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We assessed the incidence, predictors and clinical correlates of de-novo aortic regurgitation (AR), which physiologically reduces left ventricular assist device (LVAD) effectiveness due to recirculation syndrome, in the MOMENTUM 3 trial portfolio of the fully magnetically levitated HeartMate 3 (HM3) pump using the randomized pivotal trial (PT) and post-trial continued access protocol (CAP).De-novo aortic regurgitation incidence at 2 years was analysed in the randomized PT and validated in the first 1000 implanted patients of the CAP. Patients with concomitant/prior aortic valve surgery or without baseline or post-implant echocardiograms were excluded from this analysis. AR severity was assessed qualitatively by site-adjudicated echocardiograms (significant AR was defined as moderate or severe grade on echocardiogram). Of 1028 patients enrolled in the PT, 918 were eligible for inclusion in this analysis (HM3, n = 465; HMII, n = 453). At 2 years of LVAD support, freedom from significant AR was greater in the HM3 (92%) than HMII (82%) (hazard ratio 0.45, 95% confidence interval 0.27-0.75, p 0.01). Of 907 HM3 patients analysed from the first 1000 implanted CAP patients, the rate of freedom from significant AR was 90%, consistent with the PT (p = 0.3). In the combined HM3 group (n = 1372), multivariable Cox modelling identified increasing age and female sex as significant predictors. Survival free of urgent transplant or AR corrective procedure was similar between HM3 patients with and without significant de-novo AR.The development of moderate or severe grade de-novo AR is reduced with the fully magnetically levitated HM3 LVAD compared to the axial-flow HMII pump. The occurrence of significant de-novo AR with the HM3 pump is not associated with a worse outcome at 2 years of follow-up.

PDF file - 76K, Additional Patient Characteristics.

Supplementary Data from Increased Levels of Urinary PGE-M, a Biomarker of Inflammation, Occur in Association with Obesity, Aging, and Lung Metastases in Patients with Breast Cancer

Complex karyotype, defined as ≥3 cytogenetic abnormalities, is prognostic of survival in patients treated with ibrutinib or venetoclax in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). Recent studies re-evaluating this dichotomous variable have shown that higher numbers of cytogenetic abnormalities (ie, ≥5) have a worse overall survival in patients treated with chemoimmunotherapy. We sought to determine if increasing karyotypic complexity, treated as a continuous variable, was prognostic of survival for patients treated with ibrutinib for CLL. We conducted a retrospective analysis of all patients with CLL treated with single-agent ibrutinib or in combination with an anti–CD20 antibody at our institution. We included 456 patients with both treatment-naive and RR disease. Median number of prior therapies was 2 (range, 0-13), 30% of patients had presence of del(17p), and 75% expressed unmutated IGHV. Fifty percent had ≥3 cytogenetic abnormalities, including 30% with ≥5. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter progression-free survival (hazard ratio, 1.07; 95% confidence interval, 1.04-1.10; P < .0001) and overall survival (hazard ratio, 1.09; 95% confidence interval, 1.05-1.12; P < .0001). Furthermore, we found that presence of clonal evolution determined by cytogenetic analysis at progression was prognostic of subsequent survival (P = .02). This solidifies karyotypic complexity as an important prognostic factor for patients with CLL treated with ibrutinib. Further research should consider sequential karyotypic analysis as a determination of risk of progression and death in patients with CLL.

Chronic lymphocytic leukemia (CLL) transformation to aggressive lymphoma, known as Richter's Transformation (RT), has a dismal prognosis. There are limited data evaluating risk of RT in patients treated with ibrutinib. We performed a retrospective analysis to determine prognostic variables associated with development of RT and overall survival (OS) at progression after treatment with ibrutinib. We identified 559 patients with CLL treated with ibrutinib from 2010-2019. After a median follow-up of 44.5 months from ibrutinib start, 179 patients progressed and were included in our analysis. After a median follow-up of 20.8 months from progression, 54 out of 179 patients developed RT. Progression on treatment (hazard ratio [HR] 4.01 [1.60-10.00], p = .003), higher LDH (HR 1.80 for 2-fold increase [1.33-2.43], p = .0001), and lymphadenopathy without lymphocytosis (HR 2.88 [1.15-7.20], p = .02) were independent prognostic variables for the development of RT at progression. Progression with lymphadenopathy without lymphocytosis continued to be an independent prognostic variable of worse OS post-progression. In a subset analysis of 50 patients who obtained a PET-CT at progression, the median SUV

In recent years, leaders in a number of nations have undermined their public sector's capacity to deliver on its core goals. To understand this interference, it is necessary to examine the formal and informal organizational dynamics at play within bureaucracies. Considering a widely-applicable generalized organization, a formal model outlines how a leader may augment the career incentives of supervisors and lower-level workers, which shifts the alignment of policy with an organization's central mission. While hierarchy may amplify disruption, organizational culture can coalesce as a norm facilitating resistance to extreme shifts, thereby stabilizing long-term mission-compliance. Yet, should disruption lead to an exodus of mission-driven employees, durable reversals of an organization's capacity to fulfill its aims may ensue. The model highlights three trajectories disrupted organizations follow: temporary reversal, erosion, and resistance. Implications are considered for public sector institutions and international organizations as well as for the study of bureaucratic and state capacities.

