Favorable Shift Research Articles

Embryonic Mice with Lung-Specific RAGE Upregulation Have Enhanced Mitochondrial Respiration

RAGE (receptor for advanced glycation end-products) represents a class of multi-ligand pattern recognition receptors highly expressed in the vertebrate lung. Our previous work demonstrated unique patterns of RAGE expression in the developing murine lung and regulation by key transcription factors including NKX2.1 and FoxA2. The current investigation employed conditional lung-specific upregulation via a TetOn transgenic mouse model (RAGE TG) and nontransgenic controls. RAGE expression was induced in RAGE TG mice throughout gestation (embryonic day, E0-E18.5) or from E15.5-E18.5 and compared to age-matched controls. High-resolution respirometry was used to assess mitochondrial respiration and context was provided by quantifying ATP and reactive oxygen species (ROS) generation. Lung lysates were also screened by immunoblotting for MAPK/PI3K signaling intermediates. RAGE upregulation increased mitochondrial oxygen consumption in the E0-E18.5 and E15.5-E18.5 groups compared to controls. RAGE TG mice also had increased ATP concentrations, which persisted even after controlling for oxygen consumption. In contrast, ROS generation was diminished in RAGE TG animals compared to controls. Lastly, in both RAGE TG groups, pERK and pp38 were significantly decreased, whereas pAKT was significantly elevated, suggesting that RAGE signaling is likely perpetuated via pAKT pathways. Together, these data demonstrate that despite lung hypoplasia in RAGE TG mice, the remaining tissue experiences a favorable shift in mitochondrial bioenergetics without excessive redox assault and a preference for AKT signaling over ERK or p38.

Efficacy of treatment with traditional Chinese patent medicine (Fufang E'jiao Syrup) for cancer-related fatigue in patients with advanced cancer: A randomized, double-blinded, placebo-controlled, multicenter trial.

12053 Background: There is ongoing interest in finding effective drugs for cancer-related fatigue (CRF) in advanced cancer patients, although studies have had mixed results. Fufang E'jiao Syrup (FFEJS), a traditional Chinese patent medicine, has shown promise in alleviating CRF. This trial aims to investigate whether FFEJS could reduce fatigue and improve quality of life in advanced cancer patients. Methods: This prospective, multicenter, double-blinded, placebo-controlled trial was implemented at 29 hospitals in China, enrolling 611 advanced non-small cell lung cancer, colorectal cancer, and gastric cancer patients with Visual Analogue Scale for Fatigue ≥ 4 points. The study was conducted between September 23, 2019 and April 7, 2022, with a final follow-up on May 25, 2022. Participants were randomized to receive FFEJS (20 ml, 3 times per day) or a matching placebo orally for six weeks. The safety assessments were extended until the fourth week after the trial ended. The primary outcome was the change in total mean score (range: 0 [no fatigue] to 10 [extreme fatigue] points) on the Revised Piper Fatigue Scale-Chinese Version (RPFS-CV) from baseline to week 6. Secondary outcomes include quality of life (Functional Assessment of Chronic Illness Therapy-Fatigue, FACIT-F) and adverse events. FFEJS were compared with the placebo group using a linear mixed model. Results: Among 611 patients randomized (FFEJS: 303 and placebo: 308; 210 non-small cell lung cancer [34.4%], 201 colorectal cancer [32.9%], 200 gastric cancer [32.7%]; mean [SD] age, 62.8 [9.3] years; 413 [68.3%] man; mean [SD] baseline RPFS-CV total mean score, 4.86 [1.30] points), 503 (82.3%) completed the primary end point. By the end of week 6, the FFEJS group achieved normal fatigue levels (RPFS-CV < 4) compared to the placebo group (FFEJS: 3.78 vs Placebo: 4.39, adjusted mean difference 0.59 points [95% CI, 0.45 to 0.76 points]; P < .001). The adjusted mean difference for a favorable shift to a higher FACIT-F total score at week 6 comparing FFEJS with placebo was 2.77 points (97.36 vs 94.23 points; [95% CI, 0.56-4.96 points]; P = .02). There was no difference in adverse events occurrence between FFEJS and the placebo groups (110 [20%] vs 122 [18%], P = .38). Conclusions: In this randomized clinical trial among advanced cancer patients with CRF, FFEJS reducedfatigue severity and improved quality of life compared to placebo. Research is needed to assess the mechanism, clinical effect, and long-term safety of FFEJS for CRF in advanced cancer patients. Clinical trial information: NCT04147312 .

