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Background: Lymph node (LN) involvement is a strong indicator of poor prognosis for breast cancer (BC), with adjuvant chemotherapy remaining fundamental to management of these patients. SWOG S8814 was a Phase III randomized trial of postmenopausal patients with pathologic LN-positive BC who were hormone receptor positive (HR+). The objectives of the clinical trial were to compare disease free survival (DFS) and overall survival (OS) of 1) these postoperative patients treated with a combination of cyclophosphamide, doxorubicin, fluorouracil (CAF) plus tamoxifen versus tamoxifen alone; and 2) patients treated with CAF followed by tamoxifen versus CAF plus concurrent tamoxifen. In this study we sought to evaluate the potential of applying computational image analysis on whole slide images (WSI) for predicting DFS and OS in SWOG S8814. Methods: A cohort of 135 patients (N=53 DFS event) diagnosed with HR+ & LN+ BC from clinical trial ECOG 2197 was utilized as training set D1. Validation set D2 comprised 630 patients (N=260 DFS event, N=195 death) with HR+& LN+ BC from SWOG S8814. Three deep learning models were employed to respectively detect nuclei, mitosis, and tubules in WSIs. Subsequently, a total of 1,810 features relating to nuclear morphology (e.g., spatial distribution, shape, texture, orientation), mitotic activity (e.g., mitosis hotspot, mitotic rates) and tubule formation (e.g., tubular nuclei distribution, ratio of tubule to non-tubule area) were extracted from each WSI. A lasso regularized Cox regression model (IbRiS) was trained on D1 to respectively identify four features from each of the feature categories (nuclei morphology, mitotic activity, and tubule formation) most strongly associated with DFS, a continuous risk score based on the selected features was then constructed. An optimal risk threshold was identified on D1 to dichotomize the risk scores into high vs. low risk of recurrence categories. Blinded validation of the machine learning model on SWOG S8814 using Cox regression was performed by SWOG to evaluate its performance in terms of DFS and OS. Results: In D2, patients identified as high risk of recurrence by IbRiS had a significantly worse prognosis in terms of DFS with hazard ratio=1.30 (p=0.039, 95% CI=1.01-1.66). IbRiS was also found to be significantly prognostic of OS with hazard ratio=1.38 (p=0.026, 95% CI=1.04-1.83). IbRiS was however, neither prognostic of DFS (HR = 1.20; 95% CI 0.93-1.54) nor OS (HR = 1.28; 95% CI 0.96-1.71) in multivariable analysis adjusting for treatment, tumor size, and number of positive nodes. IbRiS was also not a significant predictor of chemotherapy benefit (DFS p=0.45; OS p=0.25). Conclusion: We developed a prognostic model (IbRiS) based on the combined features of nuclear morphology, mitosis count, and tubule formation that can help further risk stratify HR+ & LN+ BC patients by only using H&E slides. Citation Format: Yuli Chen, William E. Barlow, Haojia Li, Cheng Lu, Andrew Janowczyk, German Corredor, Shridar Ganesan, Michael Feldman, Pingfu Fu, Hannah Gilmore, Kathy S. Albain, Lajos Pusztai, James Rae, Daniel Hayes, Andrew K. Godwin, Alastair M. Thompson, Anant Madabhushi. Computerized Measurements of Nuclear Morphology Features, Mitosis Rate, and Tubule Formation from H&E Images Predicts Disease-Free Survival in Patients with HR+ & LN+ Invasive Breast Cancer from SWOG S8814 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-16.

