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Before the COVID-19 pandemic, teaching communication skills in health care focused primarily on developing skills during face-to-face conversation. Even experienced clinicians were unprepared for the transition in communication modalities necessitated due to physical distancing requirements and visitation restrictions during the COVID-19 pandemic. We aimed to develop and pilot a comprehensive video-mediated communication training program and test its feasibility in multiple institutional settings and medical disciplines.The education team, consisting of clinician-educators in general surgery and emergency medicine (EM) and faculty specialists in simulation and coaching, created the intervention. Surgery and EM interns in addition to senior medical students applying in these specialties were recruited to participate. Three 90-minute sessions were offered focusing on 3 communication topics that became increasingly complex and challenging: breaking bad news, goals of care discussions, and disclosure of medical error. This was a mixed-methods study using survey and narrative analysis of open comment fields.Learner recruitment varied by institution but was successful, and most (75%) learners found the experience to be valuable. All of the participants reported feeling able to lead difficult discussions, either independently or with minimal assistance. Only about half (52%) of the participants reported feeling confident to independently disclose medical error subsequent to the session.We found the program to be feasible based on acceptability, demand, the ability to implement, and practicality. Of the 3 communication topics studied, confidence with disclosure of medical error proved to be the most difficult. The optimal length and structure for these programs warrants further investigation.

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)–keyhole limpet hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen. At last evaluation, 6 (30%) and 8 patients (50%) had achieved complete remission in KLH-only and Id-KLH arms, respectively (P = .22), and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; P = .32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH. In conclusion, in this combination immunotherapy approach, we observed significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies. This trial was registered at www.clinicaltrials.gov as #NCT01426828.

The use of 7 Tesla (T) magnetic resonance imaging (MRI) is expanding across neurosurgical and neurologic specialties. However, few neurosurgical-related implants have been tested for safety at 7 T, limiting its use in patients with cranial fixation, shunt placements, and other implants. Implant safety can be determined via the American Society for Testing Materials International (ASTM) guidelines. To assess the current state of neurosurgical implant safety at 7 T, a systematic search was performed using PubMed, MEDLINE, Web of Knowledge, and citation matching. Studies written in English that included at least one neurosurgical implant and at least one safety outcome were included. Data were extracted for implant studied, implant composition, deflection angle, torque, temperature change, and ASTM guidelines followed. PRISMA reporting guidelines for scoping reviews were followed. Overall, 18 studies consisting of 45 unique implants were included. Implants included cranial fixation devices, aneurysm clips, spinal rods, pedicle screws, ventriculoperitoneal (VP) shunts, deep brain stimulation devices, and electroencephalogram (EEG) caps and electrodes. Cranial fixation devices, deep brain stimulation devices, spinal rods, and pedicle screws are likely 7 T MRI compatible based on outcomes reported. Aneurysm clips and EEG devices had variable safety outcomes. The VP shunts studied lost functionality after 7 T MRI exposure. We identified several implants that are likely compatible with 7 T MRI. Given the growth in 7 T imaging and expansion of the technology, neurosurgical implants should be constructed with the aforementioned considerations. Caution must be taken with all implants, especially aneurysm clips, programmable VP shunts, and EEG recording devices. It is also noteworthy that several implant testing reports did not report following ASTM standards. This scoping review seeks to concisely summarize all neurosurgical-related implants that have been tested for safety in 7 T MRI. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Background Three randomized clinical trials have reported similar safety and efficacy for contact aspiration and stent-retriever thrombectomy. Aim We aimed to determine whether the combined technique (stent-retriever + contact aspiration) was superior to stent-retriever alone as first-line thrombectomy strategy in a patient cohort where balloon guide catheter was universally used. Methods A prospectively maintained mechanical thrombectomy database from January 2018 to December 2019 was reviewed. Patients were included if they had anterior circulation proximal occlusion ischemic stroke (intracranial ICA or MCA-M1/M2 segments) and underwent stent-retriever alone thrombectomy or stent-retriever + contact aspiration as first-line therapy. The primary outcome was the first-pass effect (mTICI2c-3). Secondary outcomes included modified first-pass effect (mTICI2b-3), successful reperfusion (mTICI2b-3) prior to and after any rescue strategy, and 90-day functional independence (mRS ≤ 2). Safety outcomes included rate of parenchymal hematoma type-2 and 90-day mortality. Sensitivity analyses were performed after dividing the overall cohort according to first-line modality into two matched groups. Results A total of 420 patients were included in the analysis (mean age 64.4 years; median baseline NIHSS 16 (11–21)). As compared to first-line stent-retriever alone, first-line stent-retriever + contact aspiration resulted in similar rates of first-pass effect (53% vs. 51%, adjusted odds ratio (aOR) 1.122, 95%CI (0.745–1.691), p = 0.58), modified first-pass effect (63% vs. 60.4%, aOR1.250, 95%CI (0.782–2.00), p = 0.35), final successful reperfusion (97.6% vs. 98%, p = 0.75), and higher chances of successful reperfusion prior to any rescue strategy (81.8% vs. 72.5%, aOR 2.033, 95%CI (1.209–3.419), p = 0.007). Functional outcome and safety measures were comparable between both groups. Likewise, the matched analysis (148 patient-pairs) demonstrated comparable results for all clinical and angiographic outcomes except for significantly higher rates of successful reperfusion prior to any rescue strategies with the first-line stent-retriever + contact aspiration treatment (81.8% vs. 73.6%, aOR 1.881, 95%CI (1.039–3.405), p = 0.037). Conclusions Our findings reinforce the findings of ASTER-2 trial in that the first-line thrombectomy with a combined technique did not result in increased rates of first-pass reperfusion or better clinical outcomes. However, the addition of contact aspiration after initial stent-retriever failure might be beneficial in achieving earlier reperfusion.

