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The Peterson comparison formula proved by Woodward relates the three-pointed Gromov-Witten invariants for the quantum cohomology of partial flag varieties to those for the complete flag. Another such comparison can be obtained by composing a combinatorial version of the Peterson isomorphism with a result of Lapointe and Morse relating quantum Littlewood-Richardson coefficients for the Grassmannian to k-Schur analogs in the homology of the affine Grassmannian obtained by adding rim hooks. We show that these comparisons on quantum cohomology are equivalent, up to Postnikov's strange duality isomorphism., 28 pages; added several references, final version to appear in Algebr. Represent. Theory

Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk.To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores (PRS), monogenic risks, family history, and clinical risk assessments via a Genome Informed Risk Assessment (GIRA) report and will assess uptake of care recommendations after return of results.GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022.Return of a novel report for communicating monogenic, polygenic, and family history based risk factors will inform the benefits of integrated genetic risk assessment for routine health care.

Background Mechanisms of postoperative delirium remain poorly understood, limiting development of effective treatments. We tested the hypothesis that intraoperative oxidative damage is associated with delirium and neuronal injury and that disruption of the blood–brain barrier modifies these associations. Methods In a prespecified cohort study of 400 cardiac surgery patients enrolled in a clinical trial of atorvastatin to reduce kidney injury and delirium, we measured plasma concentrations of F2-isoprostanes and isofurans using gas chromatography-mass spectrometry to quantify oxidative damage, ubiquitin carboxyl-terminal hydrolase isozyme L1 to quantify neuronal injury, and S100 calcium-binding protein B using enzyme-linked immunosorbent assays to quantify blood–brain barrier disruption before, during, and after surgery. We performed the Confusion Assessment Method for the Intensive Care Unit twice daily to diagnose delirium. We measured the independent associations between intraoperative F2-isoprostanes and isofurans and delirium (primary outcome) and postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (secondary outcome), and we assessed if S100 calcium-binding protein B modified these associations. Results Delirium occurred in 109 of 400 (27.3%) patients for a median (10th, 90th percentile) of 1.0 (0.5, 3.0) days. In the total cohort, plasma ubiquitin carboxyl-terminal hydrolase isozyme L1 concentration was 6.3 ng/ml (2.7, 14.9) at baseline and 12.4 ng/ml (7.9, 31.2) on postoperative day 1. F2-isoprostanes and isofurans increased throughout surgery, and the log-transformed sum of intraoperative F2-isoprostanes and isofurans was independently associated with increased odds of postoperative delirium (odds ratio, 3.70 [95% CI, 1.41 to 9.70]; P = 0.008) and with increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 (ratio of geometric means, 1.42 [1.11 to 1.81]; P = 0.005). The association between increased intraoperative F2-isoprostanes and isofurans and increased postoperative ubiquitin carboxyl-terminal hydrolase isozyme L1 was amplified in patients with elevated S100 calcium-binding protein B (P = 0.049). Conclusions Intraoperative oxidative damage was associated with increased postoperative delirium and neuronal injury, and the association between oxidative damage and neuronal injury was stronger among patients with increased blood–brain barrier disruption. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Low-impact development (LID) is a common management practice used to infiltrate and filter stormwater through vegetated soil systems. The pollutant reduction potential of these systems is often characterized by a single pollutant removal rate; however, the biophysical properties of soils that regulate the removal of pollutants can be highly variable depending on environmental conditions. The goal of this study was to characterize the variability of soil properties and nitrogen (N) cycling rates in bioretention facilities (BRFs). Soil properties and potential N cycling processes were measured in nine curbside bioretention facilities (BRFs) in Portland, OR during summer and winter seasons, and a subset of six sites was sampled seasonally for two consecutive years to further assess temporal variability in soil N cycling. Potential N cycling rates varied markedly across sites, seasons, and years, and higher variability in N cycling rates was observed among sites with high infiltration rates. The observed seasonal and annual changes in soil parameters suggest that nutrient removal processes in BRFs may be highly variable across sites in an urban landscape. This variability has important implications for predicting the impacts of LID on water quality through time, particularly when estimated removal rates are used as a metric to assess compliance with water quality standards that are implemented to protect downstream ecosystems.

Introduction The Southern Community Cohort Study is a prospective study of low socioeconomic status (SES) blacks and whites from the southeastern US, where the burden of end-stage renal disease (ESRD) and its risk factors are high. We tested whether the 2.4-fold elevated risk of ESRD we previously observed in blacks compared to whites was explained by differences in baseline kidney function. Methods We conducted a case-cohort study of incident ESRD cases (n = 737) with stored blood and a probability sampled subcohort (n = 4238) and calculated estimated glomerular filtration rate (eGFR) from serum creatinine. 86% of participants were enrolled from community health centers in medically underserved areas and 14% from the general population in 12 states in the southeastern United States. Incident ESRD after entry into the cohort was ascertained by linkage of the cohort with the US Renal Data System (USRDS). Results Median (25th, 75th percentile) eGFR at baseline was 63.3 (36.0, 98.2) ml/min/1.73m2 for ESRD cases and 103.2 (86.0, 117.9) for subcohort. Black ESRD cases had higher median (25th, 75th) eGFR [63.3 (35.9, 95.9)] compared to whites [59.1 (39.4, 99.2)]. In multivariable Cox models accounting for sampling weights, baseline eGFR was a strong predictor of ESRD risk, and an interaction with race was detected (P = 0.029). The higher ESRD risk among blacks relative to whites persisted (hazard ratio: 2.58; 95% confidence interval: 1.65, 4.03) after adjustment for eGFR. Conclusion In this predominantly lower SES cohort, the racial disparity in ESRD risk is not explained by differences in baseline kidney function. Electronic supplementary material The online version of this article (10.1186/s12882-019-1502-z) contains supplementary material, which is available to authorized users.