Exploiting non-parallel risk premia in the South African sovereign bond market

Background: This study focuses on diversifying fixed income attribution beyond yield and duration by identifying new risk premia applicable to various investment strategies.Aim: To identify cross-sectional bond risk factors in the South African sovereign bond market, capitalising on non-parallel shifts during high-risk macroeconomic events, developing a strategy to extract persistent alpha from higher order interest rate risks and disproving the strong efficient market hypothesis.Setting: This study finds that during high-risk macro events, non-parallel shifts increase in frequency. Empirical evidence suggests that post the 2008 financial crisis, there have been increased occurrences of risk-on/off events and researchers believe high risk macro events will increase in prominence. As such, most active US fixed income managers have reduced duration risk (from parallel shifts) in favour of alternative risk premia.Method: This study exploits slope and curvature risks, by utilising a butterfly strategy. Ten bond risk factors are back-tested and analysed during interest rate cycles, curve scenarios and risk-off periods from 1998 to 2023.Results: The top-ranked strategies displayed strong and persistent outperformance over the bottom-ranked strategies for most of the bond factors especially during risk-on episodes. The Bond All-Factor Rank demonstrated improved diversification by balancing upside and downside risks. Trade costs are an important factor that requires pragmatic management.Conclusion: Geopolitical risks are increasing in frequency and developing a strategy to exploit non-parallel risk premia is an attractive proposition.Contribution: This study identified new bond risk factors beyond the conventional spread factor to extract non-parallel risk premia.

Noncontrast CT Selected Thrombectomy vs Medical Management for Late-Window Anterior Large Vessel Occlusion.

There is uncertainty whether patients with large vessel occlusion (LVO) presenting in the late 6-hour to 24-hour time window can be selected for endovascular therapy (EVT) by noncontrast CT (NCCT) and CT angiography (CTA) for LVO detection. We evaluated the clinical outcomes of patients selected for EVT by NCCT compared with those medically managed in the extended time window. This multinational cohort study was conducted at 66 sites across 10 countries. Consecutive patients with proximal anterior LVO stroke selected for EVT by NCCT or medically managed and presenting within 6-24 hours of time last seen well (TSLW) from January 2014 to May 2022 were included. The primary end point was the 90-day ordinal shift in the modified Rankin Scale (mRS) score. Inverse probability treatment weighting (IPTW) and multivariable methods were used. Of 5,098 patients screened, 839 patients were included, with a median (interquartile range) age of 75 (64-83) years; 455 (54.2%) were women. There were 616 patients selected to undergo EVT by NCCT (73.4%) and 223 (26.6%) who were medically managed. In IPTW analyses, there was a more favorable 90-day ordinal mRS shift in patients selected by NCCT to EVT vs those who were medically managed (odds ratio [OR] 1.99, 95% CI 1.53-2.59; p < 0.001). There were higher rates of 90-day functional independence (mRS 0-2) in the EVT group (40.1% vs 18.4%, OR 3.31, 95% CI 2.11-5.20; p < 0.001). sICH was nonsignificantly higher in the EVT group (8.5% vs 1.4%, OR 3.77, 95% CI 0.72-19.7, p = 0.12). Mortality at 90 days was lower in the EVT vs MM group (23.9% vs 32.3%, OR 0.61, 95% CI 0.45-0.83, p = 0.002). In patients with proximal anterior LVO in the extended time window, there was a lower rate of disability and mortality in patients selected with NCCT and CTA to EVT compared with those who were medically managed. These findings support the use of NCCT as a simpler and more inclusive approach to patient selection in the extended window. This study was registered at ClinicalTrials.gov under NCT04096248. This study provides Class III evidence that for patients with proximal anterior circulation occlusion presenting with ischemic stroke from 6 to 24 hours, compared with medical management, those undergoing thrombectomy based on NCCT have reduced disability and mortality at 90 days.

Rescue Therapy for Failed Mechanical Thrombectomy in Acute Ischemic Stroke: A Pooled Analysis of the Society of Vascular and Interventional Neurology Registry.

