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Supplementary Tables and Figures from Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor–Resistant, EGFR-Mutated Non–Small Cell Lung Cancer

Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody–drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0–52.4], and median progression-free survival was 8.2 (95% CI, 4.4–8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI–resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers.Significance:In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism.See related commentary by Lim et al., p. 16.This article is highlighted in the In This Issue feature, p. 1

The Small Satellite Dynamics Testbed (SSDT) at the Jet Propulsion Laboratory offers infrastructure that supports small satellite guidance and control testing in a relevant dynamics environment whil...

Female sex workers face a disproportionately high burden of HIV infection globally, yet their knowledge and attitudes towards new HIV prevention methods are understudied in the United States. We conducted focus group discussions and in-depth interviews in a U.S. city among street-based cis- and trans- female sex workers to identify the knowledge, attitudes, and behaviors regarding PrEP and HIV testing in collaboration with a harm-reduction community service organization. We found study participants had limited knowledge of PrEP and poor communication between female sex workers and primary care physicians a barrier to HIV prevention. Participants also expressed strong preferences for HIV testing to be conducted by medical professionals compared to self-testing. Improvement in communication between urban low-income at-risk women and their primary care physicians, and culturally sensitive HIV testing strategies, are critical to the post-COVID-19 strategy on recovery of community services targeting the most vulnerable urban populations.

OBJECTIVE The ANCHOR program offered buprenorphine treatment to people who inject drugs engaged in hepatitis C (HCV) treatment at a Washington, DC harm reduction organization. This analysis describes the program model and outcomes of the opioid care continuum at 1 year. METHODS Primary outcomes were initiation of buprenorphine and retention in care, defined by an active buprenorphine prescription at given time points. Secondary outcomes included treatment interruptions, reasons for treatment noninitiation and termination, buprenorphine and opiate use, and HIV risk behaviors. Buprenorphine and opiate use were measured by urine toxicology screens and HIV risk behavior was quantified using a validated survey. RESULTS Of 67 patients receiving HCV treatment not on opioid agonist therapy at baseline, 96% (n = 64) were interested and 73% (n = 49) initiated buprenorphine. Retention was 82% (n = 40), 65% (n = 32), and 59% (n = 29) at months 1, 6, and 12, respectively. Retention at 12 months was associated with self-reported engagement in routine medical care (P

JPL is developing the Lunar Flashlight (LF) CubeSat mission, a 6U 14 kg spacecraft whose objective is to demonstrate new technology and measure potential surface water ice deposits in the permanently shadowed region (PSR) of the moon in preparation of future possible human lunar exploration. This mission will become the first interplanetary CubeSat to orbit the Moon. It uses a new green propulsion system as well as an instrument with spectrally tuned IR laser technology to search for volatiles in a specific region of the moon. The Guidance, Navigation and Control (GNC) system is crucial for delivering the spacecraft from Earth into Lunar orbit and supporting scientific measurements. Due to the challenging lunar orbit insertion and high tip off rate out of launch vehicle's dispenser, the initial design concept using solar sail propulsion accompanied with small commercial-on-the-shelf (COTS) reaction wheels was abandoned mid-course and replaced by a green propulsion system along with larger reaction wheels, both newly developed for LF. However, using thrusters for the small CubeSat created an additional challenge of controlling the spacecraft attitude. The story of the GNC system development, qualifications, technical challenges encountered, and lessons learned are discussed in this paper.