Introduction High dietary acid load and metabolic acidosis are associated with an accelerated decline in kidney function and may contribute to the observed heterogeneity in end-stage renal disease (ESRD) risk according to APOL1 genotype. Our objective was to examine the associations of metabolic acidosis and dietary acid load with kidney disease progression, according to APOL1 genotype, among individuals with chronic kidney disease (CKD). Methods We studied 1048 African American participants in the Chronic Renal Insufficiency Cohort. Metabolic acidosis was defined as blood levels of serum bicarbonate less than 22 mEq/L, and dietary acid load was quantified by potential renal acid load (PRAL) using data from the Diet Health Questionnaire. APOL1 status was defined as having 2 risk variants, consisting of either possible combination of the G1 and G2 risk alleles. We tested associations of APOL1 and dietary and metabolic acidosis with CKD progression, defined as time to ESRD or 50% decline in eGFR. Results During a median follow-up period of 7 years, 379 participants had an incident CKD progression event (6.4 events per 100 person-years). After full adjustment, among participants with 2 APOL1 variants, the analysis failed to detect an association between metabolic acidosis or dietary acid load and CKD progression (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.96–1.11 per 1 mEq/L higher serum bicarbonate and an HR, 1.03; 95% CI, 0.92–1.15 per 10 mEq/L higher PRAL). Similar associations were noted among participants without the APOL1 high-risk genotype. Conclusion In a population at high risk of developing ESRD, metabolic acidosis and dietary acid load were not associated with CKD progression., Graphical abstract

Background Chemotherapy regimens that include the utilization of gemcitabine are the standard of care in pancreatic cancer patients. However, most patients with advanced pancreatic cancer die within the first 2 years after diagnosis, even when treated with standard of care chemotherapy. This study aims to explore combination therapies that could boost the efficacy of standard of care regimens in pancreatic cancer patients. Methods In this study, we used PV-10, a 10% solution of rose bengal, to induce the death of human pancreatic tumor cells in vitro. Murine in vivo studies were carried out to examine the effectiveness of the direct injection of PV-10 into syngeneic pancreatic tumors in causing lesion-specific ablation. Intralesional PV-10 treatment was combined with systemic gemcitabine treatment in tumor-bearing mice to investigate the control of growth among treated tumors and distal uninjected tumors. The involvement of the immune-mediated clearance of tumors was examined in immunogenic tumor models that express ovalbumin (OVA). Results In this study, we demonstrate that the injection of PV-10 into mouse pancreatic tumors caused lesion-specific ablation. We show that the combination of intralesional PV-10 with the systemic administration of gemcitabine caused lesion-specific ablation and delayed the growth of distal uninjected tumors. We observed that this treatment strategy was markedly more successful in immunogenic tumors that express the neoantigen OVA, suggesting that the combination therapy enhanced the immune clearance of tumors. Moreover, the regression of tumors in mice that received PV-10 in combination with gemcitabine was associated with the depletion of splenic CD11b+Gr-1+ cells and increases in damage associated molecular patterns HMGB1, S100A8, and IL-1α. Conclusions These results demonstrate that intralesional therapy with PV-10 in combination with gemcitabine can enhance anti-tumor activity against pancreatic tumors and raises the potential for this strategy to be used for the treatment of patients with pancreatic cancer.

We generalize the shuffle theorem and its $(km,kn)$ version, as conjectured by Haglund et al. and Bergeron et al., and proven by Carlsson and Mellit, and Mellit, respectively. In our version the $(km,kn)$ Dyck paths on the combinatorial side are replaced by lattice paths lying under a line segment whose $x$ and $y$ intercepts need not be integers, and the algebraic side is given either by a Schiffmann algebra operator formula or an equivalent explicit raising operator formula. We derive our combinatorial identity as the polynomial truncation of an identity of infinite series of $GL_{l}$ characters, expressed in terms of infinite series versions of LLT polynomials. The series identity in question follows from a Cauchy identity for non-symmetric Hall-Littlewood polynomials., 43 pages, 7 figures; v4: fixed missing reference and minor spacing mistakes

