Serial Time Research Articles

Different Glymphatic Kinetics in Spontaneous Intracranial Hypotension.

The glymphatic (glia-lymphatic) system is a paravascular pathway for the clearance of waste metabolites including amyloid β from the brain. Serial T1 relaxation time measurements after the intrathecal injection of gadolinium-based contrast agents facilitate the analysis of the temporal dynamics that may be different in patients with spontaneous intracranial hypotension (SIH) and those without SIH. 3D T1-weighted magnetization-prepared 2 rapid gradient echo sequences were acquired in 4 patients with SIH with proved CSF leaks and 12 patients without SIH before, 2-4, 6-8, and 24-48 hours after intrathecal gadobutrol injection. MR scans were warped to the Montreal Neurological Institute space and serial scans were coregistered. T1 relaxation times were measured in predefined ROIs including the subarachnoid space, cortex, white matter, and cervical lymph nodes. In the subarachnoid space and cortex, T1 relaxation times decreased after 2-4 and 6-8 hours before they increased again. In contrast, in the white matter of the temporal lobe T1 relaxation time still decreased after 24-48 hours. There was a striking difference in patients with SIH who did not show a clear contrast distribution within the brain parenchyma. T1 relaxation time curves are compatible with a convective flow driven by arterial pulsations via paravascular spaces surrounding penetrating arteries into the brain's interstitial fluid in the deep white matter. Different curves in patients with SIH and those without SIH indicate that the CSF pressure also impacts the temporal kinetics of the glymphatic system.

The importance of electrode-tissue proximity in creating pulsed field ablation lesions: insights from a sub-acute preclinical model.

We sought to evaluate the anatomic and functional lesion development over time at different atrial sites immediately following delivery of pulsed field ablation (PFA). Using a porcine model, PFA ablations were performed in the superior vena cava (SVC), right atrial lateral wall (RA), left atrial appendage (LAA), and right superior pulmonary vein (RSPV) using four different PFA profiles. Mapping was done sequentially in 5-20-min increments up to 280-min post lesion delivery for low voltage area (LVA) assessment and conduction velocity. Lesion characteristics were noted with voltage mapping immediately post ablation and at the serial time points. In 9 animals, 33 sites were ablated. None of the four different profiles across all sites showed any statistical difference on acute lesion formation or persistence. Higher tissue contact was observed in the SVC and RSPV and lower tissue contact was observed in the LAA and RA locations. Higher contact areas were noted to have higher density electroanatomic low voltage area (LVA) (12/14 vs 5/18, p = 0.01) and larger lesions on gross pathology (2 /14 vs 6/16, p = 0.01) compared to lower contact areas. Lesion regression occurred in 16/33 sites. Sustained lesions were significantly more prevalent in higher versus lower contact sites (65% vs 38%, p = 0.037). The development of significant and durable lesions for PFA in a porcine model appears to be dependent on tissue proximity and contact.

Deletion of tissue factor pathway inhibitor isoform beta or gamma, but not alpha, improves clotting in hemophilic mice

BackgroundTissue factor pathway inhibitor (TFPI) regulates tissue factor–triggered coagulation. Humans and mice express transcripts encoding for multidistributed (endothelial, platelet, and plasma) 3-Kunitz domain TFPIα and endothelial membrane–anchored 2-Kunitz TFPIβ. Mice express a third transcript, γ, that encodes plasma lipoprotein–associated 2-Kunitz TFPI. In humans, proteolysis of α and/or β produces plasma lipoprotein–associated 2-Kunitz TFPI at lower levels. In clinical trials, monoclonal antibodies that target all TFPI isoforms extend coagulation and correct bleeding in hemophilic patients but with some thrombosis risks. ObjectivesTo determine the impact of TFPI isoform-specific deletions on promoting clotting in hemophilic mice. MethodsEngineered TFPI isoform–specific, hemophilic (factor VIII-null) mice were evaluated for clotting. ResultsMice expressing any single TFPI isoform were healthy. Thrombin generation assays identified TFPIγ as the dominant anticoagulation isoform in mouse plasma. Hemostasis was assessed by serial bleeding times from a tail vein laceration. Repeatedly, after a clot forms, it was manually disrupted; the number of clots/disruptions occurring over a 15-minute period were reported. C57BL/6 and hemophilic mice clot on average 25.6 vs 5.4 times, respectively. On a hemophilia background, TFPIβ or TFPIγ-specific deletion improved clotting to 14.6 and 15.2 times, respectively (P < .0001). TFPIα-specific deletion was without impact, clotting 5.1 times. Heterozygous deletion of TFPIβ was effective, clotting 11.8 times (P < .0001). Heterozygous deletion of TFPIα or TFPIγ alone was ineffective, clotting 3.0 and 6.1 times, respectively, but heterozygous TFPIαγ deletion improved clotting to 11.2 times (P < .001). ConclusionIn hemophilic mice, endothelial TFPIβ and plasma γ-derived 2-Kunitz TFPI individually contribute more to bleeding than total TFPIα.