In this poster, we present Morpho, an open-source programmable environment for finite element modeling of shape, including shape optimization and shape shifting. We showcase example applications for a number of diverse systems like liquid crystal tactoids, swelling hydrogels and wetting on curved surfaces. We highlight our advances in the optimization algorithms under the hood as well as in the incorporation of GPU acceleration. Lastly, we summarize our code-base improvements, outreach efforts including the first Morpho workshop, and the adoption of Morpho by independent scientific researchers., Funding: National Science Foundation grant OAC-2003820

Introduction: The immunomodulatory effects of dexamethasone and prednisone have been a staple of chemotherapy regimens since Mustargen, Oncovin, procarbazine, prednisone (MOPP) was used to treat lymphomas in 1963. Since then steroids have become ubiquitous in chemotherapy and were transitioned to an anti-nausea medication in solid tumor therapies and now anti-inflammatory therapies for common side effects of immune checkpoint inhibitors. While some modern immunomodulator therapies like rituximab and mycophenolate mofetil work through specific mechanisms, steroids have a much more non-specific effect working through a wide variety of pathways. Traditionally, chemotherapies such as paclitaxel, doxorubicin, and cyclophosphamide have been thought to induce cell death purely through cell-autonomous mechanisms such as DNA damage or interference with accurate chromosome segregation during mitosis. More recently, the strong correlation between tumor-infiltrating lymphocytes (TILs) and pathological complete response (pCR) to chemotherapy has been demonstrated. We hypothesized that dexamethasone use may adversely affect the efficacy of chemotherapy due to down-regulation of TILs. Therefore, we investigated the effects of dexamethasone exposure levels on response rates to neoadjuvant therapy of triple negative breast cancer (TNBC) with doxorubicin, cyclophosphamide and paclitaxel. We evaluated TNBC due to its high sensitivity to chemotherapeutic agents in the neoadjuvant setting and because pCR following neoadjuvant chemotherapy is an indicator of better long-term outcomes in TNBC patients. Dexamethasone use as an anti-emetic in the neo-adjuvant setting is highly variable, often being substituted for with olanzapine. Methods: All patients with TNBC who received neo-adjuvant chemotherapy with doxorubicin and cyclophosphamide (AC) between January 1st, 2012 and November 31st, 2018 at The James Comprehensive Cancer Center at The Ohio State University were included in this retrospective study, which totaled 174 patients. We omitted patients who received carboplatin with the paclitaxel, or received other experimental therapies during the neoadjuvant period. The primary exposure was dexamethasone dose by chemotherapy cycle, and the primary outcome was pCR. We used logistic regression to perform an intent-to-treat analysis, and defined P Results: We have found that there is no statistical or apparent difference in pCR by average dexamethasone dose per neoadjuvant chemotherapy cycle (P = 0.51), including when adjusting for diabetes status, metformin prescription and age (P=0.85). We found that there was sufficient variation in dexamethasone dose per cycle with the main mass of observations between 10 and 60 mg/cycle. Conclusions: We did not detect a difference in dexamethasone dose per neoadjuvant chemotherapy cycle between patients who did or did not achieve pCR. Thus, based on this retrospective analysis, the use of dexamethasone as an anti-emetic for triple negative breast cancer may not be harmful or beneficial in terms of the pathologic response to chemotherapy. This suggests that its use as an agent to mitigate side effects from chemotherapy is reasonable. Citation Format: Daniel Goldstein, Mahmoud Kassem, Dionisia Quiroga, Abdul Miah, Craig Vargo, Namrata Vilas Shinde, Michael Berger, Nicole Williams, Daniel Stover, Sagar Sardesai, Maryam Lustberg, Bhuvaneswari Ramaswamy, Gary Tozbikian, Patrick Schnell, Mathew Cherian. Immunomodulation with dexamethasone in neoadjuvant chemotherapy for triple negative breast cancer [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 PS13-46.

A quantitative model of the mobility of functionalized particles at the interface is pivotal to understanding important systems in biology and nanotechnology. In this work, we investigate the emerging dynamics of particles anchored through ligand-receptor bridges to functionalized surfaces. We consider systems with reversible bridges in which ligand-receptor pairs bind/unbind with finite reaction rates. For a given set of bridges, the particle can explore a tiny fraction of the surface as the extensivity of the bridges is finite. We show how at time scales longer than the bridges' lifetime, the averaged position of the particle diffuses away from its initial value. We distill our findings into two analytic equations for the sliding diffusion constant of particles carrying mobile and fixed ligands. We quantitatively validate our theoretical predictions using reaction-diffusion simulations. Our results, along with recent literature, will allow inferring the microscopic parameters at play in complex biological systems from experimental trajectories., Comment: Version accepted for publication in The Journal of Chemical Physics. The first two authors contributed equally

Stochastic simulation is a key tool in population genetics, since the models involved are often analytically intractable and simulation is usually the only way of obtaining ground-truth data to evaluate inferences. Because of this, a large number of specialized simulation programs have been developed, each filling a particular niche, but with largely overlapping functionality and a substantial duplication of effort. Here, we introduce msprime version 1.0, which efficiently implements ancestry and mutation simulations based on the succinct tree sequence data structure and the tskit library. We summarize msprime’s many features, and show that its performance is excellent, often many times faster and more memory efficient than specialized alternatives. These high-performance features have been thoroughly tested and validated, and built using a collaborative, open source development model, which reduces duplication of effort and promotes software quality via community engagement.