BackgroundFirst pass reperfusion (FPR) has been established as a key performance metric in mechanical thrombectomy (MT). The impact of FPR may be more relevant in fast progressors. We aim to study the impact of baseline Alberta Stroke Program Early CT Score (ASPECTS) on non-contrast CT and hypoperfusion intensity ratio (HIR) on CT perfusion on clinical outcomes after FPR.MethodsA prospective MT database was reviewed for patients with isolated occlusion of the intracranial internal carotid artery and/or middle cerebral artery M1 segment who underwent MT with complete reperfusion (modified Thrombolyis in Cerebral Infarction score 2c–3) from January 2012 to May 2019. The overall population was divided into ASPECTS >7 versus ≤7 and the subgroup of patients with baseline CT perfusion was divided into HIR ResultsA total of 436 patients were included in the analyses. FPR was achieved in 254 (58.3%) patients. ASPECTS modified the effect of FPR on clinical outcomes, with FPR predicting good outcomes in patients with ASPECTS ≤7 (46% vs 29%, adjusted OR 3.748; 95% CI 1.590 to 8.838, p=0.003) while no significant effect was detected in those with ASPECTS >7 (62.3% vs 53.1%, adjusted OR 1.372; 95% CI 0.798 to 2.358, p=0.25). Similarly, FPR predicted good outcomes in patients with HIR ≥0.3 (54.8% vs 41.9%, adjusted OR 2.204; 95% CI 1.148 to 4.233, p=0.01) but not in those with HIR ConclusionsThe impact of FPR on functional outcomes is highly dependent on baseline imaging characteristics, with a more prominent influence in patients presenting with lower ASPECTS and/or higher HIR.

Despite a global footprint of shifts in flowering phenology in response to climate change, the reproductive consequences of these shifts are poorly understood. Furthermore, it is unknown whether altered flowering times affect plant population viability. We examine whether climate change-induced earlier flowering has consequences for population persistence by incorporating reproductive losses from frost damage (a risk of early flowering) into population models of a subalpine sunflower (Helianthella quinquenervis). Using long-term demographic data for three populations that span the species’ elevation range (8–15 years, depending on the population), we first examine how snowmelt date affects plant vital rates. To verify vital rate responses to snowmelt date experimentally, we manipulate snowmelt date with a snow removal experiment at one population. Finally, we construct stochastic population projection models and Life Table Response Experiments for each population. We find that populations decline (λs

Background and Purpose: Several reports have described lower mortality rates in overweight or obese patients as compared to normal weight ones. In the past decade, several studies have investigated the phenomenon, commonly known as the obesity paradox, with mixed results thus far. We sought to determine whether outcomes differ between patients with large vessel occlusion strokes (LVOS) after endovascular therapy (ET) according to their body mass index (BMI). Methods: We reviewed our prospectively collected endovascular database at a tertiary care academic institution. All patients that underwent ET for acute LVOS were categorized according to their BMI into 4 groups: (1) underweight (BMI < 18.5), (2) normal weight (BMI = 18.5–25), (3) overweight (BMI = 25–30), and (4) obese (BMI > 30). Baseline characteristics, procedural radiological as well as outcome parameters where compared. Results: A total of 926 patients qualified for the study, of which 20 (2.2%) were underweight, 253 (27.3%) had a normal weight, 315 (34%) were overweight, and 338 (36.5%) were obese. When compared with normal weight (reference), overweight patients were younger, had higher rates of dyslipidemia and diabetes and higher glucose levels, while obese patients were younger, less often smokers, and had higher rates of hypertension and diabetes and higher glucose levels. Other baseline and procedural characteristics were comparable. The rates of successful reperfusion (modified treatment in cerebral ischemia, 2b–3), parenchymal hematomas, 90-day good clinical outcomes (modified Rankin scale, 0–2), and 90-day mortality were comparable between groups. On multivariate analysis, BMI was not associated with good outcomes nor mortality. Conclusion: In patients treated with mechanical thrombectomy, BMI is not associated with outcomes. However, patients who are overweight or obese have more comorbidities and a higher stroke risk and, thus, should strive for a normal weight.

PURPOSE To overcome technical limitations of detecting low frequencies of antigen-specific-T cells in human patients, we sought to establish a highly sensitive platform for antigen-specific-T cell detection and activation using IBMAM (immortalized B cells transfected with mRNA of antigen fused to MHC-class-I-trafficking-domain [MITD]). METHODS We first established immortalized B cells in-vitro as antigen-presenting cells. B cells were isolated from CMV-seropositive normal healthy donors (NHDs), stimulated, and transduced with retrovirus containing BCL-6 and BCL-XL. Purified CD4+ T lymphocytes obtained from the NHDs PBMC were co-cultured in-vitro with autologous immortalized B cells transfected with CMVpp65 mRNA fused to MITD (IBMAM) as a model antigen and then measured for activation using IFN-g ELISA. We developed two pathways for IBMAM mediated antigen-specific T cell activation and detection. For the first pathway, if IFN-g is detected, T cells are isolated again from NHDs PBMC and expanded using rapid expansion procedures (REP). After the first REP, antigen-specific T cells are detected using IBMAM, sorted, and a second REP is performed. However, for the second pathway, if IFN-g is not detected, NHDs PBMC is stimulated twice using IBMAM and subsequently antigen-specific T cells are detected using IBMAM again. RESULTS B cells were successfully immortalized by transfecting at least 5*105 cells with retrovirus (1MOI) and co-cultured with CD40L-IL21 expressing human fibroblasts. We observed a significantly increased activation of antigen-specific CD4+ T cells when using IBMAM in comparison to controls transfected with CMVpp65 mRNA lacking the MITD fusion or a known CMVpp65 peptide pool. For pathway 1 and 2 of our platform, successful detection, activation, and expansion of CMVpp65-specific T cells were observed from low frequency NHDs samples using IBMAM. CONCLUSION We have thus established a highly sensitive method of immuno-monitoring that can be used for the detection of antigen-specific T cells in patient samples with low frequencies of antigen-specific-T cells, such as human cancer antigens.