The effects of irrelevant speech on physiological stress, cognitive performance, and subjective experience – Focus on heart rate variability

Irrelevant speech impairs cognitive performance, especially in tasks requiring verbal short-term memory. Working on these tasks during irrelevant speech can also cause a physiological stress reaction. The aim of this study was to examine heart rate variability (HRV) as a non-invasive and easy-to-use stress measure in an irrelevant speech paradigm. Thirty participants performed cognitive tasks (n-back and serial recall) during two sound conditions: irrelevant speech (50 dB) and quiet (33 dB steady-state noise). The influence of conditions as well as presentation orders of conditions were examined on performance, subjective experience, and physiological stress. Working during irrelevant speech compared to working during quiet reduced performance, namely accuracy, in the serial recall task. It was more annoying, heightened the perceived workload, and lowered acoustic satisfaction. It was related to higher physiological stress by causing faster heart rate and changes in HRV frequency-domain analysis (LF, HF and LF/HF). The order of conditions showed some additional effects. When speech was the first condition, 3-back performance was less accurate, and serial recall response times were longer, heart rate was faster, and successive heart beats had less variability (lower RMSSD) during speech than during quiet. When quiet was the first condition, heart rate was faster and reaction times in 3-back were slower during quiet than during speech. The negative effect of irrelevant speech was clear in experience, performance, and physiological stress. The study shows that HRV can be used as a physiological stress measure in irrelevant speech studies.

Temporal progression of pupil dilation and gaze behavior to emotion expressions in preschoolers with autism spectrum disorder

Previous work has shown divergent pupil dilation (PD) and gaze behavior in individuals with autism spectrum disorder (ASD), which may relate to the development of social difficulties in early life. Here, we investigated temporal dynamics of both phenotypes during naturalistic videos of a person displaying facial emotion expressions in 61 autistic and 61 non-autistic preschoolers. PD was segmented into three serial time components derived from a principal component analysis. Growth curve analysis was applied to analyze changes in looking time on eye and mouth regions over time. Groups did not differ in PD time components. Growth curve analysis revealed initially shorter looking times on the eyes and longer looking times on the mouth in autistic versus non-autistic preschoolers. However, a reversion of this pattern was observed over time, suggesting a delayed compensatory increase in eye attention during prolonged viewing periods in autistic children. Positive and negative associations of PD components and gaze behavior over time indicated a dynamic temporal relationship during emotion viewing. Our findings emphasize the need to apply time-sensitive measures in ecologically valid research, which may index etiological mechanisms of social difficulties in ASD.

Building an Annotated L1 Arabic/L2 English Bilingual Writer Corpus: The Qatari Corpus of Argumentative Writing (QCAW)

Abstract The study presents the creation of the Qatari Corpus of Argumentative Writing (QCAW) as an annotated L1 Arabic and L2 English bilingual writer corpus. It comprises 200,000 tokens of argumentative writing by Qatari university students in L1 Arabic and L2 English. The corpus includes 195 essays written by 195 students, 159 females and 36 males. The students were native Arabic speakers proficient in English as a second language. The corpus is divided into Arabic and English sections, accompanied by part-of-speech annotated files in UTF-8 encoded text format. Metadata in CSV format contains information about the students (gender, major, first and second languages) and the essays (text serial numbers, word limits, genre, writing date, time spent, and location). The current study outlines the steps for collecting and analysing the corpus, including details on essay writers, topic selection, pre-analysis text modifications, proficiency level, gender, and major ratings. Statistical analyses were applied to examine the corpus. The QCAW offers a valuable bilingual data source authored by the same students in Arabic and English, with implications for further research.

Identifying Transfer Learning in the Reshaping of Inductive Biases.