A novel population of age-associated Granzyme K (GZMK)-expressing CD8 T cells was found in mice and humans. These cells enhance local tissue senescence and inflammation and are distinct from central memory and conventional Granzyme B- or Interferon γ-producing effector memory CD8 T cells. It is unknown whether these cells drive chronic disease; thus, we induced atherosclerosis in young (3-mo) and aged (18-mo) wild-type mice via the PCSK9-AAV model and used scRNAseq to demonstrate that this GZMK-CD8 T cell population homes to atherosclerotic lesions exclusively in aged mice. Neutralizing CD8 T cells demonstrates that GZMK-CD8 cells drive age-enhance atherosclerosis. Finally, we transferred GZMK-CD8 cells from different aged donors into young CD8-/- hosts and demonstrate that GZMK-CD8 cells from aged but not young donors drive atherosclerosis. In conclusion, we identified a novel role for this recently described population of aging-specific GZMK-expressing CD8+ T cells as a critical driver of chronic disease.

The HeartWare HVAD System (Medtronic) is a durable implantable left ventricular assist device that has been implanted in approximately 20,000 patients worldwide for bridge to transplant and destination therapy indications. In December 2020, Medtronic issued an Urgent Medical Device Communication informing clinicians of a critical device malfunction in which the HVAD may experience a delay or failure to restart after elective or accidental discontinuation of pump operation. Moreover, evolving retrospective comparative effectiveness studies of patients supported with the HVAD demonstrated a significantly higher risk of stroke and all-cause mortality when compared with a newer generation of a commercially available durable left ventricular assist device. Considering the totality of this new information on HVAD performance and the availability of an alternate commercially available device, Medtronic halted the sale and distribution of the HVAD System in June 2021. The decision to remove the HVAD from commercial distribution now requires the use of the HeartMate 3 left ventricular assist system (Abbott, Inc) if a patient previously implanted with an HVAD requires a pump exchange. The goal of this document is to review important differences in the design of the HVAD and HeartMate 3 that are relevant to the medical management of patients supported with these devices, and to assess the technical aspects of an HVAD-to-HeartMate 3 exchange. This document provides the best available evidence that supports best practices. (J Thorac Cardiovasc Surg 2022;-:1-8).

Stochastic simulation is a key tool in population genetics, since the models involved are often analytically intractable and simulation is usually the only way of obtaining ground-truth data to evaluate inferences. Because of this necessity, a large number of specialised simulation programs have been developed, each filling a particular niche, but with largely overlapping functionality and a substantial duplication of effort. Here, we introducemsprimeversion 1.0, which efficiently implements ancestry and mutation simulations based on the succinct tree sequence data structure andtskitlibrary. We summarisemsprime’s many features, and show that its performance is excellent, often many times faster and more memory efficient than specialised alternatives. These high-performance features have been thoroughly tested and validated, and built using a collaborative, open source development model, which reduces duplication of effort and promotes software quality via community engagement.

The aim of this study was to evaluate a novel virtual care platform created for use in Left Ventricular Assist Device (LVAD) patients. The platform included a daily log of LVAD parameters and medication adherence, two-way messaging with providers, and educational resources. To test the feasibility of this application, we recruited 25 patients between 2017 and 2019 and followed them for 6 months post discharge. Feedback concerning the platform was very positive with an average score of 4.5 ± 0.6 (out of 5) on usability and/or satisfaction and 8.1 ± 1.8 (out of 10) on likelihood to recommend the platform. In addition, our platform was well utilized with median (IQR) engagement rates of 87 (53,100)% at 30 days and 73 (49,95)% overall. We found that patients using the platform attended significantly less outpatient visits at the 6 month mark, however there was no difference in 30-day readmission rates compared to the overall LVAD cohort.

A theranostic refers to the concept of integrating diagnostic and therapeutic capabilities into a single platform. In this work, a layer of gold was reduced around superparamagnetic iron oxide (SPIO) nanoparticles to be used as a theranostic for magnetic resonance imaging and photoablation. In addition, a gold shell was included in the particle design to improve biocompatibility, stabilise nanoparticles in suspension, and allow robust surface functionalisation. Gold-coated SPIO nanoparticles of 8 nm in diameter exhibited surface plasmon resonance while also maintaining their superparamagnetic nature. Energy dispersive spectroscopy confirmed the existence of gold at the surface of the nanoparticles, the thickness of which was 0.5 nm based on transmission electron microscopy measurements. To demonstrate their potential for targeted therapies, nanoparticles were targeted to VCAM-1 on human umbilical vein endothelial cells and detected via darkfield microscopy.

Older people exhibit dysregulated innate immunity to respiratory viral infections, including influenza and SARS-CoV-2, to increase morbidity and mortality. Nanoparticles are a potential practical therapeutic that could divert exaggerated innate immune responses away from the lungs during viral infection. However, such therapeutics have not been examined for effectiveness during respiratory viral infection, particular in aged hosts. Here, we employed a highly lethal model of influenza viral infection in vulnerable aged mice to examine the ability of biodegradable, cargo-free nanoparticles, designated ONP-302, to resolve innate immune dysfunction and improve outcomes during infection. We administered ONP-302 via intravenous injection to aged mice at day 3 post-infection when the hyperinflammatory innate immune response is already established. We found that ONP-302 treatment diverted tissue-damaging inflammatory monocytes from the lungs to the spleen without impacting viral clearance or reducing chemo-attractive signals in the infected lung. Importantly, cargo-free nanoparticles reduced lung damage and histological lung inflammation and improved gas exchange and, ultimately, the clinical outcomes in influenza-infected aged mice. ONP-302 improves outcomes in influenza-infected, vulnerable, aged mice. Thus, our study provides vital fundamental information concerning a practical therapeutic which, if translated clinically, could improve disease outcomes for vulnerable older patients suffering from respiratory viral infections. Supported by COUR Pharmaceuticals