Purpose Physical activity and recreation are very important for people with disabilities and provide benefits for self-esteem, social relationships, employment, rehabilitation, and education. Para Table Tennis is an adaptive sport where participants compete in table tennis while sitting in a wheelchair. However, athletes generally use their everyday wheelchair instead of a device specifically designed for the sport. The specific support, movements, and posture needed to participate in table tennis at the highest level are different than general day-to-day mobility and a device could be optimized for the sport. This research describes the development of a wheelchair specifically designed for para table tennis. Materials and methods The design followed a participatory action design approach which identified the specific needs for a wheelchair to be used during para table tennis. Results Three design needs were identified which included 1) locking the casters in the forward direction, 2) ability to raise the seat height as high as possible while allowing the user's knees to fit under the table, and 3) adjustable seat angle which will allow some users to have anterior tilt to get their trunk even higher while other users could have posterior tilt for stability. A new chair meeting these needs was designed and prototyped. Conclusions Para table tennis has some specific requirements related to movements and posture which were improved by a new wheelchair design specific for the sport.IMPLICATIONS FOR REHABILITATIONMany adaptive sports are improved with sport specific technology.A model client was used to develop a wheelchair specifically for adaptive table tennis.The height and angle of the seat of the new wheelchair can be adjusted for optimal stability and reach.The casters of the new wheelchair can be locked to allow only forward and backward motion.

Background and Purpose Stent-retriever (SR) thrombectomy remains the best proven treatment modality for anterior circulation large vessel occlusion strokes (LVOS). Three randomized clinical trials have reported similar safety and efficacy for contact aspiration (CA) and SR thrombectomy. The ASTER-2 trial compared combined technique (SR + CA) versus SR alone. The study failed to demonstrate differences in terms of final reperfusion and clinical outcomes across the two modalities. However, reperfusion was significantly better after the allocated treatment only with combined technique. We aim to determine whether the combined technique is superior to SR thrombectomy alone as first line strategy in a large single-center cohort where balloon-guide catheter was universally used. Methods A prospectively maintained mechanical thrombectomy database from January 2018 to December 2019 was reviewed. Patients were included if they had anterior circulation LVO due to intracranial ICA or MCA-M1 segment and underwent SR thrombectomy or combined technique as first-line therapy. The cohort was divided into two groups matched for age, baseline NIHSS score, prior IV-tPA, site of occlusion, stroke etiology, use of general anesthesia and balloon guide catheter. The primary outcome was the achievement of first-pass effect (FPE) (mTICI2c-3). Secondary outcomes included modified FPE, number of passes, successful reperfusion (mTICI2b-3) without and after rescue techniques and functional independence (90-day mRS 0–2). Safety outcomes included the rates of parenchymal hematoma (PH) type 2 and 90-day mortality. A secondary analysis was performed for the interaction between different subgroups and thrombectomy modality on successful reperfusion. Results A total of 244 patients (122 pairs) were eligible for the analysis. Patients with first-line combined technique had similar rates of FPE (56.6% vs. 51.6, p=0.44), successful reperfusion without (77% vs. 77.9%, p=0.88) and after (99.2% vs. 99.2%, p=1.00) rescue techniques and 90-day functional independence (46.6% vs. 54.4%, p=0.30) compared to SR thrombectomy. However, first-line combined technique had a significantly higher number of passes and longer reperfusion times compared to SR alone (p=0.005 and p=0.01, respectively). The rates of PH type 2 and 90-day mortality were comparable between both groups. There was no significant interaction between age, prior IV-tPA, site of occlusion and presence of favorable collaterals and the first-line treatment modality in terms of successful reperfusion. Conclusions Our findings reinforce the findings of ASTER-2 in that the first-line thrombectomy with a combined technique did not result in increased rates of successful reperfusion or a better outcome. In contrast with ASTER-2, we did not see any advantage even prior to rescue devices. Disclosures M. Mohammaden: None. D. Haussen: 2; C; Stryker, Vesalio. 4; C; Viz.AI. L. Pisani: None. A. Al-Bayati: None. A. Anderson: None. B. Liberato: None. M. Frankel: None. R. Nogueira: 2; C; Medtronic, Anaconda, Genentech, Brainomix, Viz-AI, Corindus Vascular Robotics.

The vertebrate limb serves as an experimental paradigm to study mechanisms that regulate development of the stereotypical skeletal elements. In this study, we simultaneously inactivated Sall4 using Hoxb6Cre and Plzf in mouse embryos, and found that their combined function regulates development of the proximal-anterior skeletal elements in hindlimbs. The Sall4; Plzf double knockout exhibits severe defects in the femur, tibia, and anterior digits, distinct defects compared to other allelic series of Sall4; Plzf. We found that Sall4 regulates Plzf expression prior to hindlimb outgrowth. Further expression analysis indicated that Hox10 genes and GLI3 are severely downregulated in the Sall4; Plzf double knockout hindlimb bud. In contrast, PLZF expression is reduced but detectable in Sall4; Gli3 double knockout limb buds, and SALL4 is expressed in the Plzf; Gli3 double knockout limb buds. These results indicate that Plzf, Gli3, and Hox10 genes downstream of Sall4, regulate femur and tibia development. In the autopod, we show that Sall4 negatively regulates Hedgehog signaling, which allows for development of the most anterior digit. Collectively, our study illustrates genetic systems that regulate development of the proximal-anterior skeletal elements in hindlimbs.