Background Chemotherapy regimens that include gemcitabine are considered standard of care in patients with advanced pancreatic ductal adenocarcinoma (PDAC). However, most patients with PDAC die within 2 years of diagnosis, even with these standard of care regimens. In this study, we explored the ability of intratumoral injections of PV-10, a 10% solution of rose bengal, to induce lesion-specific ablation and control of metastatic pancreatic tumors in a murine model. Methods PV-10 was cultured with human pancreatic cancer cell lines overnight and cell death was measured via Annexin-V and DAPI staining. Murine pancreatic tumor cells (Panc02) were injected subcutaneously in one flank to establish a single tumor model; to establish a bilateral tumor model, Panc02 tumor cells were implanted in the opposite flanks. On day 7, a single tumor was treated with intralesional PV-10. Gemcitabine (60 mg/kg) was injected intraperitoneally twice per week for 2 weeks. These experiments were repeated using Panc02 cells modified to overexpress the neoantigen ovalbumin (OVA). Control mouse tumor were directly injected with PBS. Tumor growth of PV-10 injected tumors and non-injected bystander tumors on the opposite flank were measured. Damage associated molecular patterns (DAMPs) in serum and immune cell frequencies within the spleens of tumor-bearing mice were measured to identify an associated systemic response with tumor lytic treatment regimen. Results We established that less than 50% of human and murine pancreatic cells were alive after a 24 hour incubation with 200µM PV-10 in vitro. The combination of intralesional PV-10 with the systemic administration of gemcitabine delayed the growth treated tumors and non-injected distal tumors. In contrast, gemcitabine monotherapy failed to delay tumor growth in bilateral Panc02 tumor models. We observed that this treatment strategy was markedly more successful in immunogenic Panc02OVA tumors resulting in lesion-specific ablation in 5/8 mice compared to 0/8 mice that were treated with gemcitabine monotherapy. This suggests that the combination therapy enhanced the immune-mediated clearance of tumors. Moreover, regression of tumors in mice that received PV-10 in combination with gemcitabine was associated with the depletion of splenic CD11b+Gr-1+ cells and increases in damage associated molecular patterns HMGB1, S100A8, and IL-1α. Conclusions Together, these results demonstrate that intralesional therapy with PV-10 can enhance the efficacy gemcitabine against pancreatic tumors. Ethics Approval Studies were performed under approved Institutional Review Board (IRB) laboratory protocols at the H. Lee Moffitt Cancer Center (Tampa, FL).

The activation of 41BB costimulatory signals by agonistic Abs enhances the expansion and function of tumor-infiltrating lymphocytes (TILs) for treating cancer patients with adoptive cell therapy. However, the impact of 41BB agonism is not limited to enhancing the activity of T cells, and the mechanism by which additional activation of this costimulatory axis in tumor-associated myeloid cells is poorly understood. In this study, we describe that the intratumoral administration of 41BB agonistic Abs led to increases in CD8 T cell infiltration followed by tumor regression in murine models. We found that granulocytes and monocytes rapidly replaced macrophages and dendritic cells in tumors following administration of anti-41BB Abs. Overall, myeloid cells from anti-41BB–treated tumors had an improved capacity to stimulate T cells in comparison with control-treated tumors. In human coculture systems, we demonstrated that the agonism of the 41BB–41BBL axis enhanced costimulatory signals and effector functions among APC and autologous TILs. Overall, these findings suggest that the effect of 41BB agonistic Abs are supported by additional costimulatory signals from tumor-associated myeloid cells,v leading to enhanced TIL expansion and function.

We prove that the $K$-$k$-Schur functions are part of a family of inhomogenous symmetric functions whose top homogeneous components are Catalan functions, the Euler characteristics of certain vector bundles on the flag variety. Lam-Schilling-Shimozono identified the $K$-$k$-Schur functions as Schubert representatives for $K$-homology of the affine Grassmannian for SL$_{k+1}$. Our perspective reveals that the $K$-$k$-Schur functions satisfy a shift invariance property, and we deduce positivity of their branching coefficients from a positivity result of Baldwin and Kumar. We further show that a slight adjustment of our formulation for $K$-$k$-Schur functions produces a second shift-invariant basis which conjecturally has both positive branching and a rectangle factorization property. Building on work of Ikeda-Iwao-Maeno, we conjecture that this second basis gives the images of the Lenart-Maeno quantum Grothendieck polynomials under a $K$-theoretic analog of the Peterson isomorphism., 24 pages

BACKGROUND:Burnout affects all medical specialists, and concern about it has become common in today’s health care environment. The gold standard of burnout measurement in health care professionals is the Maslach Burnout Inventory-Human Services Survey (MBI-HSS), which measures emotional exhaustion

We definitively establish that the theory of symmetric Macdonald polynomials aligns with quantum and affine Schubert calculus using a discovery that distinguished weak chains can be identified by chains in the strong (Bruhat) order poset on the type-$A$ affine Weyl group. We construct two one-parameter families of functions that respectively transition positively with Hall-Littlewood and Macdonald's $P$-functions, and specialize to the representatives for Schubert classes of homology and cohomology of the affine Grassmannian. Our approach leads us to conjecture that all elements in a defining set of 3-point genus 0 Gromov-Witten invariants for flag manifolds can be formulated as strong covers., Comment: 29 pages

