Initial Time Point Research Articles

Longitudinal Study of Transcriptomic Changes Occurring over Six Weeks of CHOP Treatment in Canine Lymphoma Identifies Prognostic Subtypes

The majority of canine lymphoma patients treated with the standard of care, the CHOP chemotherapy protocol, initially achieve remission but eventually relapse with a multi-drug-resistant phenotype. This study assesses gene expression profiles of canine lymphoma tumor cell populations using RNA-Seq data from 15 matched patient samples taken prior to treatment and again six weeks into treatment with CHOP. Two distinct clusters were present in the t-SNE dimensionality reduction of the gene expression profiles. There was a significant difference in progression-free survival (PFS) between the cluster groups, with a median of 43.5 days in a group of six patients and 185 days in another group of nine patients. Comparing the group with shorter PFS to the group with longer PFS, we identified 265 significantly enriched GO:BP terms in 3874 significantly up-regulated genes and 740 significantly enriched GO:BP terms in 3236 significantly down-regulated genes. Comparing the six-week timepoint against the initial timepoint, in the group with longer PFS, we identified 277 significantly enriched GO:BP terms in 413 significantly up-regulated genes and 222 significantly enriched GO:BP terms in 267 significantly down-regulated genes. In the group with shorter PFS, we only identified 27 significantly differentially expressed genes, for this comparison. We found DNA damage response genes to be enriched in the down-regulated genes in both comparisons. These results identify and characterize two transcriptionally distinct groups of canine lymphoma patients with significantly different responses to CHOP chemotherapy.

Estimating radial attenuation of vacuum pressure for dredged clays

The radial attenuation of vacuum pressure in dredged clays limits the effectiveness of vacuum consolidation. In this study, a series of model tests were conducted on five dredged clays with varying initial water contents to investigate this radial attenuation. The significant radial attenuation can be divided into two stages: the increasing and stabilization stages. In the stabilization stage, exponential radial attenuation is observed. Lower initial void ratio (e 0) and higher void ratio at liquid limit (e L) lead to a decrease in radial attenuation. Additionally, higher applied vacuum pressure (p v) results in a greater reduction in the magnitude of the radial vacuum pressure. In the increasing stage, the radial vacuum pressure increases exponentially to a stable state after start-up. The radial attenuation is attributed to the differential start-up time (i.e., initial time-point at which the increase begins) and varying increase rates. Lower e 0, higher e L, and higher p v values reduce the start-up time and raise the increase rate. A changing pattern is proposed to describe the exponential radial attenuation using three parameters: radial attenuation coefficient (k 2), increasing coefficient (k 3), and time-delay coefficient (D t). Furthermore, an empirical estimation for the radial attenuation is also suggested without relying on time-consuming tests

Using Biosensor Devices and Ecological Momentary Assessment to Measure Emotion Regulation Processes: Pilot Observational Study With Dialectical Behavior Therapy.

Novel technologies, such as ecological momentary assessment (EMA) and wearable biosensor wristwatches, are increasingly being used to assess outcomes and mechanisms of change in psychological treatments. However, there is still a dearth of information on the feasibility and acceptability of these technologies and whether they can be reliably used to measure variables of interest. Our objectives were to assess the feasibility and acceptability of incorporating these technologies into dialectical behavior therapy and conduct a pilot evaluation of whether these technologies can be used to assess emotion regulation processes and associated problems over the course of treatment. A total of 20 adults with borderline personality disorder were enrolled in a 6-month course of dialectical behavior therapy. For 1 week out of every treatment month, participants were asked to complete EMA 6 times a day and to wear a biosensor watch. Each EMA assessment included measures of several negative affect and suicidal thinking, among other items. We used multilevel correlations to assess the contemporaneous association between electrodermal activity and 11 negative emotional states reported via EMA. A multilevel regression was conducted in which changes in composite ratings of suicidal thinking were regressed onto changes in negative affect. On average, participants completed 54.39% (SD 33.1%) of all EMA (range 4.7%-92.4%). They also wore the device for an average of 9.52 (SD 6.47) hours per day and for 92.6% of all days. Importantly, no associations were found between emotional state and electrodermal activity, whether examining a composite of all high-arousal negative emotions or individual emotional states (within-person r ranged from -0.026 to -0.109). Smaller changes in negative affect composite scores were associated with greater suicidal thinking ratings at the subsequent timepoint, beyond the effect of suicidal thinking at the initial timepoint. Results indicated moderate overall compliance with EMA and wearing the watch; however, there was no concurrence between EMA and wristwatch data on emotions. This pilot study raises questions about the reliability and validity of these technologies incorporated into treatment studies to evaluate emotion regulation mechanisms.