Background Individuals with hepatitis C (HCV) represent a population that may benefit from pre-exposure prophylaxis (PrEP), given the overlapping risk factors and transmission networks of HCV and HIV. This analysis assesses the prevalence of PrEP indications among individuals with HCV monoinfection and PrEP awareness, interest, and access in this population. Methods GRAVITY was an observational study for the collection of epidemiologic data from individuals with HCV and/or HIV in Washington DC and Baltimore, with the present analysis limited to HCV-monoinfected patients. The prevalence of PrEP indications was determined using epidemiologic survey responses. Bivariate and multivariable analyses assessed for associations between PrEP indications and PrEP awareness, access, and interest. Results Among 314 HCV-monoinfected participants, 109 (35%) had an indication for PrEP. Forty-eight (44%) had a drug use indication alone, 40 (37%) had a sexual indication alone, and 21 (19%) had both drug use and sexual indications. Eighty-five (27%) participants had heard of PrEP, 32 (10%) had been offered PrEP by a provider, 114 (38%) were interested or maybe interested in PrEP, and 6 (2%) were currently taking PrEP. On bivariate analysis, PrEP awareness was significantly associated with study site (P Conclusions Though indications for PrEP were prevalent among individuals with HCV in this cohort, most patients were unaware of PrEP, had never been offered PrEP, and were not using PrEP. These data support the need for improved PrEP implementation among people with HCV.

Background: Standard therapies for patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) that has progressed after treatment with third-generation EGFR tyrosine kinase inhibitors (TKIs) offer only limited benefit. Human epidermal growth factor receptor 3 (HER3) is often expressed in primary NSCLC tumors, and HER3 expression is commonly observed in patients with EGFR mutations. HER3-DXd is a novel antibody-drug conjugate composed of a human anti-HER3 monoclonal antibody (patritumab) linked to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. HER3-DXd demonstrated efficacy and safety in a phase 1 study in patients with EGFRm NSCLC that progressed following an EGFR TKI and platinum-based chemotherapy (PBC) (U31402-A-U102; NCT03260491). In previously reported results from dose-escalation/expansion, HER3-DXd 5.6 mg/kg demonstrated a manageable safety profile and promising efficacy (confirmed objective response rate by blinded independent central review [BICR] of 39%, median duration of response of 7.0 months, and median progression-free survival of 8.2 months) in a subset of patients (n=44) with advanced EGFRm NSCLC that progressed after ≥1 line of PBC and a third-generation EGFR TKI. Trial Design: HERTHENA-Lung02 (NCT05338970) is a global, open-label, randomized, phase 3 trial evaluating the efficacy and safety of HER3-DXd vs PBC in patients (≈560) with metastatic or locally advanced nonsquamous NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) who have received 1 or 2 lines of EGFR TKI treatment including a third-generation EGFR TKI and had disease progression following treatment with a third-generation EGFR TKI. Patients are randomized 1:1 to receive either HER3-DXd 5.6 mg/kg every 3 weeks or 4 cycles of PBC containing pemetrexed (can be continued as maintenance) with cisplatin or carboplatin. Patients are stratified by prior third-generation EGFR TKI treatment (osimertinib vs other), line of prior third-generation EGFR TKI use (first vs second line), region (Asia vs rest of world), and presence of stable brain metastases (yes vs no). The primary endpoint is progression-free survival by BICR (per RECIST v1.1). The key secondary endpoint is overall survival. Other secondary endpoints include investigator-assessed progression-free survival, objective response rate, duration of response, clinical benefit rate, disease control rate, time to response (all assessed by investigator and BICR per RECIST 1.1), safety, and patient-reported outcomes. Enrollment began May 2022 and is ongoing, with sites in Asia, Australia, Europe, and North America. Citation Format: Balazs Halmos, Helena A. Yu, Yi-Long Wu, Makoto Nishio, Martin Reck, David Sternberg, Stephen Esker, Tony Mok. HERTHENA-Lung02: A randomized Phase 3 study of patritumab deruxtecan vs platinum-based chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC after progression with a third-generation EGFR tyrosine kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT066.