Consuming different food groups and nutrients can have differential effects on body weight, body composition, and insulin sensitivity.The aim was to identify how food group, nutrient intake, and diet quality change relative to usual-diet controls after 16 weeks on a low-fat vegan diet and what associations those changes have with changes in body weight, body composition, and measures of metabolic health.Secondary analysis of a randomized clinical trial conducted between October 2016 and December 2018 in four replications.Participants included in this analysis were 219 healthy, community-based adults in the Washington, DC, area, with a body mass index (BMI) between 28 and 40, who were randomly assigned to either follow a low-fat vegan diet or make no diet changes.A low-fat, vegan diet deriving approximately 10% of energy from fat, with weekly classes including dietary instruction, group discussion, and education on the health effects of plant-based nutrition. Control group participants continued their usual diets.Changes in food group intake, macronutrient and micronutrient intake, and dietary quality as measured by Alternate Healthy Eating Index-2010 (AHEI-2010), analyzed from 3-day diet records, and associations with changes in body weight, body composition, and insulin sensitivity were assessed.A repeated-measure analysis of variance model that included the factors group, subject, and time was used to test the between-group differences throughout the 16-week study. Interaction between group and time was calculated for each variable. Within each diet group, paired comparison t tests were calculated to identify significant changes from baseline to 16 weeks. Spearman correlations were calculated for the relationship between changes in food group intake, nutrient intake, AHEI-2010 score, and changes in body weight, body composition, and insulin sensitivity. The relative contribution of food groups and nutrients to weight loss was evaluated using linear regression.Fruit, vegetable, legume, meat alternative, and whole grain intake significantly increased in the vegan group. Intake of meat, fish, and poultry; dairy products; eggs; nuts and seeds; and added fats decreased. Decreased weight was most associated with increased intake of legumes (r = -0.38; P0.0001) and decreased intake of total meat, fish, and poultry (r = +0.43; P0.0001). Those consuming a low-fat vegan diet also increased their intake of carbohydrates, fiber, and several micronutrients and decreased fat intake. Reduced fat intake was associated with reduced body weight (r = +0.15; P = 0.02) and, after adjustment for changes in BMI and energy intake, with reduced fat mass (r = +0.14; P = 0.04). The intervention group's AHEI-2010 increased by 6.0 points on average, in contrast to no significant change in the control group (treatment effect, +7.2 [95% CI +3.7 to +10.7]; P0.001). Increase in AHEI-2010 correlated with reduction in body weight (r = 0.14; P = 0.04), fat mass (r = -0.14; P = 0.03), and insulin resistance as measured by the Homeostasis Model Assessment (HOMA-IR; r = -0.17; P = 0.02), after adjustment for changes in energy intake.When compared with participants' usual diets, intake of plant foods increased, and consumption of animal foods, nuts and seeds, and added fats decreased on a low-fat vegan diet. Increased legume intake was the best single food group predictor of weight loss. Diet quality as measured by AHEI-2010 improved on the low-fat vegan diet, which was associated with improvements in weight and metabolic outcomes. These data suggest that increasing low-fat plant foods and minimizing high-fat and animal foods is associated with decreased body weight and fat loss, and that a low-fat vegan diet can improve measures of diet quality and metabolic health.

(Abridged) Using the Zwicky Transient Facility alert stream, we are conducting a large campaign to spectroscopically classify all transients occurring in galaxies in the Census of the Local Universe (CLU) catalog. The aim of the experiment is to construct a spectroscopically complete, volume-limited sample of transients coincident within 100" of CLU galaxies out to 200 Mpc, and to a depth of 20 mag. We describe the survey design and spectroscopic completeness from the first 16 months of operations. We present results from a systematic search for Calcium rich gap transients in the sample of 22 low luminosity (peak absolute magnitude $M > -17$), hydrogen poor events found in the experiment (out of 754 spectroscopically classified SNe). We report the detection of eight Calcium rich gap transients, and constrain their volumetric rate to be at least $\approx 15\pm5$% of the SN Ia rate. Combining this sample with ten events from the literature, we find a likely continuum of spectroscopic properties ranging from events with SN Ia-like features (Ca-Ia objects) to SN Ib/c-like features (Ca-Ib/c objects) at peak light. Within the Ca-Ib/c events, we find two populations of events distinguished by their red ($g - r \approx 1.5$ mag) or green ($g - r \approx 0.5$ mag) spectral colors at $r$-band peak, wherein redder events show strong line blanketing signatures, slower light curves, weaker He lines and lower [Ca II]/[O I] in the nebular phase. Together, we find that the spectroscopic continuum, volumetric rates and striking old environments are consistent with the explosive burning of He shells on low mass white dwarfs. We posit that Ca-Ia and red Ca-Ib/c objects are consistent with the double detonation of He shells with high He burning efficiency, while green Ca-Ib/c objects could arise from less efficient He burning scenarios such as detonations in low density He shells or He shell deflagrations., 30 figures, 6 tables. Submitted to ApJ

Let A be a central simple algebra central over a number field K whose ring of integers is R. An outlier is an element r of R so that: r is a reduced norm of an element of A, but not the norm of an algebraic integer in A. We study properties and distribution of outliers. We end with a structure theorem about products of super singular elliptic curves over GF(p).