Background: Adjuvant chemotherapy is a common treatment for breast cancer patients with aggressive tumors, but imposes severe side effects. Although lymph node involvement is associated with higher likelihood of mortality, a subset of LN+ patients can survive without relapse, even without adjuvant chemotherapy. SWOG-8814 (S8814) was a randomized clinical trial of hormone receptor positive, LN+ post-menopausal women (pathologic stage T1-3N1-2) to compare patient outcome between endocrine therapy alone (tamoxifen), chemotherapy (cyclophosphamide, doxorubicin, and 5-fluorouracil) followed by 5 years of tamoxifen, and chemotherapy with concurrent tamoxifen. In this work, we evaluated the ability of a machine learning approach called multiple instance learning (MIL) to predict long-term overall (OS) and disease-free survival (DFS) in patients from the S8814 clinical trial via analysis of digitized H&E tissue slides. Methods: The training set (St, n=121) consisted of digitized H&E Whole Slide Images (WSIs) of ER+ LN+ patients from ECOG-2197 - a clinical trial to compare patient outcome under chemotherapy with doxorubicin/docetaxel vs. doxorubicin/cyclophosphamide. For each WSI, the nuclei of ten tumor patches (2000 × 2000 pixels) were automatically segmented by a pretrained machine learning algorithm called Convolutional Neural Networks (CNN). The results of the CNN’s segmentations were used to obtain ten corresponding feature vectors of 3963 features relating to nuclear morphology and spatial arrangement. Five top discriminative features (Haralick texture, Delaunay triangulation, orientation entropy, perimeter kurtosis, architecture) were identified by reliefF-MI feature filtering and forward selection on St. A Normalized Set Kernel Support Vector Machine classifier was trained on St to construct a MIL binary classifier (M+), which generates a continuous survival score to predict which patients would have >10-years of DFS and OS. The score cutoff thatmaximized F1 score on St was used to generate binary predictions of patient outcome. Blinded validation of the risk scores on S8814 was performed by SWOG. Results: M+ was significantly prognostic of OS in univariate analysis (HR=0.72, p=0.020, 95% CI= 0.55 – 0.95) on S8814. M+ stratifications remained statistically significant after multivariable analysis controlling for treatment, number of positive lymph nodes, and tumor size (HR = 0.71, p=0.017, 95% CI=0.54-0.94). M+ predictions did not achieve statistical significance for DFS in univariate analysis (HR=0.81, p=0.081, 95% CI 0.64-1.03) nor multivariable analysis (HR=0.81, p=0.080, 95% CI 0.63-1.03). M+ was not predictive of chemotherapy benefit for OS (p=0.88) and DFS (p=0.65). There was no correlation of the generated continuous score with Recurrence Score (r=-0.05), previously shown to be a predictive factor for chemotherapy benefit. Conclusion: Our findings demonstrate that nuclear morphology provides insight into overall survival in ER+ LN+ breast cancer patients. Future work will involve combining the MIL based morphologic predictor with other clinicopathologic factors to improve DFS risk stratification. Funding: Funding NIH/NCI grants U10CA180888, U10CA180819, U24CA196175; and in part by Genomic Health, INC. (now Exact Sciences Corp.) Citation Format: Daniel Shao, William E. Barlow, Haojia Li, Cheng Lu, Kathy S. Albain, James Rae, Daniel F. Hayes, Andrew K. Godwin, Alastair M. Thompson, Anant Madabhushi, Lajos Pusztai. Computer analysis of nuclear morphology with Multiple Instance Learning Predicts Overall Survival for Node Positive Breast Cancer Patients from SWOG S8814: A Blinded Validation Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-11.

PD-1 immune checkpoint has been intensively investigated in pathogenesis and treatments for cancer and autoimmune diseases. Cells that express PD-1 (PD-1

Software Release of "Microsaccade-inspired Event Camera for Robotics"

BACKGROUND: Although the pain visual analog scale (VAS-pain) is a ubiquitous patient-reported outcome instrument, it remains unclear how to interpret changes in scores. Therefore, our purpose was to calculate the minimal clinically important difference (MCID) and substantial clinical benefit (SCB) for the VAS-pain instrument in a non-shoulder hand and upper extremity postoperative population. METHODS: Adult postoperative patients treated by one of five fellowship-trained orthopaedic hand surgeons at a single tertiary academic medical center were identified. Inclusion required VAS-pain scores at baseline (up to 3 months preoperatively) and follow-up (up to 4 months postoperatively) in addition to a response to a pain-specific anchor question at follow-up. MCID estimates were calculated with 1) the 1/2 standard deviation (SD) method and 2) an anchor-based approach. SCB estimates were calculated with 1) an anchor-based approach and 2) a receiver operator curve (ROC) method that maximized the sensitivity and specificity for detecting a “Much improved” status. RESULTS: A total of 667 and 148 patients were included in the MCID and SCB analyses, respectively. The 1/2 SD MCID estimate was 1.6, and the anchor-based estimate was 1.9. The anchor-based SCB estimate was 2.2. ROC analysis yielded an SCB estimate of 2.6, with an area under the curve of 0.72 consistent with acceptable discrimination. CONCLUSIONS: We propose MCID values in the range of 1.6 to 1.9 and SCB values in the range of 2.2 to 2.6 for the VAS-pain instrument in a non-shoulder hand and upper extremity postoperative population. CLINICAL RELEVANCE: These MCID and SCB estimates may be useful for powering clinical studies, and when interpreting VAS-Pain score changes or differences reported in the hand surgery literature. These values are to be applied at a population level, and should not be applied to assess the improvement, or lack thereof, for individual patients.

Background: Evaluating the minimal clinically important differences (MCIDs) in patient-reported outcome scores is essential for use of clinical outcomes data. The purpose of the current study was to calculate MCID of Patient Reported Outcome Information System Physical Function (PROMIS PF) scores for ankle fracture patients. Methods: All patients who underwent operative fixation for ankle fractures at a single level 1 trauma center were identified by Current Procedural Terminology code. PROMIS PF scores were collected. Patients had to complete an anchor question at 2 time points postoperatively to be included in this study. Anchor-based and distribution-based MCIDs were calculated. Results: A total of 331 patients were included in the distribution-based analysis, and 195 patients were included in the anchor-based analysis. Mean age was 45.3 years (SD 17.5), and 59.4% of participants were female. MCID for PROMIS PF scores was 5.05 in the distribution-based method and 5.43 in the anchor-based method. Conclusion: This study identified MCID values based on 2 time points postoperatively for PROMIS PF scores in the ankle fracture population. Both methods of MCID calculation resulted in equivalent MCIDs. This can be used to identify patients outside the normal preoperative and postoperative norms and may help to make clinically relevant practice decisions. Level of Evidence: Level I, diagnostic study, testing of previously developed diagnostic measure on consecutive patients with reference standard applied.