We aimed to evaluate the association between rescue therapy (RT) and functional outcomes compared to medical management (MM) in patients presenting after failed mechanical thrombectomy (MT). This cross-sectional study utilized prospectively collected and maintained data from the Society of Vascular and Interventional Neurology Registry, spanning from 2011 to 2021. The cohort comprised patients with large vessel occlusions (LVOs) with failed MT. The primary outcome was the shift in the degree of disability, as gauged by the modified Rankin Scale (mRS) at 90 days. Additional outcomes included functional independence (90-day mRS score of 0-2), symptomatic intracranial hemorrhage (sICH), and 90-day mortality. Of a total of 7,018 patients, 958 presented failed MT and were included in the analysis. The RT group comprised 407 (42.4%) patients, and the MM group consisted of 551 (57.5%) patients. After adjusting for confounders, the RT group showed a favorable shift in the overall 90-day mRS distribution (adjusted common odds ratio = 1.79, 95% confidence interval [CI] = 1.32-2.45, p < 0.001) and higher rates of functional independence (RT: 28.8% vs MM: 15.7%, adjusted odds ratio [aOR] = 1.93, 95% CI = 1.21-3.07, p = 0.005) compared to the MM group. RT also showed lower rates of sICH (RT: 3.8% vs MM: 9.1%, aOR = 0.52, 95% CI = 0.28-0.97, p = 0.039) and 90-day mortality (RT: 33.4% vs MM: 45.5%, aOR = 0.61, 95% CI = 0.42-0.89, p = 0.009). Our findings advocate for the utilization of RT as a potential treatment strategy for cases of LVO resistant to first-line MT techniques. Prospective studies are warranted to validate these observations and optimize the endovascular approach for failed MT patients. ANN NEUROL 2024;96:343-355.

Revealing the source: How awareness alters perceptions of AI and human-generated mental health responses

In mental health care, the integration of artificial intelligence (AI) into internet interventions could significantly improve scalability and accessibility, provided that AI is perceived as being as effective as human professionals. This longitudinal study investigates the comparative perceptions of ChatGPT and human mental health support professionals across three dimensions: authenticity, professionalism, and practicality. Initially, 140 participants evaluated responses from both sources without knowing their origin, revealing that AI-generated responses were rated significantly higher across all dimensions. Six months later, the same cohort (n = 111) reassessed these messages with the source of each response disclosed, aiming to understand the impact of source transparency on perceptions and trust towards AI. The results indicate a shift in perception towards human responses, only in terms of authenticity (Cohen's d = 0.45) and reveal a significant correlation between trust in AI and its practicality rating (r = 0.25), but not with authenticity or professionalism. A comparative analysis between blind and informed evaluations revealed a significant shift in favour of human response ratings (Cohen's d = 0.42–0.57), while AI response ratings experienced minimal variation. These findings highlight the nuanced acceptance and role of AI in mental health support, emphasizing that the disclosure of the response source significantly shapes perceptions and trust in AI-generated assistance.

Abstract SY38-02: Clinical investigations of obesity in cancer: BMI and other confounders

Abstract SY38-02: Clinical investigations of obesity in cancer: BMI and other confounders

Sex Differences in Prognosis of Childhood Arterial Ischemic Stroke: Results From Chinese Pediatric Ischemic Stroke Registry Multicenter Registry

BackgroundCurrent studies on the impact of sex in the prognosis of childhood arterial ischemic stroke (AIS) are limited. We aimed to explore the sex differences in outcomes in patients with childhood AIS. MethodsA retrospective analysis was conducted using the prospective data from the Chinese Pediatric Ischemic Stroke Registry. Baseline characteristics between sexes were compared in the total population cohort, propensity score (PS)-matched cohort, and inverse probability of treatment weighting cohort. Multivariate logistic regression and ordinal regression were used to analyze the association of sex with outcomes. Mixed-effects regression model was applied to further analyze the improvement in pediatric modified Rankin Scale (mRS) scores between sexes from 90 days to one year. Survival analysis was used to estimate the recurrence rates during the follow-up period. ResultsA total of 468 patients were finally included. Multivariate logistic regression showed that there were no significant differences between females and males in achieving favorable outcome (odds ratio [OR] 1.04, 95% confidence interval [CI] 0.63 to 1.72), functional independence (OR 0.98, 95% CI 0.59 to 1.63), or shift to worse pediatric mRS scores (OR 0.83, 95% CI 0.59 to 1.17) at 90-day. Mixed-effects regression and survival analysis indicated that females and males exhibited comparable functional recovery from 90 days to one year and had similar recurrent risk during the follow-up period. ConclusionsThis nationally-representative observational study indicated that both male and female pediatric patients with AIS exhibited comparable similar clinical outcomes at 90 days, as well as similar improvements and risks of recurrence during the follow-up period.