Transfer learning, the reuse of newly acquired knowledge under novel circumstances, is a critical hallmark of human intelligence that has frequently been pitted against the capacities of artificial learning agents. Yet, the computations relevant to transfer learning have been little investigated in humans. The benefit of efficient inductive biases (meta-level constraints that shape learning, often referred as priors in the Bayesian learning approach), has been both theoretically and experimentally established. Efficiency of inductive biases depends on their capacity to generalize earlier experiences. We argue that successful transfer learning upon task acquisition is ensured by updating inductive biases and transfer of knowledge hinges upon capturing the structure of the task in the inductive bias that can be reused in novel tasks. To explore this, we trained participants on a non-trivial visual stimulus sequence task (Alternating Serial Response Times, ASRT); during the Training phase, participants were exposed to one specific sequence for multiple days, then on the Transfer phase, the sequence changed, while the underlying structure of the task remained the same. Our results show that beyond the acquisition of the stimulus sequence, our participants were also able to update their inductive biases. Acquisition of the new sequence was considerably sped up by earlier exposure but this enhancement was specific to individuals showing signatures of abandoning initial inductive biases. Enhancement of learning was reflected in the development of a new internal model. Additionally, our findings highlight the ability of participants to construct an inventory of internal models and alternate between them based on environmental demands. Further, investigation of the behavior during transfer revealed that it is the subjective internal model of individuals that can predict the transfer across tasks. Our results demonstrate that even imperfect learning in a challenging environment helps learning in a new context by reusing the subjective and partial knowledge about environmental regularities.

Prototype design and experimental study of fission neutron imaging at China Mianyang research reactor

Taking advantage of the special reaction principle between neutrons and elements, the neutron imaging method is better suited to testing the structure and the defects of light materials that are covered by heavy materials. In contrast to thermal or cold neutron imaging, the fast neutrons are best suited to testing the large samples composed of various materials. Fission neutrons emitted from the reactor are more stable than those from other neutron sources. Based on the beamline for thermal neutron imaging at China Mianyang Research Reactor (CMRR), a combination of filters could increase the proportion of the fission neutrons. Various fission neutron collimators were calculated, designed and measured. The flux of fission neutrons was close to 3 × 105 cm−2 s−1, when the collimation ratio was about 172. A fission neutron imaging system was built as well. The field of view (FOV) was as large as 400 mm × 400 mm, and the experimental spatial resolution was better than 0.5 mm. The fission neutron tomography was tested. The reconstruction results were comparable to the tomography performed in NECTAR at FRM-II. In addition, a serial time acquisition method was applied in the tomography to reduce the white noise. The ART reconstruction method may improve the quality of the reconstruction images.

Parallel path detection for fraudulent accounts in banks based on graph analysis.

This article presents a novel parallel path detection algorithm for identifying suspicious fraudulent accounts in large-scale banking transaction graphs. The proposed algorithm is based on a three-step approach that involves constructing a directed graph, shrinking strongly connected components, and using a parallel depth-first search algorithm to mark potentially fraudulent accounts. The algorithm is designed to fully exploit CPU resources and handle large-scale graphs with exponential growth. The performance of the algorithm is evaluated on various datasets and compared with serial time baselines. The results demonstrate that our approach achieves high performance and scalability on multi-core processors, making it a promising solution for detecting suspicious accounts and preventing money laundering schemes in the banking industry. Overall, our work contributes to the ongoing efforts to combat financial fraud and promote financial stability in the banking sector.