Background Recent data suggest that sodium (Na+) is stored in the muscle and skin without commensurate water retention in maintenance hemodialysis (MHD) patients. In this study, we hypothesized that excessive Na+ accumulation would be associated with abnormalities in peripheral insulin action. Methods Eleven MHD patients and eight controls underwent hyperinsulinemic–euglycemic–euaminoacidemic clamp studies to measure glucose (GDR) and leucine disposal rates (LDR), as well as lower left leg 23Na magnetic resonance imaging to measure Na+ concentration in the muscle and skin tissue. Results The median GDR and LDR levels were lower, and the median muscle Na+ concentration was higher in MHD patients compared with controls. No significant difference was found regarding skin Na+ concentration between group comparisons. Linear regression revealed inverse relationships between muscle Na+ concentration and GDR and LDR in MHD patients, whereas no relationship was observed in controls. There was no association between skin Na+ content and GDR or LDR in either MHD patients or controls. Conclusions These data suggest that excessive muscle Na+ content might be a determinant of IR in MHD patients, although the causality and mechanisms remain to be proven.

Emm55 is a bacterial gene derived from Streptococcus pyogenes (S. pyogenes) that was cloned into a plasmid DNA vaccine (pAc/emm55). In this study, we investigated the anti-tumor efficacy of pAc/emm55 in a B16 murine melanoma model. Intralesional (IL) injections of pAc/emm55 significantly delayed tumor growth compared to the pAc/Empty group. There was a significant increase in the CD8(+) T cells infiltrating into the tumors after pAc/emm55 treatment compared to the control group. In addition, we observed that IL injection of pAc/emm55 increased antigen-specific T cell infiltration into tumors. Depletion of CD4(+) or CD8(+) T cells abrogated the anti-tumor effect of pAc/emm55. Combination treatment of IL injection of pAc/emm55 with anti-PD-1 antibody significantly delayed tumor growth compared to either monotherapy. pAc/emm55 treatment combined with PD-1 blockade enhanced anti-tumor immune response and improved systemic anti-tumor immunity. Together, these strategies may lead to improvements in the treatment of patients with melanoma.

ObjectiveTo examine whether lifestyle factors, including sedentary time and physical activity, could independently contribute to risk of end-stage renal disease (ESRD).Study designCase-cohort study.SettingSouth-eastern USA.ParticipantsThe Southern Community Cohort Study recruited ~86 000 black and white participants from 2002 to 2009. We assembled a case cohort of 692 incident ESRD cases and a probability sample of 4113 participants.PredictorsSedentary time was calculated as hours/day from daily sitting activities. Physical activity was calculated as metabolic equivalent (MET)-hours/day from engagement in light, moderate and vigorous activities.OutcomesIncident ESRD.ResultsAt baseline, among the subcohort, mean (SD) age was 52 (8.6) years, and median (25th, 75th centile) estimated glomerular filtration rate (eGFR) was 102.8 (85.9–117.9) mL/min/1.73 m2. Medians (25th–75th centile) for sedentary time and physical activity were 8.0 (5.5–12.0) hours/day and 17.2 (8.7–31.9) MET-hours/day, respectively. Median follow-up was 9.4 years. We observed significant interactions between eGFR and both physical activity and sedentary behaviour (p2. The inverse association is most pronounced at physical activity levels >27 MET-hours/day. High levels of sitting time were associated with increased ESRD risk only among those with reduced kidney function (eGFR ≤30 mL/min/1.73 m2); this association was attenuated after excluding the first 2 years of follow-up.ConclusionsIn a population with a high prevalence of chronic kidney disease risk factors such as hypertension and diabetes, physical activity appears to be associated with reduced risk of ESRD among those with preserved kidney function. A positive association between sitting time and ESRD observed among those with advanced kidney disease is likely due to reverse causation.

We introduce a type $A$ crystal structure on decreasing factorizations of fully-commutative elements in the 0-Hecke monoid which we call $\star$-crystal. This crystal is a $K$-theoretic generalization of the crystal on decreasing factorizations in the symmetric group of the first and last author. We prove that under the residue map the $\star$-crystal intertwines with the crystal on set-valued tableaux recently introduced by Monical, Pechenik and Scrimshaw. We also define a new insertion from decreasing factorization to pairs of semistandard Young tableaux and prove several properties, such as its relation to the Hecke insertion and the uncrowding algorithm. The new insertion also intertwines with the crystal operators., Comment: 37 pages; in revision 1 Sections 3.1, 4.3 and 4.4 were updated; in revision 2 the phrase 321-avoiding is replaced by fully-commutative, typos are fixed, reference added