Background Daily oral preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) prevents human immunodeficiency (HIV) among people who inject drugs (PWID). Despite rising HIV incidence and injection drug use (IDU), PrEP use remains low and there is limited research about uptake, adherence, and retention among PWID. Methods The ANCHOR investigation evaluated a community-based care model collocating hepatitis C virus (HCV) treatment, medication for opioid use disorder (OUD), and PrEP in individuals in Washington, DC, and Baltimore, Maryland. PrEP counseling was conducted from HCV treatment day 0 until week 24. Subjects could start any time during this window, were followed for 48 weeks, and were assessed for adherence by self-report and dried blood spot TDF analysis. Results One hundred ninety-eight participants were enrolled, of whom 185 (93%) were HIV negative. Twenty-nine individuals (15.7% of HIV-negative cohort) initiated PrEP. One hundred sixteen participants (62.7%) met 2014 Centers for Disease Control and Prevention (CDC) PrEP criteria due to IDU (82 [44.3%]), sex (9 [4.9%]), or both practices (25 [13.5%]). Providers recommended PrEP to 94 individuals (50.8%), and recommendation was associated with PrEP uptake. Median treatment duration was 104 days (interquartile range, 28–276 days), with 8 participants retained through week 48. Adherence was variable over time by self-report and declined by TDF analysis. No HIV seroconversions occurred. Conclusions This cohort of people with HCV and OUD experienced low uptake of PrEP despite the majority meeting CDC criteria. High rates of disruption and discontinuation, compounded by variable adherence, made TDF/FTC a suboptimal prevention strategy. Emerging modalities like long-acting formulations may address these barriers, but PWID have been excluded from their development to date.

Background People who inject drugs have a high prevalence of hepatitis C virus (HCV) and significant disease associated with drug use; however, HCV treatment often occurs in absence of interventions to address opioid use disorder and drug use–related harms. The impact of concurrent initiation of opioid agonist therapy (OAT) on HCV treatment and drug use outcomes is unknown. Methods In this prospective, open-label, observational trial at a harm reduction organization’s drop-in center in Washington, DC, 100 patients with chronic HCV infection, opioid use disorder, and ongoing injection drug use were treated with sofosbuvir-velpatasvir for 12-weeks and offered buprenorphine initiation. The primary end point was sustained virologic response (SVR), and secondary end points included uptake of and retention in OAT, change in risk behavior, and determinants of SVR. Results Eighty-two patients (82%) achieved SVR, which was not associated with baseline OAT status (P = .33), on-treatment drug use (P >.99), or imperfect daily adherence (P = .35) but was significantly associated with completing 2 or more 28-pill bottles of sofosbuvir-velpatasvir (P Conclusions The Novel Model of Hepatitis C Treatment as an Anchor to Prevent HIV, Initiate Opioid Agonist Therapy, and Reduce Risky Behavior study demonstrates high uptake of buprenorphine collocated with HCV treatment, and it shows that concurrent initiation of OAT with HCV treatment can result in high rates of SVR while reducing risks associated with drug use. Clinical Trials Registration NCT03221309.

Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most

ASTERIA (Arcsecond Space Telescope Enabling Research in Astrophysics) was a CubeSat space telescope that operated in low-Earth orbit, having been deployed from the International Space Station in 2017. A key enabling feature of the ASTERIA mission is the low level of pointing error that has been demonstrated under ASTERIA's fine pointing control mode. Prior to launch, the ASTERIA mission performed analysis and simulations to estimate the in-flight pointing performance. This analysis used reaction wheel models provided by JPL's Small Satellite Dynamics Testbed (SSDT), which had performed Kistler table testing to characterize the jitter caused by the reaction wheels of the Blue Canyon Technologies XACT attitude control unit within ASTERIA. These models were subsequently incorporated into the SSDT simulation. The main source of jitter on ASTERIA is the set of rotating reaction wheels that are used for maintaining fine pointing during observations. Therefore, to benefit all SmallSat missions devoted to photometric or spectroscopic astrophysics applications, an on-orbit flight data acquisition and jitter testing campaign was performed in an attempt to validate the SSDT's simulation models. This paper describes the process used to validate several simulation models and attempt to characterize the ASTERIA jitter by analyzing the size of the resulting spot size for the target stars as a function of wheel speed, having commanded four wheel speeds for each of three stars of known brightness. After summarizing the on-orbit observation and jitter level measurement process, this paper compares the results obtained from the flight operational environment to the corresponding set of simulation jitter levels. Though the flight data obtained during this experiment was not sufficient to validate the simulation's jitter model, other models have been validated with flight data, including the magnetic field, orbit propagation, sun position, and long-duration orbit decay models, which may be used by all other projects that use the SSDT's simulation to increase system capability knowledge.