A microsimulation model of smoking prevalence in England: exploring potential impacts of ‘Tobacco 21’ and e-cigarette policy scenarios on socioeconomic and regional inequalities

Background The burden of morbidity and mortality in England, is greater among priority groups such as those with lower income or routine and manual occupations. Using a microsimulation model, we estimate projected changes in smoking prevalence according to socio-economic position under selected policy scenarios that are relevant to ongoing policy implementation and debate. Methods Initiated using real-world data from adult (16+) respondents to the Smoking Toolkit Study (STS), the ‘QuitSimX’ microsimulation model projects individual-level smoking uptake and cessation in England over time. The simulation was run under two separate policy scenarios, raising the age of sale of tobacco products to 21 (simulations run from 2013–2023), and moving a proportion of all individuals quitting using a certain method (such as over the counter nicotine replacement therapy), or no method, to using e-cigarettes instead (simulations run from 2015–2025). Under each scenario, the size of effect were specified, and the outcomes simulated and assessed by indicators of socio-economic position. Absolute and relative inequalities were examined by comparing at the initial and final timepoint the i) absolute difference in smoking prevalence between less and more advantaged groups subgroups and ii) the ratio of smoking prevalence. Results While absolute and relative inequalities in smoking prevalence declined across the simulated period under all policy scenarios and the counterfactual ‘no intervention’ scenario, at the final time point absolute and relative inequalities between social grades and regions were similar across all scenarios, with the exception that the relative (but not absolute) inequality under the most impactful tobacco 21 scenario as marginally higher than under the baseline scenario. Conclusion A microsimulation model of smoking in England illustrates that absolute inequalities are projected to decrease under a Tobacco 21 or quitting with e-cigarettes scenario but that some policy solutions (Tobacco 21) may result in an increase in relative inequalities.

Associations among screen time, sleep, mental health and cognitive functioning in school-aged children during the COVID-19 pandemic, November 2020 through to August 2022

ObjectiveTo examine children’s screen time use and sleep patterns over 2 years of the pandemic and the downstream associations with children’s executive functions and behavioural problems, as well as the moderating effects of parental factors. MethodThis longitudinal cohort study examined school-aged children’s lifestyle and behavioural changes over 2 years of the pandemic across 6 timepoints (November 2020 to August 2022). Latent growth modeling (LGM) was used to identify changes in screen time and sleep duration and multivariate LGM was used to determine how parental stress, positive parenting, changes in children’s screen time and sleep over time were associated with children’s executive functions and mental health outcomes at the final time point. ResultsA total of 198 parents (children’s mean age = 9.14 years) were recruited and followed up. Non-school screen time was elevated at the initial timepoint (3.6 ± 2.3 h). Positive parenting at the initial timepoint was associated with lower screen time use in children (β = −.19, p < .001; β = −.19, p < .001, in internalizing and externalizing models). Children whose screen time use was constant during the pandemic had shorter sleep durations (β = −.45, p < .05 in internalizing model). Executive function was predicted by sleep duration at the first timepoint (β = −.55, p < .001; β = .73, p < .001, in internalizing and externalizing models) and changes in screen time during the pandemic was associated with both internalizing and externalizing symptoms (β = .58, p < .05; β = .54, p < .05, in internalizing and externalizing models). ConclusionChildren’s screen time decreased slightly but remained significantly higher than Canadian and International guidelines during 2 years of the pandemic. Positive parenting styles can have a significant impact on children's screen time use. Reducing excessive screen time can help improve sleep patterns and, consequently, cognitive, and emotional well-being in children.

Moment-to-moment within-person associations between maternal autonomy support and child defeat predicting child behavioral adjustment.

This study examines mother-child mutual regulation processes during a challenging puzzle task as predictors of preschoolers' behavioral adjustment 6 months later in a Chinese sample (N = 101, 46 boys, Mage = 57.41 months, SD = 6.58). Mother-child mutual regulation was measured by the moment-to-moment bidirectional within-person associations between maternal autonomy support and child defeat (i.e., expression of frustration, incapacity to complete the task, or giving up). Children whose mother provided more autonomy support after increases of child defeat showed lower levels of externalizing problems 6 months later, and children who showed less defeat after increases of maternal autonomy support showed higher levels of prosocial behaviors 6 months later. These predictive effects were significant after controlling for child behavioral adjustment at the initial time point, and mean levels of mother's autonomy support and child's defeat throughout the task. The mutual regulation processes did not significantly predict child internalizing problems. The findings suggest that the coordinated mother-child mutual regulation patterns in real time may have positive implications for preschoolers' behavioral adjustment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Poly(ADP-Ribose) Polymerases-Inhibitor Talazoparib Inhibits Muscle Atrophy and Fatty Infiltration in a Tendon Release Infraspinatus Sheep Model: A Pilot Study.