Moving From CT to MRI Paradigm in Acute Ischemic Stroke: Feasibility, Effects on Stroke Diagnosis and Long-Term Outcomes.

The relative value of computed tomography (CT) and magnetic resonance imaging (MRI) in acute ischemic stroke (AIS) is debated. In May 2018, our center transitioned from using CT to MRI as first-line imaging for AIS. This retrospective study aims to assess the effects of this paradigm change on diagnosis and disability outcomes. We compared all consecutive patients with confirmed diagnosis of AIS admitted to our center during the MRI-period (May 2018-August 2022) and an identical number of patients from the preceding CT-period (December 2012-April 2018). Univariable and multivariable analyses were performed to evaluate outcomes, including the number and delay of imaging exams, the rate of missed strokes, stroke mimics treated with thrombolysis, undetermined stroke mechanisms, length of hospitalization, and 3-month disability. The median age of the 2972 included patients was 76 years (interquartile range, 65-84), and 46% were female. In the MRI-period, 80% underwent MRI as first acute imaging. The proportion of patients requiring a second acute imaging modality for diagnostic ± revascularization reasons increased from 2.1% to 5% (Punadj <0.05), but it decreased in the subacute phase from 79.0% to 60.1% (Padj <0.05). In thrombolysis candidates, there was a 2-minute increase in door-to-imaging delay (Padj <0.05). The rates of initially missed AIS diagnosis was similar (3.8% versus 4.4%, Padj=0.32) and thrombolysis in stroke mimics decreased by half (8.6% versus 4.3%; Padj <0.05). Rates of unidentified stroke mechanism at hospital discharge were similar (22.8% versus 28.1%; Padj=0.99). The length of hospitalization decreased from 9 (interquartile range, 6-14) to 7 (interquartile range, 4-12) days (Padj=0.62). Disability at 3 months was similar (common adjusted odds ratio for favorable Rankin shift, 0.98 [95% CI, 0.71-1.36]; Padj=0.91), as well as mortality and symptomatic intracranial hemorrhage. A paradigm shift from CT to MRI as first-line imaging for AIS seems feasible in a comprehensive stroke center, with a minimally increased delay to imaging in thrombolysis candidates. MRI was associated with reduced thrombolysis rates of stroke mimics and subacute neuroimaging needs.

Anesthetic management for large vessel occlusion acute ischemic stroke with tandem lesions

BackgroundEndovascular therapy (EVT) stands as an established and effective intervention for acute ischemic stroke in patients harboring tandem lesions (TLs). However, the optimal anesthetic strategy for EVT in TL patients...

Efficacy of Endovascular Thrombectomy in Acute Basilar Artery Occlusion with Low PC-ASPECTS: A Nationwide Prospective Registry-Based Study.

We evaluated the efficacy of endovascular thrombectomy (EVT) on the functional outcome of patients with acute basilar artery occlusion and low posterior circulation acute stroke prognosis early computed tomography score (PC-ASPECTS). We identified patients with acute ischemic stroke due to basilar artery occlusion and PC-ASPECTS of 6 or less, presenting within 24 h between August 2008 and April 2022. The primary outcome was a favorable functional outcome, defined as a modified Rankin Scale (mRS) score of 0-3 at 90 days. The secondary outcomes included an mRS score of 0-2, a favorable shift in the ordinal mRS scale, the occurrence of symptomatic intracranial hemorrhage (sICH), and mortality at 90 days. We compared the outcome of patients treated with EVT and those without EVT, using the inverse probability of treatment weighting methods. Out of 566 patients, 55.5% received EVT. In the EVT group, 106 (33.8%) achieved favorable outcomes, compared to 56 patients (22.2%) in the conservative group. EVT significantly increased the likelihood of achieving a favorable outcome compared to conservative treatment (relative risk [RR] 1.39, 95% confidence interval [CI], 1.11-1.74, p = 0.004). EVT was associated with a favorable shift in the mRS (RR 1.85, 95% CI, 1.49-2.29, p < 0.001) and reduced mortality without an increase in the risk of sICH. It did not have an impact on achieving an mRS score of 0-2. Patients with acute basilar artery occlusion and a PC-ASPECTS of 6 or less might benefit from EVT without an increasing sICH. ANN NEUROL 2024;95:788-799.