Introduction: Identification of Large Vessel Occlusion (LVO) in acute ischemic stroke (AIS) patients is critical for proper decision-making. Limited availability of trained experts and delays in LVO recognition can have a detrimental effect on outcomes. We sought to evaluate an artificial intelligence-based algorithm for LVO detection in AIS. Methods: A retrospective analysis of a prospectively-collected database of AIS patients admitted to a large volume stroke center between 2014-2018 was performed. Experienced vascular neurologists graded CTA for presence and site of LVO. Concurrently, studies were analyzed by the Viz-LVO Algorithm® version 1.4 (GA) - a convolutional neural network programmed to detect occlusions from the internal carotid artery terminus (ICA-T) to the sylvian fissure, which would include all MCA M1-segment and most M2-segment lesions. CTA readings were categorized as LVOs (ICA-T, MCA-M1, MCA-M2) versus non-LVOs/more distal occlusions. Comparisons between human and AI-based readings were done by accuracy analysis and calculating Cohen’s kappa. Results: A total of 610 CTAs were analyzed. The AI algorithm rejected 3.4% of the CTAs due to poor quality. Viz-LVO identified LVOs with an overall sensitivity of 81.3%, specificity of 87.8%, and accuracy of 83.2% (AUC 0.845 (95%CI:0.81-0.88, p Conclusion: Our study demonstrates that automated AI reading allows for fast and accurate identification of LVO strokes. Future efforts should be made to improve the detection of the more distal occlusions.

Introduction: Intracerebral hemorrhages (ICHs) accounts for approximately 15% of all strokes but carry high rates of morbidity and mortality. The location and volume of hematoma are strongly associated with outcomes. As novel treatments become established, early detection and proper volume measurement are becoming increasingly important. We aim to evaluate an artificial intelligence-based algorithm (Viz-ICH® v1.4) for ICH detection, volume measurement, and its differentiation from intraventricular hemorrhage (IVH). Methods: We performed single center retrospective analysis of non-contrast CTs (NCCTs), randomly picked from prospective cohort of acute stroke patients, with and without parenchymal ICHs, admitted to our stroke center from 02/14-03/17. Experienced stroke neurologists graded NCCTs with a semi-automated tool (OsiriX MD v.9.0.1) for presence and volume of ICH, and also presence of intraventricular hemorrhage (IVH). AI- and human-based readings were compared. Results: A total of 211 NCCTs were evaluated including 163 ICHs and 48 controls. The ICH location was basal ganglionic in 55.8%, Lobar in 23.3% and posterior fossa in 12% of the cases and 51.5 % of patients had associated IVH with mean volume 41.94 cc. The AI algorithm demonstrated high accuracy for ICH detection and volumetric measurement (Table). The maximal running time of the algorithm was under 15s. Conclusion: The presence and volume of ICHs can be accurately detected by AI Viz-ICH Algorithm, with good differentiation from IVH which will help in early triage of these patients.

Scanning tunneling microscopy measurements on Ag(111)/$\mathrm{Mo}{\mathrm{S}}_{2}$ reveal atomically flat preferred, or ``magic,'' heights occurring at 6, 10, and 14 atomic layers. These results are consistent with Ag growth on a variety of semiconducting substrates and correlate with electronic energy savings in electronic structure calculations of freestanding Ag(111) films. Thus, under certain conditions, Ag will spontaneously form quantized structures independent of the substrate. To explain this, we have found Fermi surface nesting vectors in the bulk Ag band structure which account for these results and the fact Ag that is gapped along the surface normal. This model extends to a range of metallic systems which exhibit electronic confinement, epitaxial growth, and minimal strain. As with $\mathrm{Au}\text{/}\mathrm{Mo}{\mathrm{S}}_{2}$, the Ag/$\mathrm{Mo}{\mathrm{S}}_{2}$ system exhibits this behavior at unusually high temperatures so that these principles might be used for control over device features at the nanometer scale under standard fabrication conditions.

Background and Purpose: Ethnic disparities in stroke are well described, with a higher incidence of disability and increased mortality in Blacks versus Whites. We sought to compare the clinical outcomes between those ethnic groups after stroke endovascular therapy (ET). Methods: We performed a retrospective review of the prospectively acquired Grady Endovascular Stroke Outcomes Registry between September 1, 2010 and September 30, 2015. Patients were dichotomized into two groups – Caucasians and African-Americans – and matched for age, pretreatment glucose level, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Baseline characteristics as well as procedural and outcome parameters were compared. Results: Out of the 830 patients treated with ET, 308 pairs of patients (n = 616) underwent primary analysis. African-Americans were younger (p < 0.01), had a higher prevalence of hypertension (p < 0.01) and diabetes (p = 0.04), and had higher Alberta Stroke Program Early CT Score values (p = 0.03) and shorter times to treatment (p = 0.01). Blacks more frequently had Medicaid coverage and less private insurance (29.6 vs. 11.4% and 41.5 vs. 60.3%, respectively, p < 0.01). The remaining baseline characteristics, including baseline NIHSS score and CT perfusion-derived ischemic core volumes, were well balanced. There were no differences in the overall distribution of 90-day modified Rankin scale scores (p = 0.28), rates of successful reperfusion (84.7 vs. 85.7%, p = 0.91), good outcomes (49.1 vs. 44%, p = 0.24), or parenchymal hematomas (6.5 vs. 6.8%, p = 1.00). Blacks had lower 90-day mortality rates (18 vs. 24.6%, p = 0.04) in univariate analysis, which persisted as a nonsignificant trend after adjustment for potential confounders (OR 0.52, 95% CI 0.26–1.03, p = 0.06). Conclusions: Despite unique baseline characteristics, African-Americans treated with ET for large vessel occlusion strokes have similar outcomes as Caucasians. Greater availability of ET may diminish the ethnic/racial disparities in stroke outcomes.