Structural muscle changes, including muscle atrophy and fatty infiltration, follow rotator cuff tendon tear and are associated with a high repair failure rate. Despite extensive research efforts, no pharmacological therapy is available to successfully prevent both muscle atrophy and fatty infiltration after tenotomy of tendomuscular unit without surgical repair. Poly(ADP-ribose) polymerases (PARPs) are identified as a key transcription factors involved in the maintenance of cellular homeostasis. PARP inhibitors have been shown to influence muscle degeneration, including mitochondrial hemostasis, oxidative stress, inflammation and metabolic activity, and reduced degenerative changes in a knockout mouse model. Tenotomized infraspinatus were assessed for muscle degeneration for 16 weeks using a Swiss Alpine sheep model (n = 6). All sheep received daily oral administration of 0.5 mg Talazoparib. Due to animal ethics, the treatment group was compared with three different controls from prior studies of our institution. To mitigate potential batch heterogeneity, PARP-I was evaluated in comparison with three distinct control groups (n = 6 per control group) using the same protocol without treatment. The control sheep were treated with an identical study protocol without Talazoparib treatment. Muscle atrophy and fatty infiltration were evaluated at 0, 6 and 16 weeks post-tenotomy using DIXON-MRI. The controls and PARP-I showed a significant (control p < 0.001, PARP-I p = 0.01) decrease in muscle volume after 6 weeks. However, significantly less (p = 0.01) atrophy was observed in PARP-I after 6 weeks (control 1: 76.6 ± 8.7%; control 2: 80.3 ± 9.3%, control 3: 73.8 ± 6.7% vs. PARP-I: 90.8 ± 5.1% of the original volume) and 16 weeks (control 1: 75.7 ± 9.9; control 2: 74.2 ± 5.6%; control 3: 75.3 ± 7.4% vs. PARP-I 93.3 ± 10.6% of the original volume). All experimental groups exhibited a statistically significant (p < 0.001) augmentation in fatty infiltration following a 16-week period when compared to the initial timepoint. However, the PARP-I showed significantly less fatty infiltration (p < 0.003) compared to all controls (control 1: 55.6 ± 6.7%, control 2: 53.4 ± 9.4%, control 3: 52.0 ± 12.8% vs. PARP-I: 33.5 ± 8.4%). Finally, a significantly (p < 0.04) higher proportion and size of fast myosin heavy chain-II fiber type was observed in the treatment group. This study shows that PARP-inhibition with Talazoparib inhibits the progression of both muscle atrophy and fatty infiltration over 16 weeks in retracted sheep musculotendinous units.

Functional and multi-omics signatures of mitapivat efficacy upon activation of pyruvate kinase in red blood cells from patients with sickle cell disease.

Mitapivat, a pyruvate kinase activator, shows great potential as a sickle cell disease (SCD)-modifying therapy. The safety and efficacy of mitapivat as a long-term maintenance therapy are currently being evaluated in two open-label studies. Here we applied a comprehensive multi-omics approach to investigate the impact of activating pyruvate kinase on red blood cells (RBC) from 15 SCD patients. HbSS patients were enrolled in one of the open-label, extended studies (NCT04610866). Leukodepleted RBC obtained from fresh whole blood at baseline, prior to drug initiation, and at longitudinal timepoints over the course of the study were processed for multi-omics through a stepwise extraction of metabolites, lipids and proteins. Mitapivat therapy had significant effects on the metabolome, lipidome and proteome of SCD RBC. Mitapivat decreased 2,3-diphosphoglycerate levels, increased adenosine triphosphate levels, and improved hematologic and sickling parameters in patients with SCD. Agreement between omics measurements and clinical measurements confirmed the specificity of mitapivat on targeting late glycolysis, with glycolytic metabolites ranking as the top correlates to parameters of hemoglobin S oxygen affinity (p50) and sickling kinetics (t50) during treatment. Mitapivat markedly reduced levels of proteins of mitochondrial origin within 2 weeks of initiation of treatment, with minimal changes in reticulocyte counts. In the first 6 months of treatment there were also transient elevations of lysophosphatidylcholines and oxylipins with depletion of free fatty acids, suggestive of an effect on membrane lipid remodeling. Multi-omics analysis of RBC identified benefits for glycolysis, as well as activation of the Lands cycle.

Prediction of Effectiveness and Toxicities of Immune Checkpoint Inhibitors Using Real-World Patient Data.

