiomics-based model predictive of OS in glioblastoma using preoperative MRI scans to identify these differences and guide clinical care. METHODS The primary endpoint was OS, determined from the date of surgery to death or last follow-up. T1, FLAIR, T2, and post-contrast T1 (T1c) MRI sequences were obtained for all patients. Using HD-GLIO-AUTO, lesion segmentation yielded three masks corresponding to the regions of contrast enhancement, non-enhancement, and total volume. Radiomics features were extracted from each region from the T2 and T1c sequences independently (i.e. either from T2 or T1c) and in combination. Age at surgery and gender were also considered. The data was split into training (75%) and test (25%) sets, stratifying for age at surgery. Kaplan-Meier analysis and the Coxnet model were used. For Coxnet, Elastic Net was used as the penalty, with optimization of the L1 coefficient using 5-fold cross-validation and evaluation via the concordance index (C-index). RESULTS From 3 institutions, 383 patients were included. Median OS was 395 days: 346 patients died, and 37 were right-censored. Age > 65 years was predictive of decreased OS (p < 0.005), but gender was not (p=0.16). For the Coxnet model, the C-index was 0.67 (standard deviation: 0.01) considering T2 and T1c sequences for the total lesion volume, with a C-index of 0.65 for the test set. For the enhancing volume, the model had a C-index of 0.71 for the test set using T1c sequences. Overall, C-indices ranged from 0.62-0.71. CONCLUSIONS We present a novel radiomics-based model predictive of OS in glioblastoma across a multi-institutional dataset. Ongoing efforts will incorporate immediate postoperative imaging and IDH and MGMT status into the proposed model to further improve prognostic ability and help guide clinical decision-making.

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

72 Background: The integration of biopsychosocial screening programs (BSP) has been promoted as a way by which to identify unmet needs and to provide tailored treatments to patients. Studies have reported mixed outcomes regarding the impact of such services on hospital admissions during cancer treatment. This study sought to evaluate the effect of a BSP on hospital admissions and length of stay among a large, heterogenous sample of patients diagnosed with cancer (March 2020 to December 2021). Methods: We enrolled consecutive patients diagnosed with cancer receiving treatment at a single institution located in the capital of Brazil. We assessed patients’ characteristics via chart review (e.g., age, sex, histology, hospital admission, length of hospitalization). In addition, as per the BSP protocol, patients were assessed via standardized self-report questionnaires (Distress Thermometer, FACT-G, Patient-Generated Subjective Global Assessment), and appropriate interventions are provided. This program was offered at no cost to all patients and engagement was voluntary. We compared the number of hospital admissions and length of stay between groups (patients who participated in the BSP vs. those who did not). Mixed linear models adjusted for selected characteristics (age, type of cancer and disease stage) were assessed. Results: A total of 1014 patients were included in this analysis. From the total sample, 84% participated in the BSP and 20% were hospitalized for an average of 9 days (ranging from 1-80 days). Mostly patients were female (63%), median age was 63 years old. Breast cancer (26%), hematological (18%), and gastrointestinal cancer (14%) were the most common types of cancer, and the majority had advanced disease (stage III-IV; 67%). Compared to those who engaged in the BSP, patient’s characteristics were well balanced, however, the proportion of patients hospitalized during their cancer treatment was higher among patients who did not participate in the BSP (27% vs 8%: P = 0.001), as was the length of hospitalization spent more days in the hospital than patients who has participated in the BSP (M = 9.5 days vs M = 4.2 days; P = 0.001). Conclusions: Our findings suggest the benefit of a BSP in reducing hospitalizations and length of stay among patients with cancer. An integrated model of care may assist in targeting patient’s unmet needs and may positively impact clinical and hospital-based outcomes. This is the first study to evaluate the effects of a BSP among a Brazilian population using real world data.