The results of clinical trials evaluating CD19-targeting chimeric antigen receptor (CAR) T cells are impressive, with overall response rates of up to 90% in B cell acute lymphoblastic leukemia (ALL) and 50-80% in lymphoma. Despite initial responses, antigen-negative relapse is common following treatment with CD19-targeted therapies and is estimated to occur in up to 39% of patients. One approach of addressing this problem is to utilize dual-targeting CAR T cells, a strategy that has recently been applied to CD19/CD22 for ALL, CS1/BCMA, and BCMA/GPRC5D for multiple myeloma. Dual-targeting CARs can simultaneously target two tumor antigens and, therefore, potentially eradicate heterogeneous tumors. The initial response to dual-targeted CAR T cells is expected to provide greater tumor coverage compared to single-targeted therapy, and can potentially circumvent antigen escape. Moreover, if one tumor antigen becomes downregulated during treatment, the second targeting domain will continue to be reactive to tumors. Therefore, it is critical to identify novel targets that can be combined with CD19 in a dual-targeted immunotherapeutic platform. To expand the potential for dual targeting of ALL, we developed a CAR T cell therapy against a novel target, B-cell activating factor receptor (BAFF-R), based on the remarkable specificity of anti-BAFF-R antibodies that we previously generated. BAFF-R is expressed almost exclusively on B cells, including in patients with CD19-negative relapse, making it an ideal immunotherapeutic target. Studies demonstrate that the role of BAFF-R in B cell function and survival is conclusive, an important feature that may mitigate the tumor's ability to escape therapy through antigen loss, particularly if a non-redundant role for BAFF-R is confirmed. BAFF-R-CAR T cells demonstrate in vitro effector function and in vivo therapeutic efficacy in CD19-negative models, including patient-derived xenograft models, and are currently being evaluated clinically for the treatment of ALL (NCT04690595). We hypothesized that simultaneous targeting of CD19 and BAFF-R in a bispecific CAR platform could confer a therapeutic advantage and avoid the challenges of sequential administration of CD19 and BAFF-R monospecific CAR T cells. We leveraged our experience with CD19- and BAFF-R-CAR T cells to develop a dual-targeting, bispecific CAR with a 41BB costimulatory domain (CD19/BAFF-R dual CAR). Here, we identified the optimal orientation of the single-chain variable fragment (loop scFv) domains within the dual construct and tested the CD19/BAFF-R dual CAR T cells for their in vitro effector function and in vivo anti-leukemia activity. To evaluate the specific targeting to CD19 and BAFFR, we developed Nalm-6-BAFF-R-knockout (KO) and Nalm-6-CD19-KO cell lines. CD19/BAFF-R dual CAR T cells specifically released IFN-g following incubation with Nalm-6 CD19-/- or BAFF-R-/- cells (P Our unique CD19/BAFF-R dual-targeting CAR T cells will be the first to target this combination of tumor-associated antigens. Our study demonstrated the reliability of bispecific CD19/BAFF-R dual CAR T cell therapy in inducing remission in ALL consisting of CD19-/- and BAFF-R-/- tumors. We hypothesize that simultaneous immunotherapy targeting of heterogeneous leukemic cell populations may diminish the likelihood of antigen escape and may have a significant impact on leukemia treatment by improving the therapeutic benefits of CAR T cell therapy. Figure 1 Figure 1. Disclosures Wang: Pepromene Bio, Inc.: Consultancy. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company. Kwak: Pepromene Bio, Inc.: Consultancy, Current equity holder in publicly-traded company. Qin: Pepromene Bio, Inc.: Consultancy, Current equity holder in publicly-traded company.

Background: The minimal stroke severity justifying endovascular intervention remains elusive. However, a significant proportion of patients presenting with large vessel occlusion stroke (LVOS) and mild symptoms go untreated and face poor outcomes. We aimed to evaluate the clinical outcomes of patients presenting with LVOS and low symptom scores (National Institutes of Health Stroke Scale [NIHSS] score ≤8) undergoing endovascular therapy (ET). Methods: We performed a retrospective analysis of a prospectively collected ET database between September 2010 and March 2016. Endovascularly treated patients with LVOS and a baseline NIHSS score ≤8 were included. Baseline patient characteristics, procedural details, and outcome parameters were collected. Efficacy outcomes were the rate of good outcome (90-day modified Rankin Scale score 0-2) and of successful reperfusion (modified Treatment in Cerebral Infarction [mTICI] score 2b-3). Safety was assessed by the rate of parenchymal hematoma (parenchymal hematoma type 1 [PH-1] and parenchymal hematoma type 2 [PH-2]) and 90-day mortality. Logistic regression was used to identify predictors of good clinical outcomes. Results: A total of 935 patients were considered; 72 patients with an NIHSS score ≤8 were included. Median [IQR] age was 61.5 years [56.2-73.0]; 39 patients (54%) were men. Mean (SD) baseline NIHSS score, computed tomography perfusion core volume, and ASPECTS were 6.3 (1.5), 7.5 mL (16.1), and 8.5 (1.3), respectively. Twenty-eight patients (39%) received intravenous tissue plasminogen activator. Occlusions locations were as follows: 29 (40%) proximal MCA-M1, 20 (28%) MCA-M2, 6 (8%) ICA terminus, and 9 (13%) vertebrobasilar. Tandem occlusion was documented in 7 patients (10%). Sixty-seven patients (93%) achieved successful reperfusion (mTICI score 2b-3); 52 (72%) had good 90-day outcomes. Mean final infarct volume was 32.2 ± 59.9 mL. Parenchymal hematoma occurred in 4 patients (6%). Ninety-day mortality was 10% (n = 7). Logistic regression showed that only successful reperfusion (OR 27.7, 95% CI 1.1-655.5, p = 0.04) was an independent predictor of good outcomes. Conclusion: Our findings demonstrate that ET is safe and feasible for LVOS patients presenting with mild clinical syndromes. Future controlled studies are warranted.