Although immune checkpoint inhibitors (ICIs) have improved outcomes in certain patients with cancer, they can also cause life-threatening immunotoxicities. Predicting immunotoxicity risks alongside response could provide a personalized risk-benefit profile, inform therapeutic decision making, and improve clinical trial cohort selection. We aimed to build a machine learning (ML) framework using routine electronic health record (EHR) data to predict hepatitis, colitis, pneumonitis, and 1-year overall survival. Real-world EHR data of more than 2,200 patients treated with ICI through December 31, 2018, were used to develop predictive models. Using a prediction time point of ICI initiation, a 1-year prediction time window was applied to create binary labels for the four outcomes for each patient. Feature engineering involved aggregating laboratory measurements over appropriate time windows (60-365 days). Patients were randomly partitioned into training (80%) and test (20%) sets. Random forest classifiers were developed using a rigorous model development framework. The patient cohort had a median age of 63 years and was 61.8% male. Patients predominantly had melanoma (37.8%), lung cancer (27.3%), or genitourinary cancer (16.4%). They were treated with PD-1 (60.4%), PD-L1 (9.0%), and CTLA-4 (19.7%) ICIs. Our models demonstrate reasonably strong performance, with AUCs of 0.739, 0.729, 0.755, and 0.752 for the pneumonitis, hepatitis, colitis, and 1-year overall survival models, respectively. Each model relies on an outcome-specific feature set, though some features are shared among models. To our knowledge, this is the first ML solution that assesses individual ICI risk-benefit profiles based predominantly on routine structured EHR data. As such, use of our ML solution will not require additional data collection or documentation in the clinic.

Iterative learning control approach for linear discrete time-varying systems with different initial time points

Different from the existing iterative learning control (ILC) works for dynamical systems with iteration-varying trial lengths, in which the terminal time points are not identical, this paper presents an ILC approach for linear discrete time-varying (LDTV) systems with different initial time points. A piecewise ILC law is designed by using the segment compensation techniques in time axis. Through a rigorous mathematical analysis, it is theoretically proved that as the mathematical expectation of the iterative initial state equals to the desired initial state, the ILC tracking error at the maximum universal time interval can be driven into a bounded region in mathematical expectation sense. Particularly, the mathematical expectation of the ILC tracking error at the maximum universal time interval can even be driven to zero under a certain initial state condition. Numerical simulations are provided to verify the effectiveness of the proposed ILC scheme.

503 - Visualizing 3-year treatment outcome trajectories of dupilumab in adults with moderate-to-severe atopic dermatitis in real world practice

Abstract Background Atopic dermatitis (AD) is a chronic inflammatory skin disease with high global prevalence and profound negative impact on the quality of life of children and adults. RELIEVE-AD, a prospective, longitudinal cohort study, included adults with moderate-to-severe AD who initiated dupilumab in real-world clinical practice. Results from RELIEVE-AD showed significant improvements in patient-reported disease control, quality of life, and treatment satisfaction in the overall study population that were sustained through 3 years of dupilumab treatment. Objective To report on response to dupilumab treatment over time at the individual patient-level in adults with moderate-to-­severe AD, using 3-year data from RELIEVE-AD. Methods RELIEVE-AD is a single-arm, prospective, observational study of adults with moderate-to-severe AD prescribed dupilumab and enrolled in the US dupilumab patient support program, who agreed to participate in online surveys at baseline and Months 1, 2, 3, 6, 9, 12, and 30–36. Post hoc analysis of the RELIEVE-AD 3yr data, describing changes from baseline through all post-dupilumab initiation time points at individual patient level, using Sankey plots to assess variability of individual patient response over time for the following patient-reported outcomes: Atopic Dermatitis Control Tool (ADCT) total score-based disease control status, AD-related health status, and AD treatment satisfaction. Results Of 698 patients who completed the baseline survey, 425 completed the Months 30–36 survey. Disease control (as measured by the ADCT) increased rapidly from 5.9% at baseline to 61.0% at Month 1, further increasing to 80.7% at Months 30–36. Patients reported improved AD-related health status at Month 30–36, with 70.9% reporting “Excellent” or “Very Good”, compared to 2.8% at baseline. At Months 30–36, 86.8% of patients reported being “Extremely Satisfied/Very Satisfied/Somewhat Satisfied” with their AD treatment, compared to 17.7% at baseline. All endpoints were significant vs baseline (P &amp;lt; 0.001). Sankey plots of the three outcomes indicated that the majority of patients maintained response over time after achieving the initial response. Conclusion The majority of patients who completed the survey reported benefits of dupilumab, such as AD control, treatment satisfaction, and health status, which remained stable or significantly improved during long-term treatment up to 36 months.