Background: Aggressive lymphoma arising in the setting of chronic lymphocytic leukemia (CLL), known as Richter's syndrome (RS), is associated with poor outcomes with standard of care therapies. There is limited capacity for PET-CT to distinguish patients (pts) who develop RS after ibrutinib (Mato Haematologica 2019). Data on outcomes of pts with RS having previously received ibrutinib is limited. Here we sought to determine if clinical characteristics associated with iwCLL criteria for progression (Hallek Blood 2018) predict the risk of RS and overall survival (OS) in pts treated with ibrutinib. Methods: We conducted a retrospective analysis of pts with CLL treated with ibrutinib from 2010-2019 at The Ohio State University. We identified pts that progressed after ibrutinib and classified the progression by 2018 iwCLL criteria. We then identified who developed RS on or after progression. Risk of developing RS was assessed through Fine and Gray model treating death as the competing risk. OS was measured from time of progression and estimated using Cox model. Results: We analyzed 559 pts who had received ibrutinib for CLL, and identified 179 pts who progressed per iwCLL criteria. 94% of the pts who progressed were relapsed/refractory prior to ibrutinib. 116 pts progressed on ibrutinib, and the median time to progression from ibrutinib start was 40.8 months (mos) (range: 0.2-103.9). 63 pts progressed after stopping ibrutinib due to an adverse event or development of a resistance mutation, and the median time to progression from ibrutinib start for these pts was 28.5 mos (range: 0.7-92.9). Of the 179 pts who progressed, 54 developed RS. Of these 54 pts; 83% had enlarging lymphadenopathy, 9% had an enlarging liver or spleen, 17% had constitutional symptoms, 31% had increasing lymphocytosis, 15%, 15%, and 2% had worsening thrombocytopenia, anemia, or neutropenia respectively. No pts had worsening of CLL in the bone marrow (BM) and 2% had new appearance of other organ involvement. As lymphadenopathy and lymphocytosis were the most common clinical features identified we analyzed them jointly; 61% had lymphadenopathy without lymphocytosis, 9% had lymphocytosis without lymphadenopathy, 22% had both, and 7% had neither. Among pts with RS, median time from progression to RS was 0.4 mos (range: 0-49.3). Nine pts had biopsy confirmed RS on the date of progression. Median time from ibrutinib start to RS was 27.8 mos (range: 0.7-92.9). We performed a univariable analysis to determine whether clinical signs of relapse were associated with subsequent risk of RS, and found that presence of lymphadenopathy without lymphocytosis at progression was significantly associated with risk of RS (HR 3.58, 95% CI 1.44-8.88, p=0.006) (Table 1, Figure 1A). To determine if there was an association between clinical features of progression and OS we evaluated all 179 pts that progressed; 72% had enlarging lymphadenopathy, 10% had an enlarging liver or spleen, 15% had constitutional symptoms, 46% had increasing lymphocytosis, 15%, 17%, and 2% had worsening thrombocytopenia, anemia, or neutropenia respectively, only 2% had worsening of CLL in the BM, and 1% had new appearance of other organ involvement. When analyzed jointly; 45% had lymphadenopathy without lymphocytosis, 20% had lymphocytosis without lymphadenopathy, 26% had both, and 9% had neither. Median OS from progression was 24.4 mos (95% CI: 18.6-45.5), while median OS from RS diagnosis was 4.0 mos (95% CI: 2.1-7.1). Median OS from progression was 15.2 mos (95% CI: 7.8-24.6), and 49.9 mos (95% CI: 20.0-NR) for the lymphadenopathy without lymphocytosis and the lymphocytosis without lymphadenopathy groups respectively (Figure 1B). On univariable analysis lymphadenopathy without lymphocytosis was associated with a shorter OS (Table 1). These findings were maintained on multivariable analysis, with lymphadenopathy without lymphocytosis remaining an independent predictor of OS (HR 2.12, CI 1.17-3.87, p=0.01). Conclusions: Here we show that pts who have received prior ibrutinib for CLL who progress with lymphadenopathy have a higher likelihood of having RS than those pts who progress without lymphadenopathy. Furthermore, pts who progressed with lymphadenopathy without lymphocytosis have a shorter OS. Our data suggests that consideration should be given to perform a biopsy to rule out RS in any pts progressing with lymphadenopathy after receiving ibrutinib therapy for CLL. Figure 1 Figure 1. Disclosures Kittai: Abbvie: Consultancy; Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy. Bhat: Beigene: Consultancy; Onclive: Honoraria; AstraZeneca: Consultancy; Aptitude Health: Honoraria. Bond: Kite/Gilead: Honoraria. Byrd: Pharmacyclics LLC: Research Funding; Acerta Pharma: Research Funding; Genentech, Inc.: Research Funding; Janssen Pharmaceuticals, Inc.: Research Funding. Rogers: Genentech: Consultancy, Research Funding; Janssen: Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Research Funding. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding.