Objective The US Preventive Services Task Force (USPSTF) requires the estimation of lifetime pack-years to determine lung cancer screening eligibility. Leading electronic health record (EHR) vendors calculate pack-years using only the most recently recorded smoking data. The objective was to characterize EHR smoking data issues and to propose an approach to addressing these issues using longitudinal smoking data. Materials and Methods In this cross-sectional study, we evaluated 16 874 current or former smokers who met USPSTF age criteria for screening (50–80 years old), had no prior lung cancer diagnosis, and were seen in 2020 at an academic health system using the Epic® EHR. We described and quantified issues in the smoking data. We then estimated how many additional potentially eligible patients could be identified using longitudinal data. The approach was verified through manual review of records from 100 subjects. Results Over 80% of evaluated records had inaccuracies, including missing packs-per-day or years-smoked (42.7%), outdated data (25.1%), missing years-quit (17.4%), and a recent change in packs-per-day resulting in inaccurate lifetime pack-years estimation (16.9%). Addressing these issues by using longitudinal data enabled the identification of 49.4% more patients potentially eligible for lung cancer screening (P Discussion Missing, outdated, and inaccurate smoking data in the EHR are important barriers to effective lung cancer screening. Data collection and analysis strategies that reflect changes in smoking habits over time could improve the identification of patients eligible for screening. Conclusion The use of longitudinal EHR smoking data could improve lung cancer screening.

Background: Endometrial carcinoma (EC) is one of the most prevalent gynecologic malignancies and requires further classification for treatment and prognosis. Long non-coding RNAs (lncRNAs) and immunogenic cell death play a critical role in tumor progression. Nevertheless, the role of lncRNAs in immunogenic cell death in EC remains unclear. This study aimed to explore the role of immunogenic cell death (ICD) related-lncRNAs in EC via bioinformatics and establish a prognostic risk model based on the ICD related-lncRNAs. We also explored immune infiltration and immune cell function across prognostic groups and made treatment recommendations. Methods: A total of 552 EC samples and clinical data of 548 EC patients were extracted from The Cancer Genome Atlas (TCGA) database and UCSC Xena, respectively. A prognostic-related feature and risk model were developed using the least absolute shrinkage and selection operator (LASSO). Subtypes were classified with consensus cluster analysis and validated with t-Distributed Stochastic Neighbor Embedding (tSNE). Kaplan-Meier analysis was conducted to assess differences in survival. Infiltration by immune cells was estimated by ssGSEA, TIMER algorithm. By using the "pRRophetic" R package, the IC50 of drugs was compared among risk subgroups. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was performed to verify the expression of lncRNA in clinical EC tissues and cell lines. Result: In total, 16 immunogenic cell death-related lncRNAs with prognostic values were identified. Using SCARNA9, FAM198B-AS1, FKBP14-AS1, FBXO30-DT, LINC01943, and AL161431.1 as risk model, their predictive accuracy and discrimination were assessed. We divided EC patients into high-risk and low-risk groups based on the risk model. The analysis showed that the risk model was an independent prognostic factor. The prognosis of the high- and low-risk groups was different, and the overall survival (OS) of the high-risk group was lower. The low-risk group had higher immune cell infiltration and immune scores. Consensus clustering analysis divided the samples into four subtypes, of which cluster 4 had higher immune cell infiltration and immune scores. Conclusion:A prognostic signature composed of 6 immunogenic cell death related-lncRNAs in EC was established, and a risk model based on this signature can be used to predict the prognosis of patients with EC.

Histone lactylation has been reported to involve in tumorigenesis and development. However, its biological regulatory mechanism in endometrial carcinoma (EC) is yet to be reported in detail. In the present study, we evaluated the expression of global lactylation in EC tissues by immunohistochemistry and western blot, and it was elevated. The non-metabolizable glucose analog 2-deoxy-d-glucose (2-DG) and oxamate treatment could decrease the level of lactylation so as to inhibit the proliferation and migration ability, induce apoptosis significantly, and arrest the cell cycle of EC cells. Mechanically, histone lactylation stimulated USP39 expression to promote tumor progression. Moreover, USP39 activated PI3K/AKT/HIF-1α signaling pathway via interacting with and stabilizing PGK1 to stimulate glycolysis. The results of present study suggest that histone lactylation plays an important role in the progression of EC by promoting the malignant biological behavior of EC cells, thus providing insights into potential therapeutic strategies for endometrial cancer.