A new MIB-based time integration method for transient heat conduction analysis of discrete and continuous systems

By incorporating the matched interface and boundary (MIB) method into time integration computation, a new MIB-based time integration (MIBTI) approach is proposed for solving transient heat conduction problems in this work. Indeed, this is a truly effective time-domain MIB method that can directly discretize space and time derivatives, and the transient heat conduction problem (an initial-value problem) is transformed into a pseudo-space boundary-value problem. The initial and final time points are regarded as boundary points in the transformed space domain. Two algorithms are developed to deal with the final time point. Unlike conventional recursive schemes for time integration, all unknown variables can be determined by solving the transformed boundary-value problem in the present approach. Various discrete and continuous systems without and with internal heat sources under different boundary conditions are considered to examine the working performance of the proposed method. The applicability of the time stability criterion in the conventional recursive schemes to the proposed method is also discussed. It is found that excellent numerical stability and convergence can be achieved by using the present MIBTI method for solving transient heat conduction problems.

Possible effects of plasminogen activator inhibitor-1 on promoting angiogenesis through matrix metalloproteinase 9 in advanced mycosis fungoides.

Mycosis fungoides (MF) progresses slowly before advancing to skin tumors followed by lymph node and visceral involvement. Among MF progression, stage IIB is an initial time point of tumor formation in MF. Since MF in tumor stage possess abundant blood vessels, it is important to evaluate the pro-angiogenic factors before and after MF in stage IIB. In this report, we investigated pro-angiogenic soluble factors in MF patients, as well as its pro-angiogenetic effects on tumor cells and stroma cells. We first evaluated the serum levels of pro-angiogenic factors in 9 MF patients without tumor formation and 8 MF patients with tumor formation. Among them, the serum MMP-9 and plasminogen activator inhibitors 1 (PAI-1) was significantly increased in MF with tumor formation compared in MF without tumor formation, leading to favorable formation of human dermal microvascular endothelial cells tube networks. Moreover, PAI-1 stimulation significantly increased the mRNA expression and protein production MMP-9 on monocytes derived M2 macrophages and HUT-78. Furthermore, since MMP-9 production from tumor cells as well as stromal cells is suppressed by bexarotene, we evaluate the baseline serum pro-angiogenic factors including MMP-9 in 16 patients with advanced cutaneous T cell lymphoma treated with bexarotene. The serum levels of MMP-2 and MMP-9 was significantly increased in bexarotene non-responded patients compared to responded patients. Our present study suggested the significance of MMP-9 and PAI-1 for the progression of MF stage toward to the tumor stage, and could be a therapeutic target in future.

Effects of an Emergency-Based FASE Strategy on Treating Geriatric Patients with Femoral Neck Fracture: A Retrospective Propensity Score-Matched Study.

This study aims to assess the impacts of the Fast Access to Surgery in Emergency (FASE) strategy on (1) the workflow of multidisciplinary team (MDT) during hospitalization; (2) the clinical outcomes of geriatric femoral neck fracture (FNF) patients. A retrospective study was conducted in a single trauma center to evaluate the clinical data of geriatric FNF patients admitted through emergency from July 2017 to June 2022. The FASE strategy was implemented since Jan 1st 2020, and patients were categorized into the FASE group or the control group according to the time of admission (before/after the initiation timepoint of FASE strategy). Propensity score matching (PSM) was utilized to limit confounding bias between the two groups. Finally, 344 patients were included after a one-to-one matching. The FASE strategy resulted in a slightly prolonged duration in emergency (6.02±5.99h vs 2.72±4.22h, p<0.001) but was meanwhile associated with significant decreases in time to surgery (61.16±38.74h vs 92.02±82.80h, p<0.001), actual surgery delay (67.18±39.04h vs. 94.25±84.41h, p<0.001) and total length of hospital stay (10.57±4.93h vs 12.50±4.73h, p <0.001). Besides, despite the consistency of transfusion rate between the two groups, improved blood management was achieved in the FASE group, as evidenced by a smaller drop in hemoglobin levels (-20.49±17.02 g/L vs -25.28±16.33 g/L, p = 0.013) in patients without preoperative or intraoperative transfusion. However, no significant differences were observed regarding the overall clinical outcomes such as mortality or postoperative complications. The Fast Access to Surgery in Emergency (FASE) for geriatric FNF patients effectively optimized the preoperative evaluation workflow, which significantly shortened time to surgery and length of hospital stay, and reduced perioperative blood loss. FASE strategy improved the surgical workflows and turnover efficiency of geriatric FNF patients, therefore could play an important role in the optimal MDT co-management for geriatric FNF patients.

In Vivo Evaluation of Bone Regenerative Capacity of the Novel Nanobiomaterial: β-Tricalcium Phosphate Polylactic Acid-co-Glycolide (β-TCP/PLLA/PGA) for Use in Maxillofacial Bone Defects.

