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Abstract BIVV003 is a gene-edited autologous cell therapy in clinical development for the potential treatment of sickle cell disease (SCD). Hematopoietic stem cells (HSC) are genetically modified with mRNA encoding zinc finger nucleases (ZFN) that target and disrupt a specific regulatory GATAA motif in the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF). We characterized ZFN-edited HSC from healthy donors and donors with SCD. Results of preclinical studies show that ZFN-mediated editing is highly efficient, with enriched biallelic editing and high frequency of on-target indels, producing HSC capable of long-term multilineage engraftment in vivo, and express HbF in erythroid progeny. Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD.

Purpose: To evaluate the feasibility and safety of intravitreal injection of autologous CD34+ stem cells from bone marrow (BMSCs) in eyes with vision loss from retinitis pigmentosa (RP). Design: Phase I prospective, open-label, single-center study. Participants: Seven eyes (7 patients) with RP with best-corrected visual acuity (BCVA) of 20/60 to 20/400 or visual field constriction to within 10°. Methods: A comprehensive examination with ETDRS BCVA, macular OCT, perimetry, and fluorescein angiography was performed at baseline, 1 to 3 months, and 6 months after study treatment. Bone marrow aspiration, isolation of CD34+ BMSCs under good manufacturing practice conditions, and intravitreal cell injection were performed on the same day. The CD34+ cells were isolated from bone marrow using a Ficoll gradient and the Miltenyi CliniMACS system. Isolated CD34+ cells were released for clinical use if viability, sterility, and purity met the release criteria accepted by the United States Food and Drug Administration for this clinical study. Main Outcome Measures: Number of CD34+ cells isolated for injection and adverse events associated with study treatment during follow-up. Secondary outcome measures are changes in BCVA and perimetry. Results: All isolated CD34+ cells passed the release criteria. A mean of 3.26 ± 0.66 million viable CD34+ cells (range 1.6 to 7.05 million) were injected intravitreally per eye. No adverse event was noted during the study follow-up except for 1 participant who was noted with transient cells in the anterior chamber with mild elevation in intraocular pressure at 18 hours after study injection which normalized by 24 hours. Best-corrected visual acuity remained within 2 lines of baseline or improved in all participants at 6 months follow-up. Perimetry was stable or improved in all eyes during study follow-up except 1 eye with transient improvement at 1 month and worsening of both eyes at 6 months. Conclusions: Intravitreal injection of autologous CD34+ BMSCs is feasible and appears to be well tolerated in eyes with vision loss from RP. A larger randomized prospective study would be needed to evaluate further the safety and potential efficacy of this cell therapy for vision loss associated with RP. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Network control, optimization, and security analysis are facilitated by accurate microgrid state estimation. By utilizing phasor measurement units (PMUs), a combined robust centralized dynamic algebraic approach is proposed in this paper for estimating algebraic states (voltage phasors) as well as dynamic states (associated with synchronous generators and wind turbines). Assuming that a load is placed on each bus, an innovative PMU placement method is also presented to provide measurements for all dynamic and algebraic state variables. As a robust link between algebraic state estimation and dynamic state estimation, the output results of the least absolute value (LAV) estimator, which is robust against bad data, are fed to dynamic state estimators as pseudo measurements. Next, to address the nonlinearity of synchronous generator and wind turbine models, an unscented Kalman filter (UKF) is applied to estimate dynamic states precisely. The numerical tests on a microgrid test system show that the suggested approach is suitable for both algebraic and dynamic state estimation. Synchronous generators and wind turbines are modeled using nonlinear models of the 9th and third orders, respectively, and static loads are modeled as voltage‐frequency dependent ones.

Abstract Background Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival. Methods Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 μg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration. Results Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%. Conclusions AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted. Trial registration NCT, NCT03400917 , Registered 10 January 2018,

Abstract Background Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care. Methods Adults with R/R B-ALL received a single infusion of KTE-X19 (1 × 106 CAR T cells/kg). Long-term post hoc subgroup assessments of ZUMA-3 were conducted. Outcomes from matched patients between historical clinical trials and ZUMA-3 patients were assessed in the retrospective historical control study SCHOLAR-3. Results After 26.8-months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients (N = 55) in phase 2 was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients (N = 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 (N = 49) and matched historical controls (N = 40) was 25.4 and 5.5 months, respectively. Conclusions These data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult R/R B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population. Trial Registration: NCT02614066.