Background Bacterial co-infection has been reported with COVID-19, but the extent of co-infection nationally is unclear. We sought to describe the temporal and spatial trends in bacterial co-infection across the US among COVID-19 positive admissions to Veterans Affairs (VA) hospitals. Methods This retrospective cohort study included patients admitted to VA hospitals from March 1, 2020 through May 31, 2022 with a positive COVID-19 test within the previous 14 days and up to 2 days after admission. We summarized temporal and spatial patterns of bacterial co-infection, defined as a positive clinical microbiology culture for the bacterial pathogens listed in Table 1, defined as either community-onset (COI, within 2 calendar days of admission), or hospital-onset (HOI, > 2 calendar days after admission). We performed a univariate analysis including facility and patient factors and generated descriptive statistics to describe the frequency of occurrence over time and space overall, and within each organism. Organisms Table 1:List of organisms included in our study Results By the end of June 2021, there were 35,299 hospitalizations observed from 33,383 patients admitted with positive COVID-19 tests in VA. Co-infection was detected among 7.4% of hospitalizations (2.9% for COI and 4.7% for HOI). VA patients older than 70, Asian or unknown race, higher Charlson Comorbidity Index were more likely to experience HOI and COI. Facility-level rates of HOI and COI over the study period presented substantial geographic variability, ranging from 0 to 45.5 per 1000 patient days and from 0 to 6.98 per 100 hospitalizations for HOI and COI, respectively [Fig 1]. Between March 2020 and June 2021, monthly facility-level rates of HOI and COI also varied substantially within and between facilities [Fig 2]. Average monthly co-infection rates increased in the first three months of the pandemic, with HOIs subsequently declining gradually and COIs remaining stable across VA. The correlation coefficients between hospital mortality and facility-level co-infection rates for HOI and COI ranged from –0.5 to 0.7 [Fig 3]. Spatial variation Fig 1:Plot for spatial distribution across VA facilities of HOIs and COIs, measured as Co-Infections per 100 patient hospitalizations Temporal variation Fig 2:Plot for temporal distribution across VA facilities of HOI and COI, measured as Co-Infections per 100 patient hospitalizations Mortality correlation Fig 3:Plot for spatial distribution of the correlation coefficients between hospital mortality and HOI and COI Conclusion Bacterial co-infection was infrequent during hospitalization with COVID-19 in the VA healthcare system, and has mild to moderate association with hospital mortality. However, substantial geographic and temporal variation was observed. Disclosures Karim Khader, PhD, BioFire Diagnostics: Grant/Research Support.

Background Bacterial co-infection has been reported with COVID-19, but risk factors for bacterial co-infection remain unclear due to limited large scale studies. We seek to identify predictive factors associated with risk of co-infection with multidrug-resistant organisms for patients hospitalized at Veterans Affairs (VA) hospitals with COVID-19. Methods This retrospective cohort study included Veterans admitted to VA hospitals from March 1, 2020 through May 31, 2022 with a confirmed positive COVID-19 test within the previous 14 days and up to 2 days after admission. Outcomes of interest were hospital-onset co-infection (HOI, > 2 calendar days after admission) and community-onset co-infection (COI, within 2 calendar days of admission). Potential risk factors included both patient- (e.g. vital sign, medication use) and facility-level covariates (e.g. bed size, antibiotic use rate). We compared the covariate distributions for patients with and without HOI and COI. Our analytical approaches included variance inflation factors to detect the presence of multicollinearity among these factors, and Least Absolute Shrinkage and Selection Operator to identify the subset of factors associated with HOI and COI. We conducted a two-stage analysis, first performing feature selection among the individual-level risk factors followed by identification of facility-level risk factors. Optimal models were identified using 10-fold cross validation. Results By July 2021, 33,383 patients were admitted to VA with positive COVID-19 test. We found that medications for ventilator induction (OR with 95% CI: 2.9 (2.2, 3.9)), norepinephrine (OR with 95% CI: 1.6 (1.2, 2.2)) and antimicrobial therapies for gram-positive infections (OR with 95% CI: 4.5 (3.6, 5.6)) [Table 1] were associated with the increased risk of HOI and patients in facilities with high C difficile infection rates were more likely to have COI detected (OR with 95% CI: 1.14 (1.11, 1.18)) [Table 2]. Homeless Veterans had higher risk of developing an HOI (OR with 95% CI: 1.5 (1.1, 2.0)), but not a COI. Conclusion Risk factors for HOI and COI in COVID-19 were distinct, with specific classes of medications and antibiotics as well as patient factors resulting in increased risk for HOI. Further work is needed to better understand the risk factors for COI. Disclosures Karim Khader, PhD, BioFire Diagnostics: Grant/Research Support.