Maxillofacial bone defects are treated by autografting or filling with synthetic materials in various forms and shapes. Electrospun nanobiomaterials are becoming popular due to their easy placement and handling; combining ideal biomaterials extrapolates better outcomes. We used a novel electrospun cotton-like fiber made from two time-tested bioresorbable materials, β-TCP and PLLA/PGA, to check the feasibility of its application to maxillofacial bone defects through an in vivo rat mandibular bone defect model. Novel β-TCP/PLLA/PGA and pure β-TCP blocks were evaluated for new bone regeneration through assessment of bone volume, inner defect diameter reduction, and bone mineral density. Bioactive/osteoconductivity was checked by scoring the levels of Runt-related transcription factor x, Leptin Receptor, Osteocalcin, and Periostin biomarkers. Bone regeneration in both β-TCP/PLLA/PGA and β-TCP was comparable at initial timepoints. Osteogenic cell accumulation was greater in β-TCP/PLLA/PGA than in β-TCP at initial as well as late phases. Periostin expression was more marked in β-TCP/PLLA/PGA. This study demonstrated comparable results between β-TCP/PLLA/PGA and β-TCP in terms of bone regeneration and bioactivity, even with a small material volume of β-TCP/PLLA/PGA and a decreased percentage of β-TCP. Electrospun β-TCP/PLLA/PGA is an ideal nanobiomaterial for inducing bone regeneration through osteoconductivity and bioresorbability in bony defects of the maxillofacial region.

EXPLORING THE WITHIN-PERSON RELATIONSHIP BETWEEN DAILY DISCRIMINATION AND DAILY STRESS REACTIVITY

Abstract Experiencing discrimination has been associated with a variety of negative impacts such as poorer health and well-being. Some research has shown that those who experienced discrimination at an initial timepoint were more likely to have poorer health and well-being outcomes 20 years later through the mediating role of threat appraisals and stress reactivity. Research has demonstrated a link between experiencing discrimination and affective reactions to everyday stressful experiences, however, these associations have only been studied at the between-person level. For the current study, we examined the within-person relationship in daily stress reactivity in relation to experiencing discrimination on a daily basis over the course of 20 years. Participants (n = 1,315) completed waves 1 to 3 of the Midlife in the United States (MIDUS) survey with each wave about 10 years apart in which participants were asked to self-report their daily discrimination. Participants also completed the National Study of Daily Experiences (NSDE) which was a daily diary design over 8 consecutive days asking about their daily stress reactivity. Results found that during timepoints when people experienced greater than their average level of discrimination, they also reacted more negatively to daily stressful events (b = .002, 95% CI [0.001, 0.002]). These results are particularly striking because they show that within-person changes in reported discrimination are related to changes in affective responses to daily stressors. These findings suggest that experiencing discrimination is related to greater reactivity to daily stressors, which may lead to worse physical and mental health over time.

Abstract B011: Dynamics of predicted tumor neoepitope burden in a pan-cancer solid tumor pediatric cohort

Abstract Human leukocyte antigen (HLA) binding of tumor neoepitopes confers clinical value in certain adult malignancies. However, the prevalence of tumors that result in HLA binding of neoepitopes in pediatric malignancies is not as well-characterized. We set out to establish the feasibility of predicting neoepitope burden and the prevalence of predicted neoepitope across a previously established cohort of pediatric oncology patients. Additionally, because this analysis requires knowledge of each patient’s HLA haplotype for predicting binding of tumor peptides, we also set out to develop a novel algorithm to profile HLA haplotypes within the context of a larger whole genome (WGS) and RNAseq analysis pipeline. Finally, in this high-risk pediatric oncology cohort, we sought to determine the dynamics of predicted neoepitope burden at multiple time points in disease progression, including relapsed/refractory disease and metastatic disease. A previously established cohort of 147 high-risk pediatric oncology patients, including solid tumors CNS tumors, and leukemias/lymphomas was used for this analysis. This comprised patients with relapsed/refractory disease (66), and rare diagnoses (14). For these 147 patients, tumor/normal WGS (tumor ~60X; germline ~30X), as well as tumor RNAseq (polyA selected, ≥20 million reads) was performed. In addition to the initial timepoints, additional tumor samples were profiled for 27 patients, resulting in 179 total samples. A special focus on longitudinal analysis is devoted to osteosarcoma patients (12 with multiple timepoints). WGS and RNAseq were analyzed using a previously established pipeline. Somatic variants (SNVs), mutational burden, structural rearrangements (SVs), mutational signatures, and copy-number alterations (CNAs) were identified using WGS. As part of this new analysis, HLA class I haplotypes were identified from WGS integrated with RNAseq expression. Putative neoepitopes were predicted from expressed protein altering somatic variants using MHCFlurry. Importantly, HLA and neoepitope analysis was able to use intermediate data from the existing WGS/RNAseq analysis pipeline, resulting in significantly faster turnaround times. Our results demonstrate that our algorithm for determining HLA haplotypes by sampling already-mapped WGS and RNASeq performs with comparable accuracy to similar previously published methods that rely on unmapped data. In terms of predicted of tumor neoepitope burden, of the 171 samples with at least one protein altering variant, 166 are predicted to have at least one bound neoantigen (median=6). Of these, 133 samples are predicted to have at least one bound neoantigen that is clonal and expressed in RNA (median=3). Further characterization of the neoepitope burden of these tumors and the evolution of predicted neoepitope burden across multiple time points will be shared at the meeting. Citation Format: Charles W Macaulay, Marcus R Breese, E. Alejandro Sweet-Cordero. Dynamics of predicted tumor neoepitope burden in a pan-cancer solid tumor pediatric cohort [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B011.