Favorable subgingival plaque microbiome shifts are associated with clinical treatment for peri-implant diseases

We performed a longitudinal shotgun metagenomic investigation of the plaque microbiome associated with peri-implant diseases in a cohort of 91 subjects with 320 quality-controlled metagenomes. Through recently improved taxonomic profiling methods, we identified the most discriminative species between healthy and diseased subjects at baseline, evaluated their change over time, and provided evidence that clinical treatment had a positive effect on plaque microbiome composition in patients affected by mucositis and peri-implantitis.

Abstract WP188: Differences in Outcomes Due to Anesthesia Management During Endovascular Treatment of Patients With Acute Ischemic Stroke Due to Tandem Lesions

Background: Endovascular therapy (EVT) has been reported to be safe and effective for acute ischemic stroke (AIS) patients with tandem lesions (TLs). However, the optimal anesthetic management during EVT for TL patients is unknown. We aimed to assess the impact of anesthesia modality on clinical outcomes in AIS patients with TLs. Methods: Patient level data were pooled from 16 centers for anterior circulation TLs from 2015-2020. Patients were divided into general anesthesia (GA) and procedural sedation (PS). Multivariable logistic regression was used to assess the association of outcomes including modified Rankin Score (mRS) 0-2, ordinal shift is mRS, symptomatic intracranial hemorrhage (sICH), successful reperfusion (mTICI score ≥2b), excellent reperfusion (mTICI 3), first pass effect (FPE), early neurological recovery (ENI), door to skin puncture and reperfusion, and 90-day mortality. Results: Among 691 patients, 595 (GA:230 [38.7%] and PS:365 [61.3%]) were included in the final analysis. Patients treated with GA had lower odds of mRS 0-2 (36.6% vs. 52.5%, aOR: 0.56, 95% CI: 0.38-0.84, p =0.005) and favorable shift in 90 days mRS (aOR: 0.71, 95% CI: 0.51-0.99, p =0.041) when compared to PS. No differences were noted for sICH (3.9% vs. 4.7%, aOR: 0.66, 95% CI: 0.26-1.66, p =0.38), successful reperfusion (89.1% vs 86.5%, aOR: 1.59, CI: 0.87-2.89, p=0.13), excellent reperfusion (48.5% vs 50.3%, aOR: 0.85, CI: 0.56-1.30, p=0.462), FPE (53.6% vs 63.4%, aOR: 0.67, CI 0.45-1.0, p=0.05), ENI (38.9% vs 38.8%, aOR: 0.70, CI: 0.44-1.12, p=0.138), mortality at 90 days (20.3% vs 16.3%, aOR: 0.74, CI: 0.29-1.87, p=0.525), door to skin puncture (80 [46-117.5] mins vs 54 [21-100], p=0.607) and skin puncture to reperfusion (59 [39.5-85.5] mins vs 54 [38-81], p=0.836). Conclusions: In patients with AIS with TLs treated with EVT, GA was associated with lower odds of functional independence without a significant increased risk of sICH, mortality, or treatment delays.

Abstract TMP37: Improved Outcomes for Acute Ischemic Stroke Patients After Implementation of the RapidAI Platform in a Comprehensive Stroke Center in Santiago, Chile

Introduction: In Latin America (LATAM), the prevalence of stroke is alarmingly high. The advancement of artificial intelligence (AI) technologies has potential to dramatically improve healthcare outcomes. RapidAI is a software solution that utilizes AI to quickly analyze imaging data to identify vascular occlusions and salvageable tissue. Physicians receive notifications and can review source images on the Rapid mobile app (RMA). Methods: This was a retrospective analysis of 1,672 consecutive acute stroke patients (AIS) treated at Clinica Alemana de Santiago between 2014-2023. Primary outcomes were the number of AIS patients treated with thrombolysis (IV tPA), mechanical thrombectomy (MT), or decompressive craniectomies as well as time to treatment. Secondary outcomes included discharge Modified Rankin score (mRS) and hospital length of stay (LOS). Results: This analysis included 824 patients pre-RapidAI installation and 848 after installation of Rapid CTP with hypodensity, CTA, ASPECTS, LVO and RMA communication. The baseline NIHSS and last know well to hospital arrival was balanced between the 2 study cohorts. Median time to IV tPA improved by 42 minutes (80 to 38 minutes, p &lt; 0.0001). IV tPA utilization increased from 23% to 30% post-Rapid (p = 0.0033). MT procedure utilization increased from 5% pre-Rapid to 10% (p &lt; 0.0001). Decompressive craniectomies were reduced from 13 to 4, LOS was unchanged. There was a favorable shift in the distribution of mRS scores at discharge in post-Rapid patients (p = 0.031) and a significant increase in mRS 0-1 outcomes (61% vs 45%). Discussion: Following implementation of the AI software platform in a comprehensive stroke center like Clinica Alemana, there was a significant increase in patients treated with IV tPA, faster door to tPA and/or MT times, a decrease in the number of DCTs, and improved discharge mRS scores. This work supports future studies expanding the use of AI technology for improving stroke outcomes in LATAM.