Over the past two years, JPL has used the ASTERIA (Arcsecond Space Telescope Enabling Research In Astrophysics) CubeSat as an in-flight test platform during extended missions. ASTERIA successfully completed its prime mission in early 2018, and continued to operate in low Earth orbit (LEO) for an additional twenty months. This paper describes demonstrations that were performed on the spacecraft and on the ground-based testbed during the extended mission. These demonstrations fall into three categories: Autonomy technology maturation, hardware characterization, and science discovery. Autonomy technology maturation supported three development efforts. The first shifted the spacecraft commanding paradigm from time-based sequences to Task Networks (tasknets), which allow simpler commanding and more robust onboard execution. The second demonstrated onboard orbit determination in Low Earth Orbit (LEO) without GPS. This activity used a fully-independent means of spacecraft orbit determination for Earth orbiters using only passive imaging. The third technology provided in situ hardware health state estimation using a model-based reasoning technique. These three technologies were demonstrated either in flight or on the testbed individually, and then were combined to demonstrate the capability to perform autonomous navigation on board without ground intervention, even in the presence of anomalies. Hardware characterization involved both onboard and ground-based activities. On board, nonstandard attitude control modes were commanded to characterize the spacecraft pointing jitter as a function of target brightness, reaction wheel speed, controller gain, and the number of guide stars. The results provide insights into the contribution of jitter to the ASTERIA photometry and inform the feasibility of future astrophysics small satellite missions for which jitter control is an enabling technology. On the ground, the ASTERIA Operations Team coordinated with Amazon Web Services (AWS) to configure their new ground stations to communicate with ASTERIA to prove out their viability. ASTERIA used AWS ground stations for nominal operations for the last four months of the mission. Finally, ASTERIA continued to perform exoplanet science as the spacecraft was well-suited to execute long-term monitoring of stars such as alpha Centauri to search for small transiting planets. The science team also imaged a number of interesting objects including a comet, an asteroid, cities at night, and the moon, and coordinated with other projects on Targets of Opportunity for follow-up confirmations and co-observations. Throughout the prime and the extended missions, the ASTERIA spacecraft proved to be a mighty platform that “will go into history as an innovative milestone.” [1]

Independent deep-space CubeSat missions require efficient propulsion systems capable of delivering several km/s of ΔV. The ion Electrospray Propulsion System under development at MIT's Space Propulsion Laboratory is a high ΔV propulsion system that is a promising technology for propulsion of independent deep-space CubeSat missions due to its mechanical simplicity and small form factor. However, current electrospray thrusters have demonstrated lifetimes up to an order of magnitude lower than the required firing time for a mission to a near-Earth asteroid starting from geostationary orbit. A stage-based concept is proposed where the propulsion system consists of a series of electrospray thruster arrays. When a set of thrusters reaches its lifetime limit, it is ejected from the spacecraft exposing new thrusters thereby increasing the overall lifetime of the propulsion system. Such a staging strategy is usually not practical for in-space thrusters. However, the compactness of micro-fabricated electrospray thrusters means that their contribution to the overall spacecraft mass and volume is small relative to other subsystems. Mechanisms required for this stage-based approach are proposed and demonstrated in a vacuum environment. In addition, missions to several near-Earth asteroids with orbital elements similar to those of Earth are analyzed with a particular focus on the escape trajectory. With a stage-based approach, independent deep-space CubeSat missions become feasible from a propulsion standpoint., NASA (Grants 80NSSC18M0045 and 80NSSC18K1186)

As small satellites and CubeSats demonstrate their value as science-capable platforms, the community is pushing to improve reliability while expanding performance capabilities. The attitude control...