BackgroundThe therapeutic armamentarium of bladder cancer has been recently enriched with the introduction of new therapies including immune checkpoint inhibitors, receptor tyrosine kinase inhibitors and antibody drug conjugates, however treatment responses and duration of responses are still less than expected. Adoptive cellular therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has potential to treat bladder cancer, as previously demonstrated by successful expansion of tumor reactive T cells from human bladder tumors.MethodsA model system using OT-I T cells and an ovalbumin expressing MB49 tumor cell line (MB49OVA) was developed to study ACT in bladder cancer. Systemic ACT-treated mice were given T cells intravenously after lymphodepleting chemotherapy and followed by interleukin (IL)-2 administration. Intravesical ACT treated mice were given T cells directly into the bladder, without chemotherapy or IL-2. TILs were isolated from MB49 orthotopic tumors and expanded ex vivo in IL-2. Immune cell infiltrates were analyzed by flow cytometry. T cell infiltration was studied using a CXCR3 blocking antibody.ResultsSystemic ACT-treated mice had a decrease in tumor growth, increase in T cell infiltration and long-term immune protection compared with control-treated mice. OT-I T cells delivered intravesically were able to control tumor growth without lymphodepleting chemotherapy or IL-2 in MB49OVA orthotopic tumors. Intravesical delivery of TIL expanded from MB49 tumors was also able to decrease tumor growth in mice with MB49 orthotopic tumors. Blocking CXCR3 on OT-I T cells prior to intravesical delivery decreased T cell infiltration into the tumor and prevented the control of tumor growth.ConclusionsThis study demonstrates how TIL therapy can be used in treating different stages of bladder cancer.

We make a broad conjecture about the $k$-Schur positivity of Catalan functions, symmetric functions which generalize the (parabolic) Hall-Littlewood polynomials. We resolve the conjecture with positive combinatorial formulas in cases which address the $k$-Schur expansion of (1) Hall-Littlewood polynomials, proving the $q=0$ case of the strengthened Macdonald positivity conjecture of Lapointe, Lascoux, and Morse; (2) the product of a Schur function and a $k$-Schur function when the indexing partitions concatenate to a partition, describing a class of Gromov-Witten invariants for the quantum cohomology of complete flag varieties; (3) $k$-split polynomials, proving a substantial case of a problem of Broer and Shimozono-Weyman on parabolic Hall-Littlewood polynomials. In addition, we prove the conjecture that $k$-Schur functions defined in terms of $k$-split polynomials agree with strong tableau $k$-Schur functions., Comment: 33 pages

Bladder cancer remains a leading cause of death and one of the most expensive cancers to treat in the United States. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) is a personalized therapeutic approach that has the potential to treat bladder cancer at every stage of disease. We have previously demonstrated the ability to expand tumor reactive T cells from transurethral resection, radical cystectomy, and metastatic lymph node tumor specimens collected from bladder cancer patients. In this study, our goal is to investigate different delivery approaches of ACT in vivo to determine the best strategy to decrease tumor burden and advise clinical trial design. Experiments were performed using MB49 murine bladder cancer cells transfected to express ovalbumin (MB49OVA). MB49OVA cells are recognized by OVA-specific OT-I T cells as determined by IFN-gamma production in vitro. Our methods include both subcutaneous and orthotopic bladder tumor models. In vivo, we first tested systemic delivery of OT-I T cells (5.0 × 10e6) by tail vein injection after lymphodepletion with a regimen of cyclophosphamide followed by fludarabine in mice bearing subcutaneous MB49OVA tumors. ACT-treated mice experienced significant tumor regression (p=0.02), improved survival (median survival PBS=47 days, ACT=undefined, p=0.01), and increased tumor infiltration of CD3+, CD4+, and CD8+ T cells. OT-I T cells as well as endogenous OVA-specific CD8+ T cells were detectable in the spleens and tumors of treated mice. Next we tested the efficacy of intravesical delivery of OT-I T cells in mice bearing orthotopic MB49OVA tumors, without prior lymphodepletion. OT-I T cells (4.0 × 10e6) were delivered directly to the bladder via catherization and tumor growth was monitored weekly via ultrasound imaging. Infiltration of CellTrace Violet-labeled OT-I T cells into orthotopic tumors was detected after 3 hours of incubation by flow cytometry analysis of resected tumor. Orthotopic bladder tumor growth was significantly abrogated in ACT-treated mice compared with PBS control-treated mice (p=0.001) and improved survival was observed (median survival PBS=35 days, ACT=undefined). An increase in CD8+ T-cell infiltration was measured in tumors of mice at day 60 post treatment. In order to evaluate the efficacy of TIL transfer in these bladder tumor models, T cells infiltrating subcutaneous MB49OVA tumors were isolated and cultured in vitro in media containing IL-2. After 1 week, bladder TIL demonstrated reactivity against MB49OVA and MB49 parental cells as determined by IFN-gamma production. Future work will implement the adoptive transfer of MB49 TIL for the treatment of orthotopic bladder tumors alone or in combination with anti-PD-L1 therapy. Taken together, these data suggest that ACT using bladder tumor-specific T cells has the potential to reduce bladder tumor burden when given either systemically or intravesically directly into the bladder. Citation Format: Brittany L. Bunch, Jennifer Morse, Sarah Asby, Michael Poch, Shari Pilon-Thomas. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) for the treatment of bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A01.