Short term e-bicycle riding results in favorable cardiometabolic shifts in moderately active adults

PurposeElectric bikes (EB) are a form of active transportation with demonstrated health benefits. The purpose of this study was to determine the influence of riding an EB for one week on indices of cardiometabolic health in middle-aged adults.MethodsAdults (n = 22; age = 57.1 ± 11.3 year; BMI = 27.7 ± 4.9) participated in a 2 week study. During Week 1, participants were instructed to continue regular activities. Starting Week 2 participants were provided an EB to ride at least 3 days for a minimum of 30 min·day−1. Physical activity (PA) and glucose were measured continuously. Body composition, blood lipids, glucose, insulin, hemoglobin A1c (HbA1c), plasma endothelin-1 (ET-1), and carotid-femoral pulse wave velocity (cf-PWV) were measured on days 1 and 14.Data and Statistical analyses or Statistics. Each participant served as their own control. Paired t-tests compared dependent variables between week 1 (without EB) and week 2 (with EB).ResultsWhen provided an EB for one week, moderate to vigorous PA increased by 6–9 min·day−1 (P < 0.05) and sedentary time decreased by ~ 77 min·day−1 (P < 0.05). Data from 24 h continuous glucose monitoring showed the percentage of time in healthy range (70–120 mg·dl−1 glucose) increased (P < 0.05) from week 1 to week 2. Compared to day 1, cf-PWV was lower at day 14 (P < 0.05) following one week of riding an EB.ConclusionModerately-active, middleaged adults showed improved continuous glucose regulation and lower central arterial stiffness following one week of riding an EB.

Abstract 158: Rescue Strategy for Failed Mechanical Thrombectomy in Acute Ischemic Stroke: An Analysis of the SVIN Registry

Background: Mechanical thrombectomy (MT) fails to achieve successful reperfusion in up to 20% of large vessel occlusions (LVOs). Rescue strategies (RS) have shown promise in multicenter studies and meta-analyses. We aimed to evaluate the association between RS with functional outcomes compared to medical management (MM) in patients who underwent failed MT. Methods: This is a cross-sectional study using prospectively collected data from the Society of Vascular and Interventional Neurology (SVIN) Registry from 2018 to 2021. We included all adult patients with anterior circulation LVOs who experienced a failed MT (mTICI 0-2a after multiple attempts to clot retrieval) at the 14 participating centers. The patients were divided into two groups: those who received RS (including balloon angioplasty alone, intracranial stenting with or without balloon angioplasty) and those who only received MM. The primary outcome was the shift in the degree of disability, as measured by the mRS at 90 days. Additional outcomes included functional independence (90-day mRS score of 0-2), sICH, and mortality at 90 days. Results: A total of 642 patients were included in the analysis. The RS group consisted of 294 (45.8%) patients, while the MM group comprised 348 (54.2%) patients. A mTICI score of 2b-3 was achieved in 242/293 (82.6%) patients in the RS group. After adjusting for confounders, the RS group showed a favorable shift in the overall 90-day mRS distribution (acOR=1.97, 95%CI 1.36-2.85, p =&lt;0.001) and higher rates of functional independence (RS: 30.7% vs. MM: 12%, aOR=2.39, 95%CI 1.34-4.26, p =0.003) ( Figure ) compared to the MM group. RS also showed lower rates of sICH (RS: 2.7% vs. MM: 9%, aOR=0.32, 95%CI 0.14-0.71, p =0.005) and 90-day mortality (RS: 29.5% vs. MM: 49.7%, aOR=0.49, 95%CI 0.33-0.74, p =&lt;0.001). Conclusion: Our findings support the use of RS as a potential alternative for stroke patients with failed MT. Further prospective studies are needed to validate these observations.

MRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumors

BackgroundDespite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically “cold” tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines. mRNA-based immunotherapeutics have also garnered widespread interest for their potential to revolutionize cancer treatment. In this study, we developed a novel and scalable approach for the production of personalized mRNA-based therapeutics that target multiple tumor rejection antigens in a single therapy for the treatment of refractory brain tumors.MethodsTumor-specific neoantigens and aberrantly overexpressed tumor-associated antigens were identified for glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (O.R.A.N). Personalized tumor antigen-specific mRNA vaccine was developed for each individual tumor model using selective gene capture and enrichment strategy. The immunogenicity and efficacy of the personalized mRNA vaccines was evaluated in combination with anti-PD-1 immune checkpoint blockade therapy or adoptive cellular therapy with ex vivo expanded tumor antigen-specific lymphocytes in highly aggressive murine GBM models.ResultsOur results demonstrate the effectiveness of the antigen-specific mRNA vaccines in eliciting robust anti-tumor immune responses in GBM hosts. Our findings substantiate an increase in tumor-infiltrating lymphocytes characterized by enhanced effector function, both intratumorally and systemically, after antigen-specific mRNA-directed immunotherapy, resulting in a favorable shift in the tumor microenvironment from immunologically cold to hot. Capacity to generate personalized mRNA vaccines targeting human GBM antigens was also demonstrated.ConclusionsWe have established a personalized and customizable mRNA-therapeutic approach that effectively targets a plurality of tumor antigens and demonstrated potent anti-tumor response in preclinical brain tumor models. This platform mRNA technology uniquely addresses the challenge of tumor heterogeneity and low antigen burden, two key deficiencies in targeting the classically immunotherapy-resistant CNS malignancies, and possibly other cold tumor types.

Copper doping effect in the back surface field layer of CdTe thin film solar cells

In this work, the Solar Cell Capacitance Simulator (SCAPS-1D) is employed to evaluate the characteristics of CdTe thin films with ZnTe as the Back Surface Field (BSF) layer and estimate the effective copper doping ratio at both the atomic scale and the device operational response perspective. The electrical characteristics of ZnTe, at varying levels of copper doping, were derived using density functional theory (DFT) by applying the generalized gradient approximation (GGA) and Hubbard U corrections (DFT+U). The performance of ZnTe with different Cu concentrations as a BSF layer was evaluated by analysing the values of four key parameters that are open circuit voltage (VOC), short circuit current density (JSC), fill factor (FF), and conversion efficiency (η). The results indicate that an increase in Cu concentration from 0% to 3%, 6%, 10%, and 12% resulted in a reduction of the energy band gap. Specifically, the energy band gap decreased from 2.24 eV to 2.10 eV, 1.98 eV, 1.92 eV, and 1.88 eV, respectively. Optimal Cu doping promotes the favourable shift in the valence band maxima (VBM) and formation of p + -ZnTe, lowering thermionic emission and improving carrier lifetime, which results in an improved ohmic contact, η = 18.73% for 10% of Cu content. Excessive doping in contrast degraded the overall device performance by forming an unmatched carrier band offset at the front interface with CdS, increasing the acceptor type defect and CdTe compensation rate. Overall, the findings suggest that incorporating a controlled level of Cu, which in this case is around 10%, promotes the efficiency and stability of the proposed CdTe device configuration to a certain extent.

Intravenous Thrombolysis before Complete Angiographic Reperfusion: Beyond Angiographic Assessment to Target Microvascular Obstruction?