Deciphering the Dynamics of the B-NHL Single-Cell Landscape during BTK Inhibition

Introduction: The inhibition of Bruton's tyrosine kinase (BTK) as a therapeutic strategy has dramatically improved the management of patients with chronic lymphocytic leukemia (CLL) and other B-cell-Non Hodgkin lymphomas (B-NHL). However, therapy resistance and treatment toxicity persist as significant clinical challenges. It has been previously reported that BTK inhibition not only targets the overactivated BCR pathway in CLL and other B-NHL, but also coincides with profound alterations in the tumor microenvironment including immune cells. Therefore, it is vital to understand these tumor-immune cell interactions during BTK inhibition to enhance response and reduce toxicity, advancing personalized care for CLL and B-NHL patients in the future. Methods: We developed a high-parametric analysis pipeline based on full spectrum cytometry, a novel technology allowing for the simultaneous assessment of 40 markers at single-cell level. In order to comprehensively assess the phosphoproteome relevant to BTK inhibition we established a signaling panel covering &amp;gt;30 proteins including pBTK, pSyk, pPLCg, pS6 and pAMPKa. Additionally, we designed 3 panels with up to 40 markers characterizing T cell activation and exhaustion, cellular trafficking, inhibitory immune checkpoints and cytokine production. Using our scalable and reproducible bioinformatics pipeline, we analyzed a cohort of 160 samples, longitudinally collected from 57 patients (CLL, MCL, MZL) before BTKi treatment, directly after treatment initiation, at leukocyte peak count and during therapy up to 6 months after therapy initiation. Results: Given that T cells are a crucial arm in governing anti-lymphoma immune response, we sought to elucidate the changes associated with BTK inhibition in the T cell compartment of the patients at high resolution (figure A). We observed certain changes in the fraction of T cell subtypes, notably a decrease in central memory stem T cells and an increase in γδ T cells at leukocyte peak and during later stages of therapy. Our analysis uncovered substantial changes in the T cell marker expression over the course of BTK inhibition. This includes a reversal of exhausted phenotype marked by downregulation of PD1, CD39 and CD38 and a skewed differentiation of CD4 T cells towards Th1 phenotype illustrated by a pronounced upregulation of the transcription factor T-bet. In addition, we detected restored proliferative and cytotoxic capacity in the CD8 and CD4 T cell compartments characterized by upregulation of GRZB, CD226, CD28, CD25 and Ki67. By leveraging our platform, we successfully captured the signalosome of malignant B cells at a high resolution. As anticipated, we detected significant heterogeneity in the malignant B cell signatures across individual patients. Interestingly, even at the initial sampling timepoint following treatment start, we observed substantially altered B cell signatures encompassing both the phosphoproteome and inhibitory immune checkpoints (figure B). Our preliminary data suggest that the dynamic changes induced by BTK inhibition extend beyond the signaling nodes associated with the BCR pathway and also involve the NFkB and p53 pathways. Conclusion: In this study, we established a platform for deep and longitudinal interrogation of the tumor and immune cell compartments to capture the dynamic and patient-specific changes occurring during BTK inhibition. Our preliminary data obtained from a large patient cohort of 57 B-NHL patients reveals a profound remodeling of not only the BCR signaling pathway in tumor cells, but also of the T cell compartment. Our data will be useful for a better understanding of treatment response and toxicity in the context of BTK inhibition.