Increased Monocytic Myeloid-Derived Suppressor Cells Are Associated with Inferior Overall Survival in Patients with Newly Diagnosed Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is an aggressive malignancy associated with poor long-term outcomes. This malignancy arises in the context of an immunosuppressive milieu, which fosters immune escape and tumor growth. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous group of immature myeloid cells with immunosuppressive activity, the most potent of which are the monocytic MDSCs (mMDSCs). The impact of mMDSCs on AML relapse and overall survival has yet to be fully characterized. Therefore, we sought to address this unanswered question through a retrospective analysis of a cohort of AML patients (pts) at Roswell Park Comprehensive Cancer Center. Methods: Medical records were retrospectively reviewed under an IRB approved protocol to identify pts aged ≥ 18 years old with newly diagnosed AML treated with standard cytarabine and anthracycline based chemotherapy from 2004-2017 at Roswell Park Comprehensive Cancer Center. Demographics, disease-specific variables, baseline clinical characteristics, and treatment response were analyzed using descriptive statistics. Detailed analysis of previously collected clinical multiparameter flow cytometric data was performed utilizing WinList software to identify mMDSCs at serial clinical time points (diagnosis, after induction chemotherapy, and relapse). A mononuclear gate was created utilizing CD45 vs. SSC (blasts excluded), followed by FSC vs. SSC to eliminate dead cells and aggregates. mMDSCs were defined as the subset of marrow cells co-expressing CD14+ and HLA-DR dim and was reported as the percentage of total monocytes in the marrow aspirate sample. mMDSC populations were dichotomized into “Low” and “High” groups based on the median value of the entire cohort. Overall survival (OS) and relapse-free survival (RFS) were estimated utilizing Kaplan-Meier (KM) analysis. Results: 81 pts with newly diagnosed AML who received induction with a cytarabine and anthracycline based regimen were identified. Median age was 55 years (range 20 - 85), with 52 men (64.2%) (Table 1). Cytogenetics per ELN 2022 were high risk in 38 pts (46.9%), intermediate risk in 28 pts (34.6%), and favorable risk in 15 pts (18.5%). 6/69 (8.7%) pts had FLT3-ITD mutations. Following induction therapy, 15 pts (18.5%) had primary refractory disease with 66 (81.5%) achieving complete remission (CR). 28 pts (34.6%) underwent allo HSCT. Pts with intermediate risk disease and “High” mMDSCs at time of diagnosis and post induction chemotherapy had inferior OS compared to those with “Low” mMDSCs (16 vs. 34 months, P=0.008; 16 vs. 27 months, P=0.03) (Figure 1). There were no significant differences in RFS in intermediate or poor risk pts, and no difference in OS in poor risk pts when comparing “Low” vs. “High” mMDSCs at any time point. Mean duration of follow up was 23.7 months (range 1 - 148 months). Analysis of favorable risk cohort is ongoing. Conclusions: This retrospective analysis suggests that high numbers of marrow mMDSCs are associated with poor overall survival in pts with intermediate risk AML receiving intensive induction therapy. Of note, other risk factors for poor risk disease such as complete molecular profiling were not available. However, our findings support a potential role of mMDSCs in promoting disease recurrence. Additional studies to further quantify and delineate the biological role of mMDSCs in a larger pt cohort are needed to corroborate these findings and determine the potential role of these immune cells in therapy resistance in AML.

Single-Cell Multiomics Analysis Reveals Potential Drivers of Response to the Anti-TIM3 Inhibitor Sabatolimab Combined with Azacitidine in MDS and CMML

Background The median survival for patients with newly diagnosed (ND) higher risk myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) remains poor. The potential curability of MDS and CMML with allogeneic hematopoietic stem cell transplantation supports the concept of anti-tumor immunity and has led to interest in evaluating immune-based therapeutic approaches in myeloid neoplasms. The immune checkpoint molecule TIM-3 (encoded by the gene HAVCR2) is a target of interest in myeloid neoplasms given its expression on leukemic stem cells as well as several subsets of immune cells including T cells, monocytes, dendritic cells and NK cells. Sabatolimab (MBG453) is an investigational IgG4 anti-TIM-3 antibody currently under evaluation for myeloid neoplasms. In this exploratory study, we sought to characterize the effects of sabatolimab combined with the hypomethylating agent (HMA), azacitidine, on the immune landscape using single cell sequencing of samples from subjects with MDS and CMML treated with the combination from a previously reported phase 1b study (NCT03066648; Brunner et al 2022). Methods Following IRB approval, single-cell RNA sequencing (scRNA-seq) and associated proteomic cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) was performed on both blood (BLD) and bone-marrow (BM) derived samples from subjects with: 1) MDS (n=3) or CMML (n=2) treated with HMA therapy alone as part of standard care; 2) ND MDS (n=5) or CMML (n=3) treated with azacitidine combined with sabatolimab; and 3) relapsed/refractory MDS (n=3) treated with sabatolimab alone. Paired BLD and BM samples as well as samples from serial treatment time points were selected whenever feasible (Fig 1). A total of 206,183 cells from BM and 172,421 cells from BLD post-quality control filtering were analyzed. Further, scRNAseq data from normal BLD(200,000 cells) and BM(240,650 cells) generated as part of the human cell atlas (https://data.humancellatlas.org/explore/projects/cc95ff89-2e68-4a08-a234-480eca21ce79) were integrated with this dataset to assist with immune cell subset characterization, enable downstream comparisons to healthy hematopoietic cells, and to help define cell subsets associated with disease states. Results In baseline samples from subjects with MDS treated with azacitidine-sabatolimab, we found that an increased baseline abundance of interferon-responsive CD8 T cells in both the BM and BLD (FDR&amp;lt;0.1) was associated with response to therapy. An increased baseline abundance of plasmacytoid dendritic cells and a granulocyte population also suggested an association with response to therapy. Differential gene expression analysis of baseline samples from responding versus non-responding subjects with MDS treated with azacitidine-sabatolimab showed a higher baseline expression of TNF and IFNG in BM CD8 T cells and up-regulated expression of MHC-II machinery ( HLA-DRB1, HLA-DPA1, CD74) in myeloid cell subsets in responding subjects (FDR &amp;lt;0.1), suggesting that pre-treatment ability of these cells to be involved in antigen-presentation may play a role in response. In subjects with CMML treated with azacitidine-sabatolimab, we observed dynamic changes in cellular abundances and gene expression when comparing baseline to post-therapy timepoints. Specifically, BM CD8 T cell subsets showed an up-regulation of cytotoxicity genes ( GZMA), interferon response genes ( IFIT2, IFITM1, IFITM2) and IL32 cytokine post-therapy (FDR &amp;lt;0.1). When evaluating myelomonocytic cell populations, we observed an increase in CD16 monocytes post-treatment. Additionally, dendritic cells and monocytes showed an up-regulation of interferon response genes ( IFIT1, OAS1, IFI27). Conversely, we observed a down-regulation of metallothionein genes ( MT1E, MT1G, MT2A) as well as a collection of transcription factors ( NR4A1, FOSL2, JUN, CEBPB, CEBPD), NF-κB inhibitors ( NFKBIZ, NFKBIA) and CXCL8 in the post-treatment samples (FDR &amp;lt;0.1). Conclusions Our study provides one of the most comprehensive evaluations of the cellular dynamics of anti-TIM3 immunotherapy in patients to date, allowing for the nomination of novel putative predictive biomarkers of response and identification of potential immunomodulatory mechanisms induced by the combination of sabatolimab with azacitidine in MDS and CMML for further future analysis.