Introduction: Our group and others have previously shown that the presence of complex karyotype (>/= 3 cytogenetic abnormalities) is an important prognostic factor in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL) patients treated with ibrutinib (Woyach JCO 2017, Thompson Cancer 2015, Maddocks JAMA Oncology 2015). It has been shown recently that increasing karyotypic complexity is a prognostic marker (Baliakis Blood 2019), but whether this is relevant for patients treated with novel therapies is unclear. Here, we aimed to determine whether the degree of karyotypic complexity beyond the dichotomy of complex versus not is a prognostic variable for patients with CLL treated with ibrutinib. Methods: We conducted a retrospective analysis of all patients with CLL treated with ibrutinib as a single agent or in combination with a monoclonal anti-CD20 antibody (MOAB) from 2010 through 2019 at The Ohio State University. We included patients with both treatment-naïve (TN) and RR disease. To determine karyotype, cells were stimulated with mitogen cocktail (PWM/PMA/CpG-ODN) and analyzed according to standard laboratory procedures. FISH using probes for D13S319, D12Z3, ATM, and TP53 were done according to manufacturer's recommendations. PCR was used to determine IGHV mutational status. Cytogenetic testing was included in the analysis if done Results: We analyzed 561 patients with a median age of 65 (range 26-91). 86% were treated with ibrutinib monotherapy, 22% were TN, and median number of prior therapies was 2 (range 0-13). 96% had an ECOG performance status (PS) of 0 or 1. Median LDH, WBC, HgB and PLT were 213 U/L, 23.2 K/uL, 11.2 g/dL, and 115 K/uL respectively. With available data, del13q14, trisomy 12, del11q22, and del17p13 was present in 50%, 22%, 30%, and 29% of patients respectively; 74% of patients were IGHV unmutated. 63 patients were excluded from cytogenetic analyses as the test was not done during the specified time window. Of the 458 evaluable, 50% had >3 cytogenetic abnormalities including 30% with >5 abnormalities. After a median follow up of 55.5 months, for the entire cohort estimated median PFS was 61.6 months (95% CI 56.1-69.5), and estimated median OS was 95.4 months (95% CI 86.3-not reached). On univariable analysis, older age, RR status, higher ECOG PS and LDH, lower HgB and PLT, presence of del17p13 and increasing karyotypic complexity were found to be statistically significant predictors of worse PFS and OS. To illustrate the relationship between increasing karyotypic complexity and clinical outcome, Kaplan-Meier plots are provided grouping pts with 0-2, 3-4, and 5 or higher aberrations (Figure 1). Accounting for statistically and clinically important factors on multivariate analysis (MVA, Table 1), increasing karyotypic complexity continued to be a statistically significant predictor of both PFS (p=0.01, HR 1.08 (95% CI 1.02-1.15)) and OS (p=0.001, HR 1.14 (95% CI 1.05-1.23)). Del17p13 did not retain statistical significance independently of karyotypic complexity on MVA. The interaction effect between prior treatment status and karyotypic complexity term was not significant for OS (p=0.89) and PFS (p=0.46), suggesting the prognostic effect of karyotypic complexity is similar across TN and RR cohorts. Conclusions: In this single center retrospective analysis, we found that increasing karyotypic complexity predicts inferior survival for patients with CLL treated with ibrutinib. This highlights that it is not only important to dichotomize presence of complex karyotype as >3 abnormalities, but to describe the number of karyotypic abnormalities in subsequent studies. Disclosures Bond: Seattle Genetics: Honoraria. Byrd:Acerta Pharma: Research Funding; Trillium: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Janssen: Consultancy; Leukemia and Lymphoma Society: Other; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Vincera: Research Funding; Syndax: Research Funding. Rogers:AstraZeneca: Other: Travel; Abbvie, Acerta, AstraZeneca, Pharmacyclics: Consultancy; Abbvie, Genetech, Janssen: Research Funding. Woyach:Pharmacyclics: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding; Loxo: Research Funding; Verastem: Research Funding.

e12596 Background: Triple negative breast cancers (TNBC), characterized by the lack of expression of estrogen receptors and progesterone receptors as well as human epidermal growth factor receptor 2, are associated with high distant recurrence rate and death. As a result, the majority of patients with TNBC are treated with perioperative chemotherapy with the goal of eradicating micrometastases and preventing distrant relapse. The preoperative systemic therapy offers the advantages of permitting an assessment of chemo-sensitivity, increased rates of breast conserving surgery and the ability to adapt postoperative therapies depending on the response. Recently, neoadjuvant chemotherapy has been used at an increasing frequency. The response to neoadjuvant chemotherapy, as measured by the residual cancer burden index, for example, is correlated with the long-term prognosis of TNBC and HER2 expressing breast cancers. Previous studies suggest that tumor-infiltrating lymphocytes (TILs) may correlate with pathological complete response (pCR) rates in TNBC patients treated with neoadjuvant chemotherapy. The pathologic evaluation of TILs in TNBC has been recommended by the International TILs working group since 2014. In this study we sought to analyze the association of TILs with pCR in a cohort of TNBC patients treated with neoadjuvant chemotherapy. Methods: An IRB-approved single-institution retrospective analysis was performed on 127 patients diagnosed with TNBC who received neoadjuvant anthracycline and taxane based chemotherapy at the Ohio State University Comprehensive Cancer Center between January 1st, 2012 and November 31st, 2018. We analyzed TILs as a continuous variable as a part of a secondary analysis of this data. Whole tissue sections from archived H&E stained glass slides were scanned using Philips UltraFast Scanner at ×40 magnification with a single-focus layer. TIL scoring was performed according to guideline recommendations from the International TILs Working Group (2014). Results: A total of 127 female patients with TNBC were identified. The median age at diagnosis was 52.0 years (range 32.0, 74.0) and patients were predominately white (103, 81%), post-menopausal (68, 53.5%) and presented with invasive ductal cancer (113, 89%), stage II (88, 69%), and high grade (108, 85%). Of those patients, 56 had TILs measurement available. pCR was associated with statistically higher level of TILs in core biopsies taken prior to chemotherapy had (Wilcoxon rank-sum test, p = 0.04). Conclusions: The long-term prognosis of patients with TNBC is predicted by the response to neoadjuvant chemotherapy. Consistent with other studies, our study revealed that TILs are associated with a higher probability of pCR. Our future goals are to identify which TIL subsets correlate best with pCR and to identify the mechanism for the increased chemotherapy responsiveness of lymphocyte-infiltrated tumors.