A software model has been developed to simulate the on-orbit dynamics of a dual-mass tethered system where one or both of the tethered spacecraft are able to produce propulsive thrust. The software simulates translations and rotations of both spacecraft, with the visco-elastic tether being simulated as a lumped-mass model. Thanks to this last feature, tether longitudinal and lateral modes of vibration and tether tension can be accurately assessed. Also, the way the spacecraft motion responds to sudden tether tension spikes can be studied in detail. The code enables the simulation of different scenarios, including space tug missions for deorbit maneuvers in a debris mitigation context and general-purpose tethered formation flight missions. This study aims to validate the software through a representative test campaign performed with the MIT Synchronized Position Hold Engage and Reorient Experimental Satellites (SPHERES) planar air bearing system. Results obtained with the numerical simulator are compared with data from direct measurements in different testing setups. The studied cases take into account different initial conditions of the spacecraft velocities and relative attitudes, and thrust forces. Data analysis is presented comparing the results of the simulations with direct measurements of acceleration and Azimuth rate of the two bodies in the planar air bearing test facility using a Nylon tether. Plans for conducting a microgravity test campaign using the SPHERES satellites aboard the International Space Station are also being scheduled in the near future in order to further validate the simulation using data from the relevant operational environment of extended microgravity with full six degree of freedom (per body) motion.

Upland freshwater habitats support populations that are especially susceptible to anthropogenic change. Furthermore, their isolation from other suitable habitats, and the fragmented, dendritic structure of headwaters make dispersal an unlikely response to change. We investigated genetic structure and variation in the northern-most population of Gadopsis marmoratus, which is isolated in a tiny area in the headwaters of the Condamine River catchment, in the Murray–Darling Basin, Australia. Strong genetic structure was detected among subpopulations based on microsatellites (FST = 0.173, p < 0.0001) and mitochondrial (mt)DNA (FST = 0.369, p < 0.05). Effective population size was low, ranging between 18.8 and 48.2, depending on the estimation method used. Bayesian clustering revealed 3 genetic clusters, but they were not congruent with drainage patterns, suggesting a complex history of dispersal among headwaters that are isolated by waterfalls. Overall, these results suggest that G. marmoratus is unlik...

CubeSats are small spacecraft based on a 10cm by 10cm by 10cm (1U) cube standard that have historically only been operated in Earth orbit. Mars Cube One (MarCO) is the first CubeSat mission developed for interplanetary operation. MarCO is a technology demonstration mission comprised of two identical, solar powered 6U satellites with several key goals, including that of providing a bent pipe telecom relay to Earth for NASA's InSight (Interior Exploration using Seismic Investigations, Geodesy and Heat Transport) mission during its Entry, Descent, and Landing sequence. MarCO launched on the same rocket as InSight and makes use of the Deep Space Network for communications and ranging. It therefore has an attitude control system and propulsion system suitable for operating in several pointing modes, providing desaturations for reaction wheel momentum buildup, and thrusting to change the spacecraft trajectory. Because the spacecraft design is constrained to the CubeSat standards and because of the distances of the spacecraft from Earth and the Sun, the components used for attitude control and propulsion must meet tight size, mass, and power requirements. Autonomous modes of operation are also critical to ensure that the spacecraft can function safely with periods of several hours occurring between consecutive communication periods. A robust testing sequence was required to ensure that the spacecraft functions were exercised and that the operations team understood how the spacecraft were expected to behave after launch. This paper discusses several elements of the MarCO attitude control and propulsion systems. The paper begins with a discussion of the hardware that was selected for the two systems as well as descriptions of the interface between the attitude control and propulsion systems and the interface between these systems and the rest of the spacecraft's command and data handling system. Next, the paper summarizes the different types of tests that were performed at the system and spacecraft levels. Test data is included for some of these tests which helped define the methods by which the spacecraft is operated in space. Lastly, the paper lists a series of lessons-learned for developing attitude control and propulsion systems for interplanetary CubeSats.