Intralesional (IL) injection of Rose Bengal (PV-10) induces regression of injected and uninjected lesions in several murine tumor models. In this study, we investigated the anti-tumor response of combining IL PV-10 with blockade of the PD-1 / PD-L1 pathway and the role of immune cell populations in eliciting this response. To investigate the role of T cell subsets in mediating an immune response, B16 or M05 melanoma-bearing mice received combination therapy as well as CD8+, CD4+, or CD25+ depleting antibodies. Tumor growth was measured. T cells were collected from spleens or tumors, and phenotype, activation markers, and reactivity were measured. Splenocytes from mice treated with combination therapy had increased OVA antigen-specific CD8+ T cells in M05-tumor-bearing mice. Depletion of CD4+ T cells or regulatory T cells (Tregs) in combination with IL PV-10 and anti-PD-1 antibody treatment resulted in an enhanced anti-tumor effect. Treatment with CD8+ depleting antibody abrogated anti-tumor immunity. These results support a clinical study for the safety and anti-tumor immune responses with combination therapy of IL PV-10 and PD-1/PD-L1 blockade.

Prognostic uncertainty is one barrier to engaging in goals-of-care discussions in chronic kidney disease (CKD). The surprise question ("Would you be surprised if this patient died in the next 12 months?") is a tool to assist in prognostication. However, it has not been studied in non-dialysis-dependent CKD and its reliability is unknown.Observational study.388 patients at least 60 years of age with non-dialysis-dependent CKD stages 4 to 5 who were seen at an outpatient nephrology clinic.Trinary (ie, Yes, Neutral, or No) and binary (Yes or No) surprise question response.Mortality, test-retest reliability, and blinded inter-rater reliability.Baseline comorbid conditions, Charlson Comorbidity Index, cause of CKD, and baseline laboratory values (ie, serum creatinine/estimated glomerular filtration rate, serum albumin, and hemoglobin).Median patient age was 71 years with median follow-up of 1.4 years, during which time 52 (13%) patients died. Using the trinary surprise question, providers responded Yes, Neutral, and No for 202 (52%), 80 (21%), and 106 (27%) patients, respectively. About 5%, 15%, and 27% of Yes, Neutral, and No patients died, respectively (P0.001). Trinary surprise question inter-rater reliability was 0.58 (95% CI, 0.42-0.72), and test-retest reliability was 0.63 (95% CI, 0.54-0.72). The trinary surprise question No response had sensitivity and specificity of 55% and 76%, respectively (95% CIs, 38%-71% and 71%-80%, respectively). The binary surprise question had sensitivity of 66% (95% CI, 49%-80%; P=0.3 vs trinary), but lower specificity of 68% (95% CI, 63%-73%; P=0.02 vs trinary).Single center, small number of deaths.The surprise question associates with mortality in CKD stages 4 to 5 and demonstrates moderate to good reliability. Future studies should examine how best to deploy the surprise question to facilitate advance care planning in advanced non-dialysis-dependent CKD.

The non-negative integer cocharge statistic on words was introduced in the 1970's by Lascoux and Sch\"utzenberger to combinatorially characterize the Hall-Littlewood polynomials. Cocharge has since been used to explain phenomena ranging from the graded decomposition of Garsia-Procesi modules to the cohomology structure of the Grassman variety. Although its application to contemporary variations of these problems had been deemed intractable, we prove that the two-parameter, symmetric Macdonald polynomials are generating functions of a distinguished family of colored words. Cocharge adorns one parameter and the second measures its deviation from cocharge on words without color. We use the same framework to expand the plactic monoid, apply Kashiwara's crystal theory to various Garsia-Haiman modules, and to address problems in K-theoretic Schubert calculus., Comment: 25 pages

4-1BB (CD137) is a co-stimulatory receptor expressed on activated T cells and other immune cells and is associated with enhanced T cell proliferation, survival, and increased cytokine production upon engagement with its ligand (4-1BBL). We have previously shown that addition of agonistic 4-1BB antibody to tumor fragments increased tumor infiltrating lymphocyte (TIL) expansion in human melanoma and pancreatic tumors. Furthermore, agonistic 4-1BB antibody led to increased expression of maturation markers in resident dendritic cells (DCs) present within tumor fragments. While the role of 4-1BB in T cell biology is well described, little is known about 4-1BB signaling in tumor-resident DCs. We hypothesized that 4-1BB agonism in tumor-resident DCs would promote anti-tumor T cell immune responses. To evaluate the role of 4-1BB signaling on dendritic cells, murine bone marrow derived-DCs were cultured with agonistic 4-1BB antibody and loaded with OVA protein. Treatment with agonistic 4-1BB in vitro led to increased OVA-FITC uptake by DCs (32.6% compared to 15.9% in DCs treated with control antibody). DCs treated with agonistic 4-1BB antibody demonstrated increased T cell stimulatory capacity upon co-culture with OVA-specific OT-I and OT-II T cells. We next compared systemic and intralesional (IL) treatment with agonistic 4-1BB antibody. For the systemic model, mice were injected subcutaneously (SC) with B16 melanoma or Panc02 pancreatic tumor cells and treated by intraperitoneal injection of control or anti-4-1BB antibodies. Mice treated systemically with agonistic 4-1BB antibody exhibited a minimal reduction in tumor growth. In contrast, IL injection of agonistic 4-1BB antibody led to dramatic decreases in tumor growth. Next, we wanted to determine whether IL treatment with agonistic 4-1BB antibody would improve DC stimulatory capacity. Mice bearing B16 or Panc02 tumors were treated IL with normal control or anti-4-1BB antibody. After 7 days, tumor-resident CD11b+ DCs exhibited enhanced in vivo antigen uptake. In addition, an increased number of CD8+ T cells was measured within tumors treated with agonistic 4-1BB antibody (28.1% compared to 20% in NrIgG-treated Panc02OVA tumors and 19.45% compared to 7.3% in NrIgG treated B16-OVA tumors; p=0.0059). Together, these studies demonstrate that agonistic 4-1BB can enhance the ability of DCs to stimulate T cells and IL administration of agonistic 4-1BB antibody can significantly reduce tumor growth. This suggests that IL treatment of agonistic 4-1BB may yield greater efficacy than systemic therapy in patients with melanoma or pancreatic cancer. Citation Format: Amy Mackay Weber, Patrick Innamarato, Jennifer Morse, Scott Kidd, Sarah Asby, Amod Sarnaik, Shari Pilon-Thomas. Targeting 4-1BB in tumors enhances anti-tumor immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2403.