Background Cognitive deficits are common in patients with sepsis. Previous studies in sepsis-associated encephalopathy (SAE) implicated the C-X-C chemokine receptor type (CXCR) 5. The present study used a mouse model of SAE to examine whether CXCR5 down-regulation could attenuate cognitive deficits. Methods Sepsis was induced in adult male C57BL/6 J and CXCR5−/− mice by cecal ligation and puncture (CLP). At 14–18 days after surgery, animals were tested in a Morris water maze, followed by a fear conditioning test. Transmission electron microscopy of hippocampal sections was used to assess levels of autophagy. Primary microglial cultures challenged with lipopolysaccharide (LPS) were used to examine the effects of short interfering RNA targeting CXCR5, and to investigate the possible involvement of the p38MAPK/NF-κB/STAT3 signaling pathway. Results CLP impaired learning and memory and up-regulated CXCR5 in hippocampal microglia. CLP activated hippocampal autophagy, as reflected by increases in numbers of autophagic vacuoles, conversion of microtubule-associated protein 1 light chain 3 (LC3) from form I to form II, accumulation of beclin-1 and autophagy-related gene-5, and a decrease in p62 expression. CLP also shifted microglial polarization to the M1 phenotype, and increased levels of IL-1β, IL-6 and phosphorylated p38MAPK. CXCR5 knockout further enhanced autophagy but partially reversed all the other CLP-induced effects, including cognitive deficits. Similar effects on autophagy and cytokine expression were observed after knocking down CXCR5 in LPS-challenged primary microglial cultures; this knockdown also partially reversed LPS-induced up-regulation of phosphorylated NF-κB and STAT3. The p38MAPK agonist P79350 partially reversed the effects of CXCR5 knockdown in microglial cultures. Conclusions CXCR5 may act via p38MAPK/NF-κB/STAT3 signaling to inhibit hippocampal autophagy during sepsis and thereby contribute to cognitive dysfunction. Down-regulating CXCR5 can restore autophagy and mitigate the proinflammatory microenvironment in the hippocampus.

Objective To compare an objective with a subjective numeracy assessment for association with self-reported health status, where numeracy refers to “the degree to which individuals have the capacity to access, process, interpret, communicate, and act on numerical, quantitative, graphical, biostatistical, and probabilistic health information needed to make effective health decisions” Results We completed a secondary analysis of two population-based surveys, the Empire State Poll (n = 763) and the Program for the International Assessment of Adult Competencies (PIAAC; n = 2609). The first survey assessed numeracy with a 3-item subjective instrument. The second assessed numeracy with more than 20 math problems. Both used the same measure for self-reported health status. Lower numeracy, whether subjectively or objectively assessed, was associated with worse self-reported health, even after controlling for education and other sociodemographic confounders. The odds ratios for the association were very similar (0.91 and 0.90 respectively). A lengthy objective numeracy assessment and a brief self-report assessment had similar associations with health status. A brief self-report measure of numeracy has similar properties to a lengthy objective assessment and is likely to be more feasible to use to screen patients in practice.

Background Minimal clinically important difference (MCID) estimates are useful for gauging clinical relevance when interpreting changes or differences in patient-reported outcomes scores. These values are lacking in the setting of elbow trauma. Our primary purpose was to estimate the MCID of the Patient-Reported Outcomes Measurement Information System (PROMIS) physical function (PF) computer adaptive test (CAT), the PROMIS upper extremity (UE) CAT, and the QuickDASH using an anchor-based approach for patients recovering from elbow trauma and related surgeries. Secondarily, we aimed to estimate the MCID using the 1/2 standard deviation method. Materials & methods Adult patients undergoing treatment for isolated elbow injuries between July 2014 and April 2020 were identified at a single tertiary academic medical center. Outcomes, including the PROMIS PF CAT v1.2/2.0, PROMIS UE CAT v1.2, and QuickDASH, were collected via a tablet computer. For inclusion, baseline (6 months before injury up to 11 days postoperatively or after injury) and follow-up (11 to 150 days postoperative or after injury) PF or UE CAT scores were required, as well as a response to an anchor question querying improvement in physical function. The MCID was calculated using (1) an anchor-based approach using the difference in mean score change between anchor groups reporting “No change” and “Slightly Improved/Improved” and (2) the 1/2 standard deviation method. Results Of the 146 included patients, the mean age was 46 ± 18 years and 67 (46%) were women. Most patients (129 of 146 or 88%) were recovering from surgery, and the remaining 12% were recovering from nonoperatively managed fractures and/or dislocations. The mean follow-up was 157 ± 192 days. Scores for each instrument improved significantly between baseline and follow-up. Anchor-based MCID values were calculated as follows: 5.7, 4.6, and 5.3 for the PROMIS PF CAT, PROMIS UE CAT, and QuickDASH, respectively. MCID values estimated using the 1/2 standard deviation method were 4.3, 4.8, and 11.7 for the PROMIS PF CAT, PROMIS UE CAT, and QuickDASH, respectively. Conclusions In the setting of elbow trauma, we propose MCID ranges of 4.3 to 5.7 for the PROMIS PF CAT, 4.6 to 4.8 for the PROMIS UE CAT, and 5.3 to 11.7 for the QuickDASH. These values will provide a framework for clinical relevance when interpreting clinical outcomes studies, or powering clinical trials, for populations recovering from trauma.