A Multi-Omic Single-Cell Landscape of Cytokine Release Syndrome in Multiple Myeloma Patients after Anti-BCMA CAR-T Cell Therapy

Introduction: Chimeric antigen receptor T (CAR-T) cell therapy targeting BCMA has achieved great success in the treatment of multiple myeloma, yet cytokine release syndrome (CRS) is the most severe and common complication that limits the safety and increases the expense of CAR-T cell therapy. Precise prediction of CRS severity is critical for early intervention and control of CRS, which warrants a detailed understanding of underlying cellular and molecular mechanisms. While certain cytokines have been identified as the main contributors of CRS, a comprehensive landscape of CRS unset and progression remains enigmatic. Methods and Results: We analyzed clinical samples from patients with multiple myeloma receiving BCMA-CAR-T cell therapy, and obtained a multimodal dataset pertaining to CRS severity by multiplexed cytokine and multi-omic single-cell analyses. First, we generated a multi-plex profile to comprehensively reveal the kinetics of CRS-related cytokines. Plasma samples were collected from 6 patients with severe CRS, at serial time points: before lymphodepletion, after CAR-T infusion before CRS initiation, at CRS initiation, CRS peak and CRS recovery stage. These samples were analyzed for a 45-plex cytokine profile, and we identified 3 main cytokines (IL-2, IL-4 and IL-17A) as signatures of CRS initiation and 24 cytokines at the CRS peak stage, with the latter consisting of known CRS biomarkers (IL-1, IL-6 and CRP) and new CRS-related cytokines (IL-3, CCL20 and CXCL1). Next, we conducted single-cell multi-omic analyses on the transcriptome, immunome and epigenome of CAR-T and bystander immune cells. We collected 111 samples from 16 patients (5 with severe CRS, 6 with mild CRS and 5 non-CRS) for scRNA-seq and scTCR-seq, and 28 samples from 10 patients (3 with severe CRS, 4 with mild CRS and 3 non-CRS patients) for scATAC-seq. scRNA-seq analysis demonstrated systematic and diverse changes across cellular subpopulation and their dynamic cytokine expression across the course of CRS. Moreover, integrated scRNA-seq and scTCR-seq analyses illustrated the developmental trajectory and clonal diversity of CAR-T and endogenous T cells. Specifically, we detected clonal expansion of a CD8+ effector memory T cell subsets upon CRS recovery, which was positively correlated with the persistence of CAR T cells in vivo. Meanwhile, combined analyses of scATAC-seq and scRNA-seq deciphered the chromatin accessibility and cis-regulatory network in CAR-T cells at different CRS stages. Finally, we identified a CD40LG + CD4 + subpopulation in pre-infusion CAR-T products which was associated with CRS severity and could be used as a predictive biomarker of severe CRS. These results were further validated by sorting CD40LG+ CD4+ CAR-T cell subset from the product, and co-culture with monocytes and tumor cells. This subpopulation of CAR-T cells was shown to upregulate IL-13 production and activate monocytes, resulting in the elevation of multiple cytokines associated with CRS. Significance: Our comprehensive multi-omics analyses provide a temporal atlas of CRS at the single-cell level, delineating the critical roles of CAR-T cells, monocytes, endogenous T cells and NKT cells across the course of CRS. Further, we identified a key subpopulation in pre-infusion CAR-T products as a biomarker of CRS severity, providing clinically-relevant insights about both prediction and intervention of CRS.