Background Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported.Methods Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×10⁶ CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided.Results Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7–58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups.Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22).Conclusions In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.

Abstract This paper proposes a two‐layer method for restoring service. Firstly, a new strategy is used to obtain binary variables relating to closed switches and tie switches. In addition, after the fault occurs it is also possible to obtain optimal islands online. Secondly, a non‐linear model is solved to optimally determine the islands created in the first step, in which distributed generation resources (DGRs), energy storages (ESs) and load shedding (LSH) are reprogrammed. When LSH is performed, the sensitive loads must experience the least amount of outage possible. Therefore, the loads are categorized into residential, industrial, and sensitive categories. In order to demonstrate the validity and effectiveness of the proposed method, a modified IEEE 33‐bus system is simulated. In simulations, the proposed strategy has been compared with one of the important existing methods. Based on these results, the proposed method can reduce the cost function by modifying the critical load less than other methods. In this method, the critical LSH is 220 kW, which is 105 kW less than the compared method. By reducing the amount of load, 46,000 dollars have been saved in system expenses. The results confirm that the proposed strategy is considerably superior to the existing method.

Due to nonlinear behavior of power production of photovoltaic (PV) systems., it is necessary to apply the maximum power point tracking (MPPT) techniques to generate the maximum power. The conventional MPPT methods do not function properly in rapidly changing atmospheric conditions. In this study., a fuzzy logic controller (FLC) optimized by a combination of particle swarm optimization (PSO) and genetic algorithm (GA) is proposed to obtain the maximum power point (MPP). The proposed FLC uses the ratio of power variations to voltage variations and the derivative of power variations to voltage variations as inputs and uses the duty cycle as the output. The range of changes in fuzzy membership functions and fuzzy rules are proposed as an optimization problem optimized by the PSO-GA. The proposed design is validated for MPPT of a PV system using MATLAB/Simulink software. The results indicate a better performance of the proposed FLC compared to the common methods.

Developing the electricity market at the distribution level can facilitate the energy transactions in distribution networks with a high penetration level of distributed energy resources (DERs) and microgrids (MGs). However, the lack of comprehensive information about the marginal production cost of competitors leads to uncertainties in the optimal bidding strategy of participants. The electricity demand within the network and the price in the wholesale electricity market are two other sources of the uncertainties. In this paper, a day-ahead-market-based framework for managing the energy transactions among MGs and other participants in distribution networks is introduced. A game-theory-based method is presented to model the competition and determine the optimal bidding strategy of participants in the market. Robust optimization technique is employed to capture the uncertainties in the marginal cost of competitors. Additionally, the uncertainties in demand are modeled using a scenario-based stochastic approach. The results obtained from case studies reveal the merit of considering competition modeling and uncertainties.

Abstract Diagnostic and molecular genetic testing are key in advancing the treatment of acute myeloid leukemia (AML), yet little is known about testing patterns outside of clinical trials, especially in older patients. We analyzed diagnostic and molecular testing patterns over time in 565 patients aged ≥ 55 years with newly diagnosed AML enrolled in the Connect® MDS/AML Disease Registry (NCT01688011) in the United States. Diagnostic data were recorded at enrolment and compared with published guidelines. The percentage of bone marrow blasts was reported for 82.1% of patients, and cellularity was the most commonly reported bone marrow morphological feature. Flow cytometry, karyotyping, molecular testing, and fluorescence in situ hybridization were performed in 98.8%, 95.4%, 75.9%, and 75.7% of patients, respectively. Molecular testing was done more frequently at academic than community/government sites (84.3% vs 70.2%; P

Abstract In this paper, a particular standard MicroGrid (MG) is accurately simulated in the presence of the Electric Vehicles (EVs) participating in decentralized primary frequency control service. It examines effect of number of the participating EVs on the short-term dynamic behaviour. The simulation results confirm that frequency deviation will not definitely become zero even though an unlimited number of the EVs participate. The output power of each EV is determined according to the frequency deviation. On the other hand, the output power of each EV affects the value of the frequency deviation, especially in small-scale MGs and MGs with predominant inductance behaviour. Eventually, an equilibrium point is reached after a new EV is added that depends on the characteristics of the MG and the functions executed in the MG central controller during such a service. Additionally, effect of Reflex method, an advanced charging technique for EVs, on the frequency deviation is examined.