Recent data have suggested that ineffective tissue reperfusion despite successful angiographic reperfusion was partly responsible for unfavorable outcomes after endovascular therapy (EVT) and might be modulated by intravenous thrombolysis (IVT) use before EVT. To specifically decipher the effect played by IVT before EVT, we compared the clinical and safety outcomes of patients who experienced a complete reperfusion at the end of EVT according to IVT use before EVT. The Endovascular Treatment in Ischemic Stroke (ETIS) registry is an ongoing, prospective, observational study at 21 centers that perform EVT in France. Patients were included if they had an anterior large vessel occlusion of the intracranial internal carotid artery or middle cerebral artery (M1/M2 segments) and complete reperfusion (expanded Thrombolysis in Cerebral Infarction score = 3) with EVT within 6 hours, between January 2015 and December 2021. The cohort was divided into two groups according to IVT use before EVT, and propensity score matching (PSM) was used to balance the two groups. Primary outcome was the shift in the degree of disability as measured by the modified Rankin Scale (mRS) at 90 days. Secondary outcomes included favorable outcome (mRS 0-2) at 90 days. Safety outcomes included symptomatic intracranial hemorrhage and 90-day mortality. Outcomes were estimated with multivariate logistic models adjusted for age, National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT Score, and time from symptom onset to puncture. Among 5,429 patients included in the ETIS registry, 1,093 were included in the study, including 651 patients with complete recanalization treated with IVT before EVT. After PSM, 488 patients treated with IVT before EVT were compared to 337 patients without IVT. In the matched cohort analysis, the IVT+EVT group had a favorable shift in the overall mRS score distribution (adjusted odds ratio [aOR] = 1.41, 95% confidence interval [CI] = 1.04-1.91, p = 0.023) and higher rates of favorable outcome (61.1% vs 48.7%, aOR = 1.49, 95% CI = 1.02-2.20, p = 0.041) at 90 days compared with the EVT alone group. Rates of symptomatic intracerebral hemorrhage were comparable between both groups (6.0% vs 4.3%, aOR = 1.16, 95% CI = 0.53-2.54, p = 0.709). In clinical practice, even after complete angiographic reperfusion by EVT, prior IVT use improves clinical outcomes of patients without increasing bleeding risk. ANN NEUROL 2024;95:762-773.

Ruminal microbiota-host crosstalks promote ruminal epithelial development in neonatal lambs with alfalfa hay introduction.

Ruminal microbiota is gradually established after birth, while microbiota maturation could be highly diverse because of varied solid dietary accessibility. However, how the ruminal microbiota accreted from postnatal hay diets alters rumen epithelial development, and how this affects animal health remains largely unknown. Here, neonatal lambs were introduced to starchy corn-soybean starter or corn-soybean starter + alfalfa hay (AH) to investigate the influences of early life ruminal microbiome on rumen epithelial development using integrated 16s rRNA sequencing-metagenome-transcriptome approaches. The results showed that AH introduction elevated average daily weight gain, rumen weight and volume, rumen epithelial papillae length, and rumen muscle layer thickness. Meanwhile, the relative abundance of fibrolytic bacteria (Christensenellaceae R-7 group, Prevotellaceae UCG-001, and Succinivibrio), acetate producer (Acetitomaculum and Mitsuokella), and propionate producer Succiniclasticum was increased in the rumen content by AH supplementation (P < 0.05). Moreover, AH introduction decreased the relative abundance of total CAZymes, CBM, and GH and increased the abundance of KO genes related to volatile fatty acid (VFA) generation in the rumen content. AH lambs had a higher relative abundance of Succiniclasticum, Megasphaera, Succinivibrio, and Suttonella (P < 0.05), while a lower relative abundance of Cloacibacillus, Desulfovibrio, Dialister, Intestinimonas, Parabacteroides, and Pseudoscardovia (P < 0.05) in the rumen epithelial samples. Furthermore, these alterations in ruminal microbial structure and function resulted in ruminal epithelial cell proliferation and development pathways activation. In summary, AH introduction benefited ruminal fiber degradation and VFA generation bacteria colonization and promoted ruminal epithelial development. These findings provide new insights into ruminal microbial-host interactions in the early life.IMPORTANCEWhile it is established that a fiber-rich diet promotes rumen development in lambs, further research is needed to investigate the precise response of rumen microbiota and epithelium to high-quality alfalfa hay. Here, we observed that the inclusion of alfalfa hay led to a discernible alteration in the developmental trajectory of the rumen. Notably, there was a favorable shift in the rumen's volume, morphology, and the development of rumen papillae. Furthermore, ruminal microbial structure and function resulted in ruminal epithelial cell proliferation and development pathways activation, collectively provide compelling evidence supporting the capacity of alfalfa hay to enhance rumen development and health through ruminal micrbiota-host crosstalks. Our findings elucidate the functional response of the rumen to alfalfa hay introduction, providing new insights into strategies for promoting healthy development of the rumen in young ruminants.