Background: Breast cancer is the most common cancer worldwide. There has been emerging interest in studying differences in breast tumor phenotypes between South Asian and South American women given that racial/ethnic disparities in incidence and mortality have been demonstrated in multiple studies. South Asian women are more likely to be diagnosed with an advanced stage breast tumor despite lower incidence than in North American women. There is evidence that computer-extracted nuclear morphological features on H&E slide images may be associated with breast cancer aggressiveness, specifically recurrence and disease free survival. However, studies have mostly focused on North American women. In this work, we evaluated whether there is a difference in computer extracted features of nuclear morphology from H&E tissue slide images between South Asian (SA) and North American (NA) women and we also investigated how these differences could impact the development of population specific breast cancer prognostic models. Methods: H&E slides of breast tumors from patients who were diagnosed with ER+ early stage invasive breast cancer from Tata Memorial Centre, India (SA: 69 (20 recurrence)) and from University Hospitals Cleveland Medical Center (NA: 121 (20 recurrence)), along with outcome information were collected. All slides were digitized on either a Ventana DP 200 or a Roche Ventana iScan HT slide scanner. For each image, a conditional Generative Adversarial Network model was employed to segment the individual nuclei, which were used to generate 241 nuclear features including nuclear architecture, shape, orientation disorder, and texture features. Half of the patients (95) were randomly selected as the training set (Stra) with the remaining patients as the hold-out validation set (Stest). Three elastic net regularized Cox regression models (MSA, MNA, MSA+NA) were trained fitting between the nuclear features and disease free survival (DFS) respectively for SA subset, NA subset, and SA & NA set in Stra. The top five prognostic features were identified respectively from each of the three models (MSA, MNA, MSA+NA) which were further validated on Stest to evaluate their prognostic value in prediction of DFS. Results: We found that the prognostic features identified by MNA and MSA+NA were mostly shape features (three out of five for MNA, four out of five for MSA+NA), while the prognostic features identified by the model specifically trained with the SA population (MSA) were mostly texture features (three out of five), possibly reflecting chromatin patterns in the cell. MSA yielded a better performance (Hazard Ratio=4.99 (p=0.00928, CI=1.32-18.9) from log-rank test between model derived high and low risk categories) on SA population in Stest compared to MNA and MSA+NA. Conclusion: We found that nuclear histomorphometry features were different between breast cancer patients from South Asia and those from North America. The prognostic capability of the computational pathology-based models for South Asian women could be significantly improved by taking into account population-specific information. An additional independent validation set is needed to confirm the preliminary findings presented here. Citation Format: Haojia Li, Kaustav Bera, Paula Toro, Pingfu Fu, Vidya Rao, Shabina Siddique, Aparna Harbhajanka, Haley Sechrist, Zelin Zhang, Sangeeta Desai, Vani Parmar, Anant Madabhushi. Computerized image analysis of nuclear morphological features reveals differences in phenotype and prognosis of disease free survival of early stage ER+ breast cancers for South Asian and North American women [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-45.

Background: Sepsis-associated encephalopathy (SAE) is one of the most serious complications of sepsis, along with brain function and cognitive behavioral changes. The process of efferocytosis with microglia was restrained in SAE rats’ hippocampus. We have previously shown that milk fat globule EGF factor 8 protein (MFG-E8) evoked efferocytosis in SAE rats’ brain, and alleviated the inflammnation in hippocampus. The present study investigated the the contribution of MFG-E8 to the brain functional connectivity (FC) of hippocampus and lateral entorhinal cortex in SAE rats by resting-state functional MRI scan.Methods: Sixty adult male Sprague Dawley rats were divided randomly into Sham operation group, cecal ligation and puncture (CLP) group, CLP+MFGE8 group, and CLP+MFGE8+Cilengitide group. After cecal ligation and puncture (CLP) surgery, MFGE8 (3.3ug) was injected intracerebroventricularly (i.c.v.) and cilengitide (10 mg/kg) was injected intraperitoneal. The Morris water maze (MWM) and open filed test (OFT) were performed continuously for five days. Rats were detected by T2-MRI and rs-fMRI scan 8 days post-surgery, then brain tissues were taken for western blotting and pathological observation by HE stained. One-way ANOVA with Tukey’s post-test of all pair of columns was employed statistical analyses.Results: MFGE8 improved performance of neurobehavioral tests in MWM test and OFT. Expression of IL-1β and the proteins of MFGE8, Rac1, and LC3 were up regulated in CLP+MFGE8 group. On the contrary, expression of IL-6, Rac1, and LC3 were down regulated in CLP+MFGE8+cilengitide group. MFGE8 significantly decreased the hyperintense region in hippocampus detected by T2-MRI, and increased ALFF value in SAE rats’ bilateral sensory cortex, motor cortex and visual cortex by rs-fMRI. In addition, MFGE8 increased FC of CA1 and LEnt in same side of cerebral hemisphere, and the FC of CA1 and LEnt was consistent with the behavior result in Morris water maze test.Conclusions: MFGE8 activated efferocytosis with microglia and improved brain function and functional connectivity between CA1 and LEnt which were reflected in behavior tests and fMRI.

IntroductionAlthough the association between blood pressure and vitamin D has been well studied, the effects of dietary magnesium intake on this relationship are still unclear. Thus, this study aimed to determine the effects of dietary magnesium intake on the association between vitamin D and blood pressure.MethodsThe present study analyzed data from the continuous the National Health and Nutrition Examination Survey (NHANES) 2007–2014. We included 8,799 participants aged 20 years or older. Multivariable linear regression was performed to assess the association between vitamin D and systolic blood pressure (SBP) and diastolic blood pressure (DBP). Dietary magnesium intake was stratified by low magnesium intake (ResultsIn this cross-sectional study, we found that vitamin D was negatively related to SBP, but not to DBP. The relationship between vitamin D and SBP was different in the low and high magnesium intake group (β: −0.25 95%Cl: −0.4~0.07 vs β: −0.32 95%Cl: −0.52~-0.12). Furthermore, magnesium intake significantly modified the negative relationship between vitamin D and SBP in most of the models.ConclusionOur research showed that magnesium and vitamin D have an interactive effect in reducing SBP, which may have great importance for clinical medication.