In this paper, an accurate parameter identification algorithm is proposed for transient voltage profile calculation of the unknown transmission lines. This method is based on the virtual black-box method and uses single-ended data sampling, where the input data include voltage and current samples obtained by measuring at one end of the line in transient mode. A mathematical formulation is proposed to separate the sampled data and form a virtual black-box system with virtual inputs and outputs. The virtual black-box is designed, such that the system coefficients relating the virtual outputs and inputs are the known functions of transmission line parameters in the real world. The coefficient values are then calculated by employing the recursive least squares estimation method, which minimizes the sum of squared errors of observations. Using this method, transmission line parameters and transient voltage profile are calculated from only one terminal data with no need of measuring devices, data synchronization, and communication devices at both sides. The efficiency of the proposed method is tested and proved through the EMTP simulations.

Relapsed/refractory acute myeloid leukemia (AML) is a devastating disease with a poor prognosis and represents a major unmet medical need. We report on a real-world academic center experience of treating 25 patients with relapsed/refractory AML using venetoclax in combination with decitabine or azacitidine, which is not otherwise widely evaluated in the current literature. Our patients come from a large, socioeconomically and geographically diverse area including the majority of Northern California. Most had ELN Adverse Risk (52%) or Intermediate Risk (44%) AML, and most had an ECOG Performance Status of 1 (64%). Over half (52%) had prior hypomethylating agent exposure, and 40% had Secondary AML. We observed an overall response rate of 52%, with eight patients (32%) achieving composite complete remission. Median overall survival was 5.5 months, and for patients achieving composite complete remission this was 21.6 months. One-year estimated overall survival was 38%. Three patients were able to proceed directly to stem cell transplant for consolidation, and all three were alive at last follow-up, ranging 13.8–24.0 months. We found venetoclax in combination with hypomethylating agents to be well tolerated and potentially efficacious in securing long-term remissions for patients with relapsed/refractory AML.

Nowadays short-term voltage instability is a major threat for power system reliability and stability owing to the increasing proportion of renewable energy sources such as solar and wind power, induction motor loads, HVDC links and etc. The aim of this paper is to determine the optimal location and size of static VAR compensator (SVC) to counteract the short-term voltage instability. A multi-objective optimization problem (MOP) is defined to satisfy the two objective functions: 1) minimizing the whole investment cost 2) minimizing the undesirable behavior of transient voltage under multiple probable contingencies. Composite load model consisting of induction motor loads and other components is modeled accurately. Moreover, the system is considered with a high penetration of wind power. Severity and risk indices are proposed to measure the degree of transient voltage performances. Candidate buses for SVC deployment are determined based on trajectory sensitivity analysis. Genetic algorithm is employed to find optimal allocation of SVC. The effectiveness of proposed approach is verified on New England 39-bus system.

A microgrid is a small-scale energy system with its own generation and storage facilities and energy management system, which includes shiftable and traditional loads. The purpose of this research is to determine the size of the microgrid through (i) investigating the effect of a shiftable demand response program (DRP) on sizing of an islanded microgrid and (ii) studying the uncertainty of power output of renewable energy sources by applying the robust optimization (RO) method. Since the RO method solves the problem for lower power outputs of renewable energy sources (RES) than the predicted values, the results obtained are pessimistic and will increase the project cost. To deal with the increment of project cost, the application of a load shifting DRP is proposed to reduce the cost. In addition, DRPs are suitable means to reduce the effects of uncertain power sources. Therefore, it is shown that a shiftable DRP is effective in reducing the overall project cost and the dependency on energy storage systems by defining different scenarios and simulating them with General Algebraic Modeling System (GAMS) software. Moreover, it is indicated that the shiftable DRP and battery state of charge have correlations with solar irradiance and wind speed, respectively.