ASTERIA (Arcsecond Space Telescope Enabling Research In Astrophysics) is a CubeSat space telescope currently operating in low-Earth orbit. It is expected to remain in orbit at least through October 2019. Developed as a technology demonstration mission under the Jet Propulsion Laboratory Phaeton Program for training early-career engineers, ASTERIA has achieved sub-arcsecond pointing stability and milliKelvin thermal stability over 20-minute observations. These capabilities-unprecedented in a CubeSat platform-have enabled photometric precision better than 1000 parts per million per minute (0.1%/min) while observing nearby bright stars (apparent visual magnitude magv < 6). Following the second extended mission, we are now using the spacecraft in its third extension as a platform to demonstrate additional capabilities as well as continue science observations. This project will perform the following four well-focused activities that will raise the technology readiness of key spacecraft technologies. 1. Shift the paradigm to operate spacecraft from open-loop commanding to closed-loop command execution: We will introduce “task networks” (tasknets)which allow simpler commanding and more robust onboard execution. 2. Demonstrate onboard orbit determination in Low Earth Orbit (LEO) using autonomous navigation (Autonav)without the Global Positioning System (GPS): This activity will demonstrate a fully independent means of spacecraft orbit determination for Earth orbiters using only passive imaging. 3. Collect data on ASTERIA that will feed into future missions by characterizing the spacecraft pointing jitter as a function of target brightness, reaction wheel speed, controller gain, and number of guide stars. 4. Perform ASTERIA extended mission science: ASTERIA has demonstrated unprecedented photometric precision for a CubeSat mission. The spacecraft is uniquely suited to perform long-term monitoring of stars such as alpha Centauri for small transiting planets. The discovery of a transiting Earth-sized planet around alpha Cen A and/or B would be of the highest scientific value as such a planet would be our closest exoplanetary neighbor orbiting a Sunlike star. These demonstrations will provide in-flight testing of new autonomy technologies, maximize the scientific potential of this operational spacecraft, and provide additional characterization of hardware for future small satellite missions using similar subsystems.

In many intermittent, dryland rivers, fish are confined to isolated waterholes for much of the year. It is only during brief flow events, which typify the hydrology of these systems, that fish are able to move between waterholes and explore surrounding habitat. Because most of the river channel will dry afterwards, there is a strong advantage for selection of persistent waterholes. Two hundred and fifteen individual fish of three common large-bodied species were tagged in two isolated waterholes in the Moonie River (Queensland, Australia) over 3years. Their movements were monitored to identify the flow events that trigger fish movement between waterholes, differences in response among species and size classes and refuge selection preferences. Some individuals of all species moved during flow events and others remained within the same waterhole. There was no clear upstream or downstream preference, and most individuals used a reach of up to 20km, although some individuals ranged over more than 70km in only several days. Above a threshold flow of 2m above commence-to-flow level, timing of flow was more important than magnitude, with most movement occurring in response to the first post-winter flow event, independent of its magnitude and duration. Many of the fish that moved displayed philopatry and subsequently returned to their starting waterhole either by the end of a flow event or on subsequent events, suggesting ability to navigate and a preference for more permanent refuge pools. Maximising survival in a highly variable environment provides a plausible mechanism for maintaining these behaviours. Modifications to both flow regime and hydrological connectivity may reduce movement opportunities for fish in intermittent rivers. Our findings show that fish in intermittent systems use networks of waterholes and that management and conservation strategies should aim to maintain movement opportunities at large spatial scales to preserve population resilience.