Cladribine and Cyclophosphamide Lymphodepletion Prior to Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma

Introduction : Chemotherapy-based lymphodepletion (LD) with fludarabine and cyclophosphamide (Flu/Cy) is a standard preparatory step for chimeric antigen T-cell (CAR T) therapy and its importance for optimal CAR T expansion and efficacy is well-established. An international Flu shortage required our center and others to utilize alternative agents for LD or risk interruption in patient therapy. When unable to utilize Flu as part of the LD regimen for patients with relapsed/refractory large B-cell lymphoma (RR LBCL) that required CD19-directed CAR T as a standard of care therapy, our center adopted a standard operating procedure to substitute Flu with Cladribine (Clad), an alternate purine analogue with similar chemical structure, as part of Clad/Cy LD prior to axicabtagene ciloleucel (axi-cel). Here we report outcomes in these patients. Methods : We performed a retrospective, single-center analysis of consecutive RR LBCL patients who received Clad/Cy LD prior to axi-cel at Moffitt Cancer Center between 8/2022 and 1/2023, and compared outcomes to a historical cohort, consisting of 144 Flu/Cy axi-cel LBCL patients treated between 11/2017 and 2/2021. The Clad/Cy LD regimen, given as standard care, maintained Cy at 500 mg/m 2 and substituted Flu 30 mg/m 2 with Clad 5 mg/m 2/day with both agents given on Days -5, -4, and -3. For efficacy we compared best overall response (BOR) at 90 days and progression-free survival (PFS) comparing the two LD regimens. For safety we compared the rates of cytokine release syndrome (CRS) and neurotoxicity as graded by ASTCT criteria. We also performed correlative analyses exploring absolute lymphocyte count (ALC) kinetics, axi-cel expansion by quantitative PCR, and changes in the cytokine milieu as assessed by the enzyme-linked immunosorbent Ella™ system (Bio-Techne, Oxford, UK) at serial time points following infusion. Results : 23 patients received Clad/Cy LD followed by axi-cel for R/R DLBCL. Baseline characteristics of the study cohort based on LD are shown in the Table. Compared to the historical cohort, Clad/Cy patients received axi-cel after fewer lines of treatment (median 2 [range, 1-3] vs 2 [range, 1-7]; Rank-Sum test p&amp;lt;0.01) and had a greater proportion of relapsed (not refractory) disease (52% vs 22%, p&amp;lt;0.01). The 90-day BOR did not differ between the Clad/Cy and Flu/Cy groups (79% vs 84%; P=0.54) with a similar distribution of complete (22% vs 24%) and partial responders (57% vs 60%). With a median follow-up of 4.6 (95% CI, 3.2-6.2) months for Clad/Cy and 24.2 (95% CI, 21.5-25.8) months for Flu/Cy cohorts, PFS was similar (Figure 1B, Log-Rank p=0.84). Rates of CRS grade ≥ 2 were higher in the Clad/Cy cohort (70% vs 44%; p=0.02), but no CRS grade ≥ 3 was observed in the Clad/Cy compared to 13 (9%) of Flu/Cy patients, including three grade 5 events. Neurotoxicity ≥ grade 2 (44% vs 43%; p=0.77) and peak C-reactive protein levels (15 vs Flu/Cy 12; p=0.3) did not differ for the Clad/Cy and Flu/Cy cohorts. Both regimens had comparable peak axi-cel copy numbers (Clad/Cy 7.9 × 10 6 vs Flu/Cy 5.1 × 10 6 copies/µg). Clad/Cy resulted in a predictable decrease in the ALC from Day -5 to Day 0, but a less profound degree of lymphopenia on Day 0 (0.04 vs 0.02; p&amp;lt;0.01) with ALC 0 achieved later (Day +2 [IQR, +1 to +4] vs Day +1 [IQR, -1 to +2] for Flu/Cy). The median magnitude of change of cytokine levels (Delta = Day -5 - Day 0 concentration) differed between Clad/Cy and Flu/Cy for all tested analytes except IL-6 (3.4 vs 4.6 pg/mL for Flu/Cy; p=0.29). Clad/Cy resulted in greater increases in IL-2 (0.5 vs 0.2 for Flu/Cy; p=0.01) and GM-CSF (2.0 vs 0.9 for Flu/Cy; p=0.03), whereas Flu/Cy had higher IL-15 (31.4 vs 16.8 for Clad/Cy; p&amp;lt;0.01). Interestingly, IFN-γ tended to increase in Clad/Cy and to decrease in Flu/Cy (1.2 vs 0.0; p=0.01). Conclusions : Clad/Cy LD is feasible for axi-cel conditioning in the treatment of RR LBCL. Although it resulted in less profound LD on the day of CAR T infusion, a later ALC nadir, and a different cytokine milieu compared to Flu/Cy, it was associated with similar peak axi-cel expansion and, at short term follow-up, there appears to be similar initial efficacy and toxicity. Future analyses focusing on response durability and long-term toxicities such as infections and post-CAR T cytopenias are warranted.