Background: AF ablation approaches and outcomes vary. Very little work has been done to assess the variability of ablation costs to health systems and drivers of variability. Objective: Determine the drivers of cost variability in AF ablation procedures. Methods: We assessed the costs of AF ablation procedures performed between 2013-2020 at a single tertiary care center. Cost to the health system were inflation-adjusted and separated into facility, imaging, implant, pharmacy, supply, labs, and other services. Only patients who were outpatient and had an ablation by an operator who performed >10 procedures were included. Lasso multivariable regression was used to identify the primary drivers of variability in costs, including operator and patient characteristics. Results: 1072 patients with 1284 AF ablations were included (age: 65.1, SD: 11.0; men: 68%; CHADS2-Vasc: 2.8, SD: 1.9, beta blockers: 63%, non-white race: 6%). Procedures were performed by 8 operators. Proportional contributions to overall costs are shown in the Figure. Regression analysis demonstrated higher average cost for men, (1.25%), non-white race (2.6%), beta-blocker use (1.9%), prior ablation (0.98%), anticoagulation use (1.4%), and operator (highest operator cost increase vs. lowest, 18%). There was no relation to CHADS2-Vasc or age. Cost variability was primarily driven by supplies including catheters and other equipment. Conclusion: Cost variability was only modestly related to patient characteristics. The largest contributor to cost in AF ablations was supplies, which are primarily operator dependent.

Introduction: Overnight stay after ablation for atrial fibrillation (AF) is standard practice, in part driven by the need for bedrest required to maintain hemostasis. We aimed to measure patient reported outcomes (PROs) and costs associated with same day discharge (SDD) for AF ablation and vascular closure device implantation in clinical practice. Methods: PROs were measured in 50 patients prospectively enrolled prior to AF ablation with post procedure treatment by complete vascular device closure (n=25) versus compression hemostasis (n=25). Health-system costs for SDD patients receiving vascular device closure were compared to matched controls with one-night stays who did not receive closure devices. Results: Patients receiving vascular device closure for AF ablation had mean age 65, 17% female, with mean CHA 2 DS 2 -VASc score 3. Mean number of venous sheaths was higher among patients receiving vascular device closure (3.8 vs. 3.1, p2 DS 2 -VASc score of 2 (p=NS for each vs. matched controls). SDD with vascular closure was associated with significantly lower facility, pharmacy, and disposable costs, but higher implant costs ( Table ). Overall costs for ablation were not different based on conservative estimates for overnight stay costs. Conclusions: Vascular closure for AF ablation improves patient experience in routine clinical care. Use of vascular closure and SDD after AF ablation reduces several components of health system costs, without an overall increase, and may be cost-saving in comparative healthcare systems.

Introduction: Circulating vitamin D concentrations have been associated with the risk of type 2 diabetes (T2D). Magnesium has also been reported to be associated with lower T2D risk. Besides, magnesium is an essential cofactor for vitamin D activation. However, the effect of dietary magnesium intake on the association between vitamin D and the risk of T2D has not been studied comprehensively. Therefore, we designed this cross-sectional study to assess the effect modification of magnesium intake on the association between vitamin D and risk of T2D.Research Design and Methods: The present study analyzed data from the National Health and Nutrition Examination Survey (NHANES) continuously from 2007 to 2014, involving 10,249 participants. By having stratified participants based on magnesium intake category (low magnesium intake Results: In this cross-sectional study, the association of serum vitamin D with the incidence of T2D appeared to differ between the low magnesium intake group and the high magnesium intake group (OR: 0.968, 95%Cl: 0.919–1.02 vs. OR: 0.925, 95%Cl: 0.883–0.97). Furthermore, there was evidence of interaction between vitamin D levels and magnesium intake on decreasing the incidence of T2D (p-value for interaction = 0.001).Conclusions: The results of our study indicated that magnesium intake might affect the association of serum vitamin D with the risk of T2D. Such a finding requires further randomized controlled trials to provide more evidence.