There are many important trade-offs and constraints on cost, volume, weight, conduction losses, switching losses, microcontrollers, isolation, voltage and current levels, voltage and current ripples, battery specifications, charging–discharging algorithms, control system, switch gate drivers, and efficiency of battery chargers in electric vehicles. In this paper, a well-known power electronic topology commonly used in recent relevant studies is considered, and some important technical considerations with regard to the mentioned trade-offs and constraints are discussed in detail for the first time. The discussion concerns the practical and theoretical experiences in implementation of battery chargers and charging stations of electric vehicles exclusively, and it can be extended to various other power electronic topologies.

In this paper a new e-learning software is introduced. The software can be used (by students) to learn the operation of wind turbines in renewable energy systems. A real Rutland model wind turbine is simulated. Aerodynamic blades, mechanical parts and gearbox, electrical generator and electrical components of the turbine, as well as the controller systems of the turbine are precisely modeled and the results are graphically presented. The structure of the developed software design is not restricted to one type of wind turbine and can be developed for different types and brands of wind turbines. The wind speed can be applied using a prerecorded wind speed data or virtually generated data by statistical wind speed models. The real wind speed data can also be applied to the software, making it an online training environment. The output reports of the developed software in this paper are time plots and graphs as well as computer animations. Also a user friendly interface is provided for the software. The user can make any variations in the parameters of the wind turbine and the wind speed pattern and can examine the results.

OBJECTIVES/SPECIFIC AIMS: To date, only 1 documented case of an individual cured of HIV has been reported. He received an allogeneic bone marrow transplant with cells harboring an HIV-resistant genotype. To mimic this result, we have initiated a Phase I to evaluate the safety of an autologous stem cell gene therapy bone marrow transplant in HIV-related lymphoma patients. METHODS/STUDY POPULATION: The first cohort of patients will receive a 1:1 ratio of unmanipulated CD34 hematopoietic stem cells (HSC) and lentivector modified CD34 HSC expressing a combination of HIV-resistant genes and a selectable marker for cell sorting prior to transplantation. Safety of the HIV-resistant stem cells will be assessed by evaluating engraftment, expression of the anti-HIV genes, and the stability and sequence of the vector. RESULTS/ANTICIPATED RESULTS: One patient has been enrolled and transplanted with the HIV-resistant stem cells. After 1 and 2 months post-transplant, patient blood samples were received, processed for genomic DNA, analyzed by quantitative PCR (qPCR), and displayed successful engraftment of 16 and 12 vector copies per 100 cells, respectively. Expression of all anti-HIV genes was confirmed by qPCR. PCR on genomic DNA confirmed the correct sizes and sequences of the integrated vector and confirmed the successful engraftment of our gene modified cells. Currently, we are enrolling more patients into the trial. DISCUSSION/SIGNIFICANCE OF IMPACT: If successful, this therapy has the potential to change HIV treatment.

We hypothesize that specific bone marrow lineages and cytokine treatment may facilitate bone marrow migration into islets, leading to a conversion into insulin producing cells in vivo. In this study we focused on identifying which bone marrow subpopulations and cytokine treatments play a role in bone marrow supporting islet function in vivo by evaluating whether bone marrow is capable of migrating into islets as well as converting into insulin positive cells. We approached this aim by utilizing several bone marrow lineages and cytokine-treated bone marrow from green fluorescent protein (GFP) positive bone marrow donors. Sorted lineages of Mac-1(+), Mac-1(-), Sca(+), Sca(-), Sca(-)/Mac-1(+) and Sca(+)/Mac-1(-) from GFP positive mice were transplanted to irradiated C57BL6 GFP negative mice. Bone marrow from transgenic human ubiquitin C promoter GFP (uGFP, with strong signal) C57BL6 mice was transplanted into GFP negative C57BL6 recipients. After eight weeks, migration of GFP positive donor' bone marrow to the recipient's pancreatic islets was evaluated as the percentage of positive GFP islets/total islets. The results show that the most effective migration comes from the Sca(+)/Mac(-) lineage and these cells, treated with cytokines for 48 hours, were found to have converted into insulin positive cells in pancreatic islets in vivo. This study suggests that bone marrow lineage positive cells and cytokine treatments are critical factors in determining whether bone marrow is able to migrate and form insulin producing cells in vivo. The mechanisms causing this facilitation as well as bone marrow converting to pancreatic beta cells still need to be investigated.