There is a lack of evidence to guide appropriate donor sizing in recipients with moderate pulmonary hypertension (pHTN) awaiting heart transplantation (HTx). It is common practice to oversize donor hearts for such recipients to prevent post-operative right ventricular failure. Therefore, our objective was to determine if oversizing in pre-transplant moderate pHTN provides a survival advantage.The United Network for Organ Sharing database was analyzed to include HTx recipients from 1994 to 2016. Recipients were considered as having moderate pHTN if the pulmonary vascular resistance (PVR) was 2.5 to 5 Wood units (WU) or transpulmonary gradient (TPG) was 10 to 18 mm Hg. Heart size mismatch was determined using the predicted heart mass equations. A size mismatch of ≥15% in either direction was considered undersized or oversized, respectively. Ninety-day and 1-year survival were analyzed based on size matching via univariate and Cox regression analysis. Propensity matching was performed to specifically evaluate the effect of donor sex among male transplant recipients.Among 29,441 HTx recipients, 10,666 had moderate pHTN by PVR criteria and 12,624 HTx patients had moderate pHTN according to TPG criteria. Among patients with a PVR of 2.5 to 5 WU, oversizing was not associated with lower mortality compared with matched hearts at 90 days (7.6% vs 7.4%; p = 0.75) and 1 year (12.1% vs 11.3%; p = 0.26). Conversely, undersizing the donor was associated with a higher 90-day (10.6% vs 7.6% vs 7.4%; p0.01) and 1-year (15.3% vs 12.1% vs 11.3%; p0.01) mortality than recipients receiving oversized or matched hearts, respectively. On Cox regression analysis, there was no benefit with oversizing at 90 days (hazard ratio [HR] 0.88; p = 0.23) and 1 year (HR 0.99; p = 0.90), whereas undersizing was associated with higher 90-day (HR 1.32; p = 0.02) and 1-year mortality (HR 1.23; p = 0.03) compared to size-matched controls. Among patients with moderate pHTN based on TPG of 10 to 18 mm Hg, neither undersizing nor oversizing was predictive of mortality at 90 days and 1 year according to Cox regression analysis. Propensity matching revealed that female-to-male transplantation had similar 1-year mortality to male-to-male transplantation, and there was no advantage to oversizing female donors for male recipients.In this registry-based analysis, there was no benefit to oversizing donors for cardiac transplant recipients with moderate pHTN. Elimination of this restriction could increase the donor pool and reduce wait times for such recipients.

Background Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been reported to cause euglycemic diabetic ketoacidosis (eDKA), a diagnosis that may be challenging to establish in the emergency department (ED). Case Report This is a case report of missed eDKA in a 47-year-old male taking empagliflozin (a SGLT2 inhibitor) that presented to the ED with generalized weakness. His past medical history included multiple sclerosis (MS) diagnosed 4 years ago and type 2 diabetes mellitus. The patient attributed his weakness to MS. His neurologist was consulted and agreed with the plan to discharge the patient with diagnoses of asthenia and dehydration and a prescription of prednisone. The patient returned to the ED the next day with similar symptoms and was admitted to the hospital for treatment of eDKA. He was eventually treated per the hospital diabetic ketoacidosis (DKA) protocol and discharged home with instructions to discontinue empagliflozin. Why Should an Emergency Physician Be Aware of This? The increasing utilization of SGLT2 inhibitor in patients with type 2 diabetes mellitus will inevitably lead to more cases of eDKA seen in the ED. Emergency physicians need to consider this diagnosis in patients taking these medications that present with symptoms including weakness, nausea, vomiting, abdominal pain, and dehydration. Patients taking these medications should be warned about these symptoms, especially because they may be falsely reassured by relatively low plasma glucose levels on home glucometer readings.

Inspired by experiments on dynamic extensile gels of biofilaments and motors, we propose a model of a network of linear springs with a kinetics consisting of growth at a prescribed rate, death after a lifetime drawn from a distribution, and birth at a randomly chosen node. The model captures features such as the build-up of self-stress, that are not easily incorporated into hydrodynamic theories. We study the model numerically and show that our observations can largely be understood through a stochastic effective-medium model. The resulting dynamically extending force-dipole network displays many features of yielded plastic solids, and offers a way to incorporate strongly non-affine effects into theories of active solids. A rather distinctive form for the stress distribution, and a Herschel-Bulkley dependence of stress on activity, are our major predictions.

Introduction: Continuous flow-left ventricular assist devices (CF-LVAD) have been implicated as a risk factor for vasoplegic syndrome (VS) after orthotopic heart transplantation (OHT). Although a lack of pulsatility has been postulated as the cause, there is currently no data to support this hypothesis. Hypothesis: We hypothesized that low pulsatility as measured by the Pulsatility Index of HeartMate II CF-LVADs at OHT admission was associated with VS during CF-LVAD explant and OHT. Methods: A retrospective chart review of all adult patients that had underwent heart transplants at our center were reviewed from 2014-2017. VS was defined as a profound vasodilatory shock (SVR < 800 dyne/s/cm 5 ) despite persistent vasopressor support with a preserved cardiac index (≥ 2.2 L/min/m 2 ) occurring at any time between 6 and 48 hours post OHT. Pulsatility Index of HeartMate II CF-LVADs were obtained at the day of OHT admission. Results: A total of 103 patients underwent OHT during the 4-year study period. The median age was 57 (48-64) years, 29 (28%) were females, 75 (73%) had CF-LVAD. Overall 23 (22%) patients developed VS. As expected, VS was more prevalent in CF-LVAD explants compared to primary heart transplant (27% vs 11%, p=0.09). Mean Pulsatility Index in CF-LVAD explants with VS (n =20/75) was lower compared to CF-LVAD explants absent VS (n=55/75) (5.9 ± 1.1 vs 6.5 ± 0.9, p=0.03) (Figure 1). Multivariate logistic regression analysis of all pre-operative variables found BMI (OR 1.23, 95% CI 1.03-1.50; p=0.01) and Pulsatility Index (OR 0.43, 95% CI 0.19-0.94; p=0.03) as the only independent risk factors associated with VS among CF-LVAD explants patients post OHT. Conclusions: In conclusion, lower pulsatility index is associated with vasoplegic syndrome in HeartMate II CF-LVAD post OHT. This association warrants further investigation in order to develop strategies to avoid this complication.