74 Timed Motor Performance in Children Medically Cleared for Return to Activities Post Mild Traumatic Brain Injury

Objective:Children who sustain a mild traumatic brain injury (mTBI) are at increased odds of additive injury and continue to show altered motor performance relative to never-injured peers after being medically cleared (MC) to return to normal activities. There is a critical need to determine when children can return to activities without risk of short and long-term adverse effects, with research showing high reinjury rates for 3-12 months after RTP. The Physical and Neurological Examination for Subtle Signs (PANESS) measures subtle signs of motor impairment during gait, balance, and timed motor functions. Recent literature has demonstrated that PANESS timed motor function can distinguish between children medically cleared post-mTBI compared to never-injured controls. The present study examined performance on timed motor tasks in youth medically cleared from mTBI following medical clearance and 3-months later, compared to never-injured peers.Participants and Methods:25 children (Mage=14.16, SD=2.46; Male=68%) were enrolled within 6 weeks of medical clearance from mTBI (Mdays post MC=33, SD=13.4, Range=2-59) along with 66 typically developing, never-injured controls (Mage=13.9, SD=2.22; Male=50%). Group differences were evaluated for the Timed Motor section of the PANESS at enrollment and at a 3-month follow-up (Mdays from enrollment to follow-up=95.90, SD=12.69, Range=62-129). This 3-month follow-up occurred on average 4 months after medical clearance (Mdays from MC to follow-up=130.08, SD=17.58, Range=92 - 164). The Timed Motor section includes Repetitive (foot tapping, hand patting, and finger tapping) and Sequential (heel-toe rocking, hand pronate/supinate, finger sequencing) raw time scores, measured in seconds. The Total Timed Motor Speed score is the combination of Repetitive and Sequential Movement and the side-to-side tongue item.Results:At 3-month follow-up, mTBI participants (M=67.55, SD=8.26, Range=53.66-83.88) performed worse than controls (M=63.09, SD=10.23, Range=39.86-100.51) on Total Timed Motor Speed, t(89)= 1.95, p&lt;0.05), including when controlling for age and sex, F(1, 87)=4.67, p&lt;0.05. At the same time point, mTBI participants (M=36.54, SD=5.47, Range=28.74-49.17) performed worse on Sequential Speed than controls (M=32.93, SD=6.1, Range=21.49-56.76), t(89)=2.59, p&lt;0.01, including when controlling for age and sex, F(1, 87)=7.687, p&lt;0.01). Although groups performed similarly on Sequential Speed at the initial time point, mTBI participants exhibited a trend of less improvement from initial to follow-up (MmTBI=-1.69, Mcontrol=-3.68, t(90)=1.445, p=0.076).Conclusions:Although groups did not significantly differ on Timed Motor Speed items at the initial time point, the mTBI group showed consistently lower scores than controls at both time points and less improvement over time. Results indicate that Total Timed Motor Speed, specifically Sequential Speed, may be a sensitive marker of persisting differences in high-level motor and cognitive learning/control in children who have been medically cleared after mTBI. More data are needed to evaluate these findings over a longer time period, and future studies should examine behavioral markers concurrently with physiologic brain recovery over time.

Prognosis Discussion and Referral to Community Palliative Care Services in Patients with Advanced Pancreatic Cancer Treated in a Tertiary Cancer Centre.

Advanced pancreatic cancer is associated with a poor prognosis, often less than 1 year. Honest prognosis discussions guide early community palliative care services input, facilitating timely advance care planning and improving quality of life. The aims were to assess if patients were offered prognosis discussions and community palliative care services referral. A retrospective analysis of consecutive case-notes of new advanced pancreatic cancer patients was conducted. Chi-squared test assessed the association with prognosis discussion and community palliative care services referral. In total, 365 cases (60%) had a documented prognosis discussion at any time-point in the treatment pathway; 54.4% during the first appointment. The frequency of prognosis discussion was greater with nurse clinician review at first appointment (p < 0.001). In total, 171 patients (28.1%) were known to community palliative care services at the first appointment. Of those not known, 171 (39.1%) and 143 (32.7%) were referred at this initial time-point or later, respectively. There was a significant association between the referral to community palliative care services at first appointment and the reviewing professional (this was greatest for nurse clinicians (frequency 65.2%)) (p < 0.001), and also if reviewed by clinical nurse specialist at first visit or not (47.8% vs. 35.6%) (p < 0.01). Prognosis discussions were documented in approximately two-thirds of cases, highlighting missed opportunities. Prognosis discussion was associated with clinician review and was most frequent for nurse clinician, as was referral to community palliative care services. Clinical nurse specialist review increased referral to community palliative care services if seen at the initial visit. Multi-disciplinary review, specifically nursing, therefore, during the first consultation is imperative and additive. It should be considered best practice to offer and negotiate the content and timing of prognosis discussions with cancer patients, and revisit this offer throughout their treatment pathway. Greater attention to prognosis discussion documentation is recommended.