OBJECTIVES/SPECIFIC AIMS: The Life’s Simple 7 (LS7) metric was created by the American Heart Association with the goal of educating the public on seven modifiable factors that contribute to heart health. While it is well documented that these ideal health behaviors lower risk of cardiovascular disease (CVD) in the general population, the association between the LS7 ideal health metrics and end stage renal disease (ESRD) risk has not been examined in a lower socioeconomic population at high risk for both ESRD and CVD. Our objective is to examine the association between the LS7 score and incident ESRD in a cohort of white and black men and women in the southeastern US, where rates of CVD and ESRD are high. METHODS/STUDY POPULATION: The Southern Community Cohort Study recruited ~86,000 low-income blacks and whites in the southeastern US (2002-2009). Utilizing a nested case-control design, our analysis included 1628 incident cases of ESRD identified via linkage of the cohort with the United States Renal Data System (USRDS) from January 1, 2002 to March 31, 2015. Controls (n = 4884) were individually matched 3:1 with ESRD cases based on age, sex, and race. Demographic, medical, and lifestyle information were obtained via baseline questionnaire. The AHA definitions for ideal health were used for non-smoking (never or quit >12 months), body mass index (BMI75 min/week of vigorous physical activity or >150min/week of moderate/vigorous activity). Modified definitions were used for consuming a healthy diet [Healthy Eating Index (HEI10) score>70] and for blood pressure, fasting plasma glucose, and total cholesterol, based on self-reported no history of diagnosis of hypertension, diabetes, and hypercholesterolemia, respectively. The number of ideal health parameters were summed to generate the LS7 score, which ranged from 0-7 with higher scores indicating more ideal health. Adjusted odds ratios (95% confidence intervals) for incident ESRD associated with LS7 score were calculated using conditional logistic regression models, adjusting for income and education. The SCCS ESRD case-cohort dataset will be available by TS 2019 and analyses will be completed to adjust for baseline estimated glomerular filtration rate (eGFR) as a marker of kidney function and to examine whether eGFR modifies the relationship between LS7 and incident ESRD. RESULTS/ANTICIPATED RESULTS: At baseline, mean age was 54 years, 55% (3600) of participants were women, and 87% (5656) were black. A total of 58% (943) of ESRD cases were non-smokers compared to 54% (2633) of controls. ESRD cases had higher prevalence of BMI>25 kg/m2 (81% vs. 74%), hypertension (84% vs. 59%), hypercholesterolemia (48% vs. 34%), and diabetes (66% vs. 22%) compared to controls. A total of 18% (839) of controls and 12% (194) of ESRD cases met ideal exercise recommendations, and 20% of either cases (302) or controls (916) had a HEI10 score above 70. The median LS7 score for controls and ESRD cases was 3 and 2, respectively, and 17% (983) of participants had a low score (0-1) while 2% (105) met 6 or 7 ideal health metrics. Higher LS7 score was associated with lower odds of ESRD (P-trend3 (above median) had 75% reduced odds of ESRD (OR 0.25; 95% CI 0.22, 0.29) compared to those with a score of 2 or less. DISCUSSION/SIGNIFICANCE OF IMPACT: In the SCCS population, the presence of any 3 or more ideal health behaviors is associated with reduced odds of developing ESRD. The components of the LS7 represent important modifiable risk factors that may be targets for future interventions driven by the patient. The attributable risk due to each factor is needed to dissect which ideal behaviors are the most beneficial.