BACKGROUND AND PURPOSE Chronic hypoperfusion from athero-stenotic lesions is thought to lead to better collateral recruitment compared to cardioembolic strokes. It was sought to compare collateral flow in stroke patients with atrial fibrillation (AF) versus stroke patients with cervical atherosclerotic steno-occlusive disease (CASOD). METHOD This was a retrospective review of a prospectively collected endovascular database. Patients with (i) anterior circulation large vessel occlusion stroke, (ii) pre-treatment computed tomography angiography (CTA) and (iii) intracranial embolism from AF or CASOD were included. CTA collateral patterns were evaluated and categorized into two groups: absent/poor collaterals (CTA collateral score 0-1) versus moderate/good collaterals (CTA collateral score 2-4). CT perfusion was also utilized for baseline core volume and evaluation of infarct growth. RESULTS A total of 122 patients fitted the inclusion criteria, of whom 88 (72%) had AF and 34 (27%) CASOD. Patients with AF were older (P < 0.01) and less often males or smokers (P = 0.04 and P < 0.01 respectively). Baseline National Institutes of Health Stroke Scale and Alberta Stroke Program Early CT Score were comparable between groups. Collateral scores were lower in the AF group (P = 0.01) with patients having poor collaterals in 28% of cases versus 9% in the CASOD group (P = 0.03). Mortality rates (20% vs. 0%; P = 0.02) were higher in the AF patients whilst rates of any parenchymal hemorrhage (6% vs. 26%; P < 0.01) were higher in the CASOD group. On multivariable analysis, CASOD was an independent predictor of moderate/good collaterals (odds ratio 4.70; 95% confidence interval 1.17-18.79; P = 0.03). CONCLUSIONS Atheroembolic strokes seem to be associated with better collateral flow compared to cardioembolic strokes. This may in part explain the worse outcomes of AF-related stroke.

Background and Purpose— Pseudo-occlusion (PO) of the cervical internal carotid artery (ICA) refers to an isolated occlusion of the intracranial ICA that appears as an extracranial ICA occlusion on computed tomography angiography (CTA) or digital subtraction angiography because of blockage of distal contrast penetration by a stagnant column of unopacified blood. We aim to better characterize this poorly recognized entity. Methods— Retrospective review of an endovascular database (2010–2015; n=898). Only patients with isolated intracranial ICA occlusions as confirmed by angiographic exploration were included. CTA and digital subtraction angiography images were categorized according to their apparent site of occlusion as (1) extracranial ICA PO or (2) discernible intracranial ICA occlusion. Results— Cervical ICA PO occurred in 21/46 (46%) patients on CTA (17 proximal cervical; 4 midcervical). Fifteen (71%) of these patients also had PO on digital subtraction angiography. A flame-shaped PO mimicking a carotid dissection was seen in 7 (33%) patients on CTA and in 6 (29%) patients on digital subtraction angiography. Patients with and without CTA PO had similar age (64.8±17.1 versus 60.2±15.7 years; P =0.35), sex (male, 47% versus 52%; P =1.00), and intravenous tissue-type plasminogen activator use (38% versus 40%; P =1.00). The rates of modified Treatment In Cerebral Ischemia 2b-3 reperfusion were 71.4% in the PO versus 100% in the non-PO cohorts ( P P =0.66), 40% versus 66.7% ( P =0.12), and 25% versus 21% ( P =0.77) in PO versus non-PO patients, respectively. Multivariate analysis indicated that PO patients had lower chances of modified Treatment In Cerebral Ischemia 3 reperfusion (odds ratio 0.14; 95% confidence interval 0.02–0.70; P =0.01). Conclusions— Cervical ICA PO is a relatively common entity and may be associated with decreased reperfusion rates.