Decomposition–based multi-objective differential evolution for extractive multi-document automatic text summarization

The central challenge in Automatic Text Summarization (ATS) involves efficiently generating machine-generated text summaries through optimization algorithms. An ATS is a critical component for systems dealing with textual information processing. However, the current approach faces a significant hurdle due to the computational intensity of the process, particularly when employing complex optimization techniques like swarm intelligence optimization alongside a costly ATS repair operator. While the current approach yields impressive Recall-Oriented Understudy for Gisting Evaluation (ROUGE) metrics for the generated summary, it struggles with inefficiencies, mainly attributed to the substantial optimization time consumed by the ATS repair operator scheme. In order to address this, a novel solution called Decomposition-based Multi-Objective Differential Evolution (MODE/D) is proposed. It is built upon the foundation of Differential Evolution for Multi-Objective Optimization (DEMO) and the weighted sum method (WS), coupled with an innovative ATS repair operator scheme. Through experimentation on Document Understanding Conferences (DUC) datasets, the novel approach of MODE/D – WS is validated by evaluating the results using ROUGE metrics. The outcomes are twofold: a remarkable reduction in serial execution time and a noteworthy enhancement over existing techniques in the scholarly domain, as evidenced by improved ROUGE-1, ROUGE-2, and ROUGE-L scores.

Patient perspectives on home-spirometry in interstitial lung disease: a qualitative co-designed study

BackgroundOpportunities for home-monitoring are increasing exponentially. Home- spirometry is reproducible and reliable in interstitial lung disease (ILD), yet patients’ experiences are not reported. Given the morbidity and mortality associated with...

A CPU parallelized coupling framework for constrained flexible multibody system and granular matter based on contact-graph

This paper proposes a coupling model for simulating the interaction between particles and the flexible multibody system. The flexible rods are described using the Absolute Nodal Coordinate Formulation, and various types of contacts, including particle-particle, particle-rod, particle-rigid body contacts, and contacts within multibody objects, are considered. The contact detection is improved by combining space partitioning techniques and the bounding box method. A data structure based on a contact graph is introduced to store the contact relationships efficiently. The discrete element system and multibody system are coupled through serial time integration, with data exchanges at the program level. Numerical examples demonstrate the validity of the proposed model. Moreover, the model is applied to simulate the asteroid soil sampling with flexible brush sampler, showing good agreement with experimental data. The analysis of engineering examples provides insights for sampler design, and show the model's engineering value.

Design and Development of Student Attendance Maintenance System by using Face Recognition and Open-Source Computer Library

The main goal of this project is to create a face recognition-based offline attendance system for an educational institution to replace the current system in which teachers must call students and keep a record for future use. This was when attendance data could be easily erased or stolen physically, and it was being misused more frequently. The current system has a lot of ambiguity that causes inaccurate and inefficient attendance. And the teacher’s job is very hectic. That, the attendance is given the top priority by the administrations of the educational institutions, so to ease the position of the teachers, the new offline attendance system is being used with the technology face recognition system. The human face is one of the natural traits that can uniquely identify an individual. Therefore, it is used to trace identity as the possibility for a look to deviate or be duplicated is low. The proposed project is a new way of taking attendance where the students need to come before the camera. The designed system will automatically check the current student's database in front of the camera and save the student's data in an excel sheet with the serial number, student name, date, and time using the JSON (JavaScript Object Notation).