Rationale: Aging is a strong risk factor for atrial fibrillation (AF), the most common sustained arrhythmia in the clinical practice. Atrial inflammation correlates with increased AF susceptibility but whether chronic age-related inflammation that occurs with atherosclerosis contributes to AF is unknown. Hypothesis: Hematopoietic factors contribute to AF inducibility in aged atherosclerotic mice. Methods: We used burst electrical stimulation (tachypacing) of the right atrium to test susceptibility to AF in-vivo in young and aged atherosclerotic, low density lipoprotein receptor knockout (C57BL/6 Ldlr -/- ) mice, and young and old wildtype (C57BL/6 WT) mice. We also determined the role of the stroma vs. the hematopoietic system, by creating bone marrow chimeras in which aged or young Ldlr -/- mice were transplanted with age-matched or mismatched bone Ldlr -/- bone marrow. We used whole-cell patch-clamping investigate atrial sodium currents. Confocal microscopy and patch-clamping in current clamp mode was used to simultaneously record action potentials and Ca 2+ transients. Results: Upon atrial tachypacing, aged atherosclerotic mice underwent longer and more frequent AF episodes than young (incidence, 0.47±0.09 vs 0.12±0.02 episodes/attempts; p ) and aged WT mice (0.47±0.09 vs 0.16±0.07 episodes/attempts; p ). Importantly, young-to-old bone marrow chimeric mice exhibited reduced AF incidence (0.23 ± 0.05 episodes/attempts), whereas old-to-young chimeric mice exhibited increased AF incidence (0.45 ± 0.08 episodes/attempts). Atrial myocytes from aged atherosclerotic mice presented a 50% reduction in the cardiac inward sodium current (I Na ). Moreover, compared to young, aged atherosclerotic mice showed prolonged action potential duration (APD90: 34.0±5.0 ms vs 48.1±7.0ms; p Conclusions: Aged atherosclerotic prone mice are susceptible to AF induction. Hematopoietic factors are sufficient to increase AF propensity with aging in the atherosclerotic host possibly by causing electrophysiological remodeling and intracellular Ca 2+ handling abnormalities.

Let [math] be a prime. We characterize those finite groups which have precisely one irreducible character of degree divisible by [math] .

For A = ( a i , j ) A = \left (a_{i,j}\right ) a square integer matrix of prime determinant p p , set \[ w ( A ) = ∑ i , j | a i , j | . w(A)=\sum _{i,j}\left |a_{i,j}\right |. \] We are interested in the smallest possible value w p w_p for w ( A ) , w(A), and we show that \[ lim p → ∞ w p / log 2 ⁡ ( p ) = 5 / 2. \lim _{p\rightarrow \infty } w_p/\log _2(p)=5/2. \] We also show that w p ≤ 2.5 log 2 ⁡ ( p ) w_p \leq 2.5 \log _2(p) if and only if p = 2 , 7 , 13 , 37 p=2,7,13,37 or a Fermat prime. Our results can also be interpreted as being about addition chains or about presentations of finite cyclic groups.

For each integer t > 0 t>0 and each simple Lie algebra g \mathfrak {g} , we determine the least dimension of an irreducible highest weight representation of g \mathfrak {g} whose highest weight has width t t . As a consequence, we classify all irreducible modules whose dimension equals a product of two primes. This consequence, which was in fact the driving force behind our paper, answers a question of N. Katz.

Limited options exist for mechanical circulatory support as a bridge to transplantation in pediatric patients with advanced heart failure. This is particularly true when it comes to intracorporeal technologies. We describe the first reported experience with the use of the HVAD in the US as a successful bridge to transplantation in a 13-yr-old patient.

Introduction: Heart transplantation is the treatment of choice for end stage heart failure, but is limited to approximately 4000 globally every year due to donor shortage. Despite this, only one-third of the potential donor hearts are recovered for transplantation. Although elevated donor troponin levels have generally been considered a contraindication, the data supporting this practice is limited. Hypothesis: Elevated donor troponins in the presence of normal left ventricular ejection fraction (LVEF) do not impact outcomes after transplantation. Methods: All adult heart transplant recipients in the UNOS database between 2007 and 2014, with LVEF≥50%, and reported donor troponin I levels were included. The overall cohort was divided into groups based on clinically meaningful troponin I levels: below 1, 1-10, 10.1-20 and above 20 and compared for recipient survival and coronary allograft vasculopathy (CAV). Results: 11,640 transplants met the study criteria. On comparison of baseline characteristics, higher troponin groups had younger donors and greater donor CPR. Importantly, the ischemic time and proportion of recipients in the ICU and on temporary circulatory support were similar. As shown, there was no difference in survival (figure 1) or CAV (figure 2) up to 5 years of follow up using Kaplan-Meir analysis and cox-hazards ratio. After adjusting for differences in baseline covariates and clinically relevant factors, the findings remained unchanged. Conclusions: In this largest analysis to date, elevated donor troponin levels in the setting of preserved LVEF did not impact recipient survival or CAV up to 5 years of follow up. This finding can help expand the donor pool.