Background: Idiotypic determinants of the surface immunoglobulin (Ig) associated with a given pt's B-cell lymphoma are unique to that tumor, and can thus serve as a tumor-specific marker. This study aims to use an idiotype DNA vaccine to lengthen the smoldering phase of WM without inducing cross-resistance to available therapies. Administered vaccine used recombinant plasmid DNA encoding a fusion protein, consisting of autologous lymphoma scFv (pt-specific idiotype) and human CCL20 (macrophage inflammatory protein-3 alpha - MIP-3α) chemokine. Targeted delivery of this fusion protein to antigen-presenting cells, and subsequent processing and presentation, is hypothesized to break tolerance and generate an immune response against the idiotype, promoting eradication of antigen-expressing B-cell lymphoma cells. Methods: Pts with sWM received 3 intradermal vaccinations of pt-specific DNA vaccine at 4-week (wk) intervals (wks 0, 4 and 8). Two dose levels (500 µg; 2500 µg) were evaluated in a 3+3 design. The primary objective was to evaluate the vaccine's safety and identify the maximum tolerated dose. Secondary objectives were to assess immunogenicity of the vaccine to generate tumor-specific cellular immune responses. Results: Between 1/2016 - 1/2019, 9 pts (7 men) were treated (500 µg: n = 3; 2500 µg: n = 6). Median age at enrollment was 67 yrs (range 56-78); median time from diagnosis to 1st vaccination was 26.5 mos (8.8-120.9). MYD88 L265P + (6 pts). CXCR4 WHIM + (1 pt). With median follow up of 38 months (range: 8.8-51), 8 pts are known alive; 1 has been lost to follow up. Six have maintained stable disease; 3 have progressed to symptomatic WM at 8, 25, and 28 months respectively, from 1st vaccination). All pts completed planned therapy. No DLTs or Grade 4 AEs occurred. Ten mos. after the 3rd vaccination, 1 pt had a grade 3 pleural effusion and leukopenia with an increase in rheumatoid factor (23.1 IU/mL [normal range 0.0-15.9]) and ANA titer of 1:80; all resolved within 2 mos. Grade 1-2 AEs observed in > 3pts include: leukopenia (6), nausea (5), anemia (4), increased creatinine (4), fatigue (4). Immune correlatives have now been completed in all 9 patients. Analysis is ongoing, and complete data will be presented at the meeting. Serial pre- and post- vaccine samples analyzed by single-cell RNA seq from 3 representative patients (LPL 005, LPL 007, LPL 008) treated at the 2500 mg dose are shown in the Figure. DNA vaccine treatment significantly reduced the number of clonal B-cells in the bone marrow compartment of the 2 patients who have maintained SD (LPL 007 and LPL 008). DNA vaccine treatment also induced increases in monocytes in the tumor microenvironment of these 2 patients. In addition, T-cell receptor (TCR) sequence analysis revealed clear increases in TCR clonal expansions, consistent with a vaccine effect. In contrast, LPL 005, who had the earliest progression to symptomatic phase WM, had an increase in tumor B cells on post vaccine samples, and TCR clonotypes showed no changes. Similar changes were observed with serial bone marrow samples from the remaining patients treated on the trial, correlating with clinical outcome. Conclusions: Idiotype (scFv-CCL20) DNA vaccine therapy appears to be safe in pts with sWM. Preliminary results of serial single cell RNAseq analysis suggest that the tumor immune microenvironment is favorably altered after chemokine-tumor antigen DNA vaccine treatment and these vaccine-induced changes may correlate with clinical outcome. The immunologic changes observed suggest response to this vaccine, and warrant further investigation in a Phase II trial, possibly in combination with immune checkpoint blockade. Disclosures Thomas: Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Research Funding; Pharmacyclics: Other: Advisory Boards; Xencor: Research Funding; X4 Pharma: Research Funding. Lee:GlaxoSmithKline: Consultancy, Research Funding; Regeneron: Research Funding; Daiichi Sankyo: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Genentech: Consultancy; Sanofi: Consultancy; Genentech: Consultancy. Manasanch:Adaptive Biotechnologies: Honoraria; Glaxo Smith Kline: Honoraria; BMS: Honoraria; Takeda: Honoraria; Quest Diagnostics: Research Funding; Merck: Research Funding; JW Pharma: Research Funding; Novartis: Research Funding; Sanofi: Honoraria, Research Funding. Patel:Nektar: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Precision Biosciences: Research Funding; Celgene: Consultancy, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Oncopeptides: Consultancy. Orlowski:Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. Neelapu:Takeda Pharmaceuticals: Patents & Royalties; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; N/A: Other; Acerta: Research Funding; Karus Therapeutics: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Unum Therapeutics: Other, Research Funding; Calibr: Other; Adicet Bio: Other; Legend Biotech: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Precision Biosciences: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Novartis: Other: personal fees; Pfizer: Other: personal fees. Kwak:CJ Healthcare: Consultancy; Sellas Life Sciences Grp: Consultancy; Enzychem Life Sciences: Membership on an entity's Board of Directors or advisory committees; Antigenics: Other: equity; InnoLifes, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pepromene Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xeme Biopharma/Theratest: Other: equity; Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Celltrion, Inc.: Consultancy. OffLabel Disclosure: This study aims to use a novel idiotype DNA vaccine to lengthen the smoldering phase of WM without inducing cross-resistance to available therapies.

OBJECTIVE Given temporal changes in diabetes prevalence and stroke incidence, this study investigated age, race, and sex differences in the diabetes–stroke association in a contemporary prospective cohort, the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. RESEARCH DESIGN AND METHODS We included 23,002 non-Hispanic black and white U.S. adults aged ≥45 years without prevalent stroke at baseline (2003–2007). Diabetes was defined as fasting glucose ≥126 mg/dL, random glucose ≥200 mg/dL, or use of glucose-lowering medication. Incident stroke events were expert adjudicated and available through September 2017. RESULTS The prevalence of diabetes was 19.1% at baseline. During follow-up, 1,018 stroke events occurred. Among adults aged CONCLUSIONS In this contemporary cohort, the diabetes–stroke association varied by age, race, and sex together, with a more pronounced effect observed among adults aged

Introduction: The standard reperfusion target for thrombectomy trials has been modified TICI (mTICI) 2b-3 (≥50% ischemic territory). Recently, full reperfusion (mTICI 2c-3) has been recommended as the ideal target. The potential added benefits of additional procedural maneuvers must be balanced against their risks, particularly when dealing with residual distal occlusions often found in mTICI 2b. It remains unknown whether more precise categorization of the mTICI2b strata leads to more reasonable treatment targets. Methods: Retrospective analysis of prospectively collected thrombectomy data spanning Jun 2011-Feb 2018. Inclusion criteria: MCA and intracranial internal carotid artery occlusions. Definitions of reperfusion: mTICI0-1: no or limiteddistal filling; mTICI2a: Results: Of 557 patients, 2.2% had mTICI0-1, 3.6% had mTICI2a, 5.9% had mTICI2b-, 30.2% mTICI2b+, and 58.2% mTICI3. The usage of intravenous tPA was lower in the mTICI2b- vs. mTICI3 (18% vs. 41%;pFigure ). Mortality rates were comparable across the mTICI2b-, mTICI 2b+, and mTICI 3 groups but higher with mTICI2a (40%;p=0.01) and mTICI0-1 (50%;p Conclusion: There is broad variation in outcomes across the different degrees of reperfusion within the mTICI 2b grade. A reperfusion target of 75%-99% (mTICI2b+) may lead comparable rates of independence versus full reperfusion.

Bi-potential neuromesodermal progenitors (NMPs) produce both neural and paraxial mesodermal progenitors in the trunk and tail during vertebrate body elongation. We show that Sall4, a pluripotency-related transcription factor gene, has multiple roles in regulating NMPs and their descendants in post-gastrulation mouse embryos. Sall4 deletion using TCre caused body/tail truncation, reminiscent of early depletion of NMPs, suggesting its role in NMP maintenance. This phenotype became significant at the time of the trunk to tail transition, suggesting that Sall4 maintenance of NMPs enables tail formation. Sall4 mutants exhibit expanded neural and reduced mesodermal tissues, indicating its role in NMP differentiation balance. Mechanistically, we show that Sall4 promotion of WNT/ß-catenin signaling contributes to NMP maintenance and differentiation balance. RNA-Seq and SALL4 ChIP-Seq analyses support the notion that Sall4 regulates both mesodermal and neural development. Furthermore, in the mesodermal compartment, genes regulating presomitic mesoderm differentiation are downregulated in Sall4 mutants. In the neural compartment, we show that differentiation of NMPs towards post-mitotic neuron is accelerated in Sall4 mutants. Our results collectively provide evidence supporting the role of Sall4 in regulating NMPs and their descendants.