Under high-temperature and hygrothermal conditions, sea salt erosion can lead to asphalt-aggregate interfacial failure in porous asphalt concrete and cause aggregate raveling in coastal areas. Therefore, studying the damaging effect of sea salt erosion on an asphalt-aggregate interfacial system in a hygrothermal environment is necessary. First, the asphalt film thickness of a standard asphalt-aggregate specimen used in the simulation tests was determined according to the relationship between the tensile strength of the asphalt-aggregate specimen and the thickness of the asphalt film. The damaging effect of the salt solution was simulated by the 60°C high-temperature erosion test, and the solution type, solution concentration, and immersion duration were considered. The tensile strength and asphalt film-stripping ratio of the eroded specimens were analyzed, and the interfacial asphalt film dynamic equation σ2(t) and the stripping region interface dynamic equation σ2(t) were deduced. The results show that the 6 μm asphalt film thickness corresponds to the maximum tensile strength of the asphalt-aggregate specimen. With the increase of immersion duration, the tensile strength of asphalt-aggregate specimen decreased, and the asphalt film-stripping ratio of failure surface increased. In addition, the tensile strength of the interfacial asphalt film increased gradually due to the aging effect of the salt solution. The tensile strength of the stripping region’s interface did not descend to zero, but was obviously lower than the asphalt film. The 5% Na2SO4 solution has the highest damaging effect on the asphalt-aggregate interfacial system, followed by the 5% composite salt solution, 5% NaCl solution, water, and 10% NaCl solution..

Background In this study we sought to explore the possibility of using patient centered care (PCC) documentation as a measure of the delivery of PCC in a health system. Methods We first selected 6 VA medical centers based on their scores for a measure of support for self-management subscale from a national patient satisfaction survey (the Survey for Healthcare Experience-Patients). We accessed clinical notes related to either smoking cessation or weight management consults. We then annotated this dataset of notes for documentation of PCC concepts including: patient goals, provider support for goal progress, social context, shared decision making, mention of caregivers, and use of the patient's voice. We examined the association of documentation of PCC with patients’ perception of support for self-management with regression analyses. Results Two health centers had Conclusion Providers document PCC concepts in their clinical notes. In this pilot study we explored the feasibility of using this data as a means to measure the degree to which care in a health center is patient centered. Practice Implications: clinical EHR notes are a rich source of information about PCC that could potentially be used to assess PCC over time and across systems with scalable technologies such as natural language processing.

Despite known histological, biological, and clinical differences between lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), relatively little is known about the spatial differences in their corresponding immune contextures. Our study of over 1000 LUAD and LUSC tumors revealed that computationally derived patterns of tumor-infiltrating lymphocytes (TILs) on H&E images were different between LUAD (N = 421) and LUSC (N = 438), with TIL density being prognostic of overall survival in LUAD and spatial arrangement being more prognostically relevant in LUSC. In addition, the LUAD-specific TIL signature was associated with OS in an external validation set of 100 NSCLC treated with more than six different neoadjuvant chemotherapy regimens, and predictive of response to therapy in the clinical trial CA209-057 (n = 303). In LUAD, the prognostic TIL signature was primarily comprised of CD4+ T and CD8+ T cells, whereas in LUSC, the immune patterns were comprised of CD4+ T, CD8+ T, and CD20+ B cells. In both subtypes, prognostic TIL features were associated with transcriptomics-derived immune scores and biological pathways implicated in immune recognition, response, and evasion. Our results suggest the need for histologic subtype-specific TIL-based models for stratifying survival risk and predicting response to therapy. Our findings suggest that predictive models for response to therapy will need to account for the unique morphologic and molecular immune patterns as a function of histologic subtype of NSCLC.

BackgroundCognitive deficits are common in patients with sepsis. Previous studies in sepsis-associated encephalopathy (SAE) implicated the C-X-C chemokine receptor type (CXCR) 5. The present study used a mouse model of SAE to examine whether CXCR5 down-regulation could attenuate cognitive deficits.MethodsSepsis was induced in adult male C57BL/6J and CXCR5-/- mice by cecal ligation and puncture (CLP). At 14-18 days after surgery, animals were tested in a Morris water maze, followed by a fear conditioning test. Transmission electron microscopy of hippocampal sections was used to assess levels of autophagy. Primary microglial cultures challenged with lipopolysaccharide (LPS) were used to examine the effects of short interfering RNA targeting CXCR5, and to investigate the possible involvement of the p38MAPK/NF-κB/STAT3 signaling pathway.ResultsCLP impaired learning and memory and up-regulated CXCR5 in hippocampal microglia. CLP activated hippocampal autophagy, as reflected by increases in numbers of autophagic vacuoles, conversion of microtubule-associated protein 1 light chain 3 (LC3) from form I to form II, accumulation of beclin-1 and autophagy related gene-5, and a decrease in p62 expression. CLP also shifted microglial polarization to the M1 phenotype, and increased levels of IL-1β, IL-6 and phosphorylated p38MAPK. CXCR5 knockout further enhanced autophagy but partially reversed all the other CLP-induced effects, including cognitive deficits. Similar effects on autophagy and cytokine expression were observed after knocking down CXCR5 in LPS-challenged primary microglial cultures; this knockdown also partially reversed LPS-induced up-regulation of phosphorylated NF-κB and STAT3. The p38MAPK agonist P79350 partially reversed the effects of CXCR5 knockdown in microglial cultures.ConclusionsCXCR5 may act via p38MAPK/NF-κB/STAT3 signaling to inhibit hippocampal autophagy during sepsis and thereby contribute to cognitive dysfunction. Down-regulating CXCR5 can restore autophagy and mitigate the proinflammatory microenvironment in the hippocampus.