Establishing a program to monitor waste anesthetic gas (WAG) in order to limit personnel exposure requires measuring the levels of WAG emitted and determining the effectiveness of scavenging methods to reduce such levels. In this study, the authors used infrared spectroscopy to measure levels of WAG emitted while anesthetizing mice with isoflurane for 15 min. They evaluated four different WAG scavenging conditions during induction and maintenance anesthesia: two conditions that used passive techniques and two that used active techniques. Isoflurane concentrations were measured at three different locations: in the operator's vicinity, at the mouse-facemask interface and in the room environment. Passive scavenging of WAG improved when chambers were purged with oxygen after induction and when a diaphragm-sealed facemask delivered a reduced anesthetic flow rate during maintenance anesthesia. Active scavenging of WAG improved when a relief intake opening was provided in the induction chamber's vacuum line, vacuum draw after induction was regulated and the anesthetic flow rate and vacuum scavenging draw were balanced during maintenance anesthesia using a facemask that separated the breathing space from the scavenging zone. Additionally, time-weighted average isoflurane WAG levels detected by personal dosimeters correlated with real-time measurements made using infrared spectroscopy. These observations contribute to the development of a substantiated program for monitoring WAG air quality.

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and have been linked to acute kidney injury (AKI), chronic kidney disease (CKD) and cardiovascular disease (CVD). Patients who survive an AKI episode are at risk for future adverse kidney and cardiovascular outcomes. The objective of our study was to examine the prevalence and predictors of NSAID use among AKI survivors. Methods The Southern Community Cohort Study is a prospective study of low-income adults aged 40–79 in the southeastern US. Through linkage with Centers for Medicare and Medicaid Services, 826 participants with an AKI diagnosis (ICD-9 584.5-584.9) at any age prior to cohort enrollment were identified. At baseline, data were collected on regular use of prescription and over-the-counter NSAIDs, as well as demographic, medical and other characteristics. Additional comorbidities were ascertained via linkage with CMS or the US Renal Data System. Results One hundred fifty-four AKI survivors (19%) reported regular NSAID use at cohort enrollment (52 prescription, 81 OTC, 21 both) and the percentage of NSAID users did not vary by time since AKI event. Over 58% of users were taking NSAIDS regularly both before and after their AKI event. Hypertension (83%), arthritis (71%), heart failure (44%), CKD (36%) and diabetes (35%) were prevalent among NSAID users. In a multivariable model, history of arthritis (OR: 3.00; 95% CI: 1.92, 4.68) and acetaminophen use (OR: 2.43; 95% CI: 1.50, 3.93) were significantly associated with NSAID use, while prevalent CKD (OR: 0.63; 95% CI: 0.41, 0.98) and diabetes (OR: 0.44; 95% CI: 0.29, 0.69) were significantly inversely associated. Conclusions NSAID use among AKI survivors is common and highlights the need to understand physician and patient decision-making around NSAIDs and to develop effective strategies to reduce NSAID use in this vulnerable population. Electronic supplementary material The online version of this article (doi:10.1186/s12882-016-0411-7) contains supplementary material, which is available to authorized users.

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Background Delirium affects 20–30% of patients after cardiac surgery and is associated with increased mortality and persistent cognitive decline. Hyperoxic reperfusion of ischemic tissues increases oxidative injury, but oxygen administration remains high during cardiac surgery. We tested the hypothesis that intraoperative hyperoxic cerebral reperfusion is associated with increased postoperative delirium and that oxidative injury mediates this association. Methods We prospectively measured cerebral oxygenation with bilateral oximetry monitors in 310 cardiac surgery patients, quantified intraoperative hyperoxic cerebral reperfusion by measuring the magnitude of cerebral oxygenation above baseline after any ischemic event, and assessed patients for delirium twice daily in the ICU following surgery using the confusion assessment method for ICU (CAM-ICU). We examined the association between hyperoxic cerebral reperfusion and postoperative delirium, adjusted for the extent of cerebral hypoxia, the extent of cerebral hyperoxia prior to any ischemia, and additional potential confounders and risk factors for delirium. To assess oxidative injury mediation, we examined the association between hyperoxic cerebral reperfusion and delirium after further adjusting for plasma levels of F 2 -isoprostanes and isofurans at baseline and ICU admission, the association between hyperoxic cerebral reperfusion and these markers of oxidative injury, and the association between these markers and delirium. Results Ninety of the 310 patients developed delirium following surgery. Every 10%·hour of intraoperative hyperoxic cerebral reperfusion was independently associated with a 65% increase in the odds of delirium (OR, 1.65 [95% CI, 1.12–2.44]; P=0.01). Hyperoxia prior to ischemia was also independently associated with delirium (1.10 [1.01–1.19]; P=0.02), but hypoxia was not (1.12 [0.97–1.29]; P=0.11). Increased hyperoxic cerebral reperfusion was associated with increased concentrations of F 2 -isoprostanes and isofurans at ICU admission, increased concentrations of these markers were associated with increased delirium, and the association between hyperoxic cerebral reperfusion and delirium was weaker after adjusting for these markers of oxidative injury. Conclusions Intraoperative hyperoxic cerebral reperfusion was associated with increased postoperative delirium, and increased oxidative injury following hyperoxic cerebral reperfusion may partially mediate this association. Further research is needed to assess the potential deleterious role of cerebral hyper-oxygenation during surgery.