Serial measurements of SIRS criteria to identify unique phenotypes of sepsis: A Microbiologic Approach

Introduction: The utility of serial scoring systems in identifying distinct sepsis phenotypes remains unknown. Methods: Eligible adults were classified into culture-positive (Cx+) and culture-negative (Cx-) groups alongside pre-defined culture subgroups. Average SIRS &amp; SEP (novel scoring system) scores were calculated at t = 0 and hours 3,6,12 &amp; 24 before and after t = 0. The primary outcome was a difference in SIRS/SEP scores amongst those that were Cx+ or Cx- at any time point. Secondary outcomes were comparing total and component SIRS/SEP scores in microbiologic subgroups over serial time points. Results: 4,701 Cx+ and 3254 Cx- patients met eligibility criteria. Statistically significant differences were seen in the average SIRS score between Cx + and Cx- groups at hours six (Cx+ 1.40+1.04 vs Cx- 1.35+1.01) &amp; 12 (Cx+ 0.95+0.95 vs Cx- 0.90+0.90) after t = 0. The hematologic, urologic, and neurologic subgroups had significant differences at numerous time points before and after T = 0. Similar findings were observed with the SEP scores. Cx+ and Cx- groups (including subgroups) consistently doubled both SIRS/SEP scores before t = 0 with an eventual return to baseline values after T = 0 but at different gradients. Conclusion: Significant differences in SIRS/SEP scores were seen in Cx+ &amp; Cx- patients at sequential time points. This microbiologic approach in homogenous culture cohorts has the potential to identify distinct phenotypes of sepsis efficiently and practically. Consistent increases in SIRS/SEP scores before t = 0 and sequential decreases after t = 0 may allow for early detection, intervention, and provision for real-time monitoring of therapeutic responses in patients with concerns for sepsis.

Monitoring of the Healthy Neonatal Transition Period with Serial Lung Ultrasound.

Ultrasound has been used to observe lung aeration and fluid clearance during the neonatal transition period, but there is no consensus regarding the optimal timing of lung ultrasound. We aimed to monitor the trend of the serial lung ultrasound score (LUS) and extended LUS (eLUS) throughout the neonatal transition period (≤1, 2, 4, 8, 24, and 48 h after birth), assess any correlation to the clinical presentation (using the Silverman Andersen Respiratory Severity Score (RSS)), and determine the optimal time of the ultrasound. We found both LUS and eLUS decreased significantly after 2 h of life and had similar statistical differences among the serial time points. Although both scores had a positive, moderate correlation to the RSS overall (Pearson correlation 0.499 [p < 0.001] between LUS and RSS, 0.504 [p < 0.001] between eLUS and RSS), the correlation was poor within 1 h of life (Pearson correlation 0.15 [p = 0.389] between LUS and RSS, 0.099 [p = 0.573] between eLUS and RSS). For better clinical correlation, the first lung ultrasound for the neonate may be performed at 2 h of life. Further research is warranted to explore the clinical value and limitations of earlier (≤1 h of life) lung ultrasound examinations.

Evaluation of the Time Course on the Effectiveness of WHO Standard Pyrethroid and Carbamate Impregnated Test Papers against Anopheles stephensi, the Main Malaria Vector in Iran.

Anopheles stephensi is a major vector of malaria in some parts of the world. A standard method for determining resistance in adult mosquito populations is the bioassay test recommended by the world health organization (WHO). The papers used in this method have an expiry date. This study aimed to determine the effectiveness of outdated susceptibility test papers for use in insecticide resistance monitoring programs. Beech and Bandar Abbas strains of An. stephensi were reared in the insectary. Permethrin 0.75%, Deltamethrin 0.05%, and Bendiocarb 0.1% impregnated test papers prepared by Universiti Sains Malaysia were used. Probit analysis was used to analyze the results and prepare time-mortality regression lines of LT50 and LT90. There was a difference in the mortality of both tested strains of An. stephensi was exposed to all tested insecticides. Both expired and not expired Permethrin and Deltamethrin papers induced 100% mortality at the diagnostic time (60min), but their insecticidal properties were reduced gradually in serial times. The highest efficacy of test papers was in the first trimester after the expiry date and decreased over time. At the diagnostic time of 60 minutes, the mortality rate of both dated and expired papers was 100% in the pyrethroid insecticides, even three years after expiry dates, if stored in the package provided by the producer, in a refrigerator. This value was reduced to less than 100% in the expired papers of Bendiocarb comparing the dated papers that induced 100% mortality.