Purpose: Carotid web (CaW) is an underrecognized cause of cryptogenic stroke in young patients. The optimal imaging for CaW is unknown. We aim to evaluate the diagnostic accuracy of diverse imaging modalities for the diagnosis of CaW.Methods: Retrospective analysis of institutional neurovascular database was performed to identify patients with multimodal (CT angiogram–CTA, digital subtraction angiogram–DSA, and/or ultrasound–US) imaging diagnosis of CaW or atherosclerosis. Baseline clinical demographics were recorded. Blinded image analysis was performed for each imaging modality by separate readers. Discrepancies were settled by consensus. Two-sided Cohen's Kappa (κ) coefficient was used to evaluate the inter-rater agreement for the etiological diagnosis between imaging modalities.Results: Thirty patients/60 carotids were evaluated by CTA and 55 carotids were included. Patients with symptomatic CaW (n = 20), compared to individuals with atherosclerosis (n = 10), were younger (49 ± 9 vs. 60 ± 8 years; p < 0.01), more commonly female (75% vs. 30%; p = 0.01), and less frequently presented vascular risk factors: Hypertension (40% vs. 100%; p < 0.01), hyperlipidemia (0% vs. 50%; p < 0.01), diabetes (10% vs. 40%; p = 0.05), and smoking (5% vs. 70%; p < 0.01). High inter-rater correlation strength existed for CTA (n = 55; κ = 0.88; p < 0.0001) and DSA (n = 28; κ = 0.86, p < 0.0001) readers for lesion diagnosis while US inter-rater agreement was lower (κ = 0.553; p = 0.001). Across modalities CTA and DSA shared very high strength of agreement (κ = 0.92; p < 0.0001), compared to a less pronounced agreement between US and CTA (κ = 0.553; p = 0.001). The strength of correlation between DSA-CTA was significantly more robust as compared to US-CTA (Z = 3.58; p = 0.0003).Conclusion: CTA and DSA demonstrated comparable and superior performance as compared to US in the diagnosis of CaW.

Background Flavonoids may have beneficial cerebrovascular effects, but evidence from racially and geographically representative cohorts in comprehensive flavonoid databases is lacking. Given racial and geographic disparities in stroke incidence, representative cohort studies are needed. Objectives We evaluated the association between flavonoid intake and incident ischemic stroke in a biracial, national cohort using updated flavonoid composition tables and assessed differences in flavonoid intake by sex, race, and region of residence. Methods We evaluated 20,024 participants in the REGARDS (REasons for Geographic and Racial Differences in Stroke) study, a biracial prospective study. Participants with stroke history or missing dietary data were excluded. Flavonoid intake was estimated by using a Block98 food frequency questionnaire and the USDA's Provisional Flavonoid Addendum and Proanthocyanidin Database. Associations between quintiles of flavonoid intake and incident ischemic stroke were evaluated by using Cox proportional hazards models, adjusting for confounders. Results Over 6.5 y, 524 acute ischemic strokes occurred. Flavanone intake was lower in the Southeastern United States but higher in blacks than in whites. After multivariable adjustment, flavanone intake was inversely associated with incident ischemic stroke (HR: 0.72; 95% CI: 0.55, 0.95; P-trend = 0.03). Consumption of citrus fruits and juices was inversely associated with incident ischemic stroke (HR: 0.69; 95% CI: 0.53, 0.91; P-trend = 0.02). Total flavonoids and other flavonoid subclasses were not associated with incident ischemic stroke. There was no statistical interaction with sex, race, or region for any flavonoid measure. Conclusions Greater consumption of flavanones, but not total or other flavonoid subclasses, was inversely associated with incident ischemic stroke. Associations did not differ by sex, race, or region for the association; however, regional differences in flavanone intake may contribute to regional disparities in ischemic stroke incidence. Higher flavanone intake in blacks suggests that flavanone intake is not implicated in racial disparities in ischemic stroke incidence.

IntroductionThe minimal stroke severity justifying endovascular intervention remains elusive; however, a significant proportion of patients presenting with large vessel occlusion (LVO) and mild symptoms subsequently decline and face poor outcomes.ObjectiveTo evaluate our experience with these patients by comparing best medical therapy with thrombectomy in an intention-to-treat analysis.MethodsAnalysis of prospectively collected data of all consecutive patients with National Institutes of Health Stroke Scale (NIHSS) score ≤5, LVO on CT angiography, and baseline modified Rankin Scale (mRS) score 0–2 from November 2014 to May 2016. After careful discussion with patients/family, a decision to pursue medical or interventional therapy was made. Deterioration (development of aphasia, neglect, and/or significant weakness) triggered reconsideration of thrombectomy. The primary outcome measure was NIHSS shift (discharge NIHSS score minus admission NIHSS score).ResultsOf the 32 patients qualifying for the study, 22 (69%) were primarily treated with medical therapy and 10 (31%) intervention. Baseline characteristics were comparable. Nine (41%) medically treated patients had subsequent deterioration requiring thrombectomy. Median time from arrival to deterioration was 5.2 hours (2.0–25.0). Successful reperfusion (modified Treatment in Cerebral Infarction 2b−3) was achieved in all 19 thrombectomy patients. The NIHSS shift significantly favored thrombectomy (−2.5 vs 0; pConclusionsThrombectomy led to a shift towards a lower NIHSS in patients with LVO presenting with minimal stroke symptoms. Despite the overall perception that this condition is benign, nearly a quarter of patients primarily treated with medical therapy did not achieve independence at 90 days.