Water resource developments alter riverine environments by disrupting longitudinal connectivity, transforming lotic habitats, and modifying in-stream hydraulic conditions. Effective management of anthropogenic disturbances therefore requires an understanding of the range of potential ecosystem effects and the inherent traits symptomatic of elevated vulnerability to disturbance. Using 42 riverine fish native to South Eastern Australia as a case study, we quantified six morphological, behavioral, and life-history traits to classify species into groups reflecting potential differences in their response to ecosystem changes as a result of water resource development. Classification analysis identified five strategies based on fish life-history dispersal requirements, climbing potential, and habitat preference. These strategies in turn highlight the potential species at risk from the separate impacts of water resource development and inform management decisions to mitigate those risks. Swimming ability did not contribute to distinguishing species into functional groups, likely due to methodological inconsistencies in quantifying swimming performance that may ultimately hinder the ability of fish passage facilities to function within the physical capabilities of species at risk of habitat fragmentation. This study improves our ability to predict the performance of groups of species at risk from the multiple environmental changes imposed by humans and goes beyond broad-scale dispersal requirements as a predictor of individual species response.

Docking with potentially tumbling Targets is a common element of many mission architectures, including on-orbit servicing and active debris removal. This paper studies synchronized docking trajectories as a way to ensure the Chaser satellite remains on the docking axis of the tumbling Target, thereby reducing collision risks and enabling persistent onboard sensing of the docking location. Chaser satellites have limited computational power available to them and the time allowed for the determination of a fuel optimal trajectory may be limited. Consequently, parameterized trajectories that approximate the fuel optimal trajectory while following synchronous approaches may be used to provide a computationally efficient means of determining near optimal trajectories to a tumbling Target. This paper presents a method of balancing the computation cost with the added fuel expenditure required for parameterization, including the selection of a parameterization scheme, the number of parameters in the parameterization, and a means of incorporating the dynamics of a tumbling satellite into the parameterization process. Comparisons of the parameterized trajectories are made with the fuel optimal trajectory, which is computed through the numerical propagation of Euler’s equations. Additionally, various tumble types are considered to demonstrate the efficacy of the presented computation scheme. With this parameterized trajectory determination method, Chaser satellites may perform terminal approach and docking maneuvers with both fuel and computational efficiency.

Space missions are becoming increasingly complex, and engineers are designing multi-satellite architectures with on-orbit operations as means of accomplishing several mission objectives. Multiple concepts have emerged for autonomous robotic servicing and assembly of orbiting assets or the active removal of space debris, all of which rely on close proximity operation of independently controlled elements. In order for engineers to assess whether a chaser satellite can perform a rendezvous and docking to a given target, various factors must be assessed, including the fuel required, maximum thrust required, contact forces and torques, and the time necessary from rendezvous to secure docking. These factors may be defined for any pair of chaser and target satellites. This paper proposes a definition of a feasibility space, consisting of the set of values for the chaser and target over which a given chaser satellite can perform a soft dock to the target. This feasibility space is defined with respect to the target satellite's physical parameters and dynamic state. In order to map the feasibility space, a trajectory type must be specified. This study utilizes an Archimedes Spiral rendezvous approach path. While not a fuel or time optimal trajectory, it has been selected for this analysis because its path may be expressed analytically while the chaser faces the target's docking area throughout the maneuver, thereby keeping the docking location in the field of view of the chaser's rendezvous sensors for as much time as possible. The paper presents the analytical computation of the chaser satellite's requirements based on the expression of an Archimedes Spiral, as well as a method for mapping the feasibility space using non-dimensional parameters to aid in the extensibility for one trajectory type to multiple chasers and targets. Additionally, the paper presents a method of using the resultant feasibility space maps to assist mission planners and chaser satellite designers in determining the likelihood of soft docking success for a given point in the feasibility space. The processes discussed in the paper can be applied to other trajectory types and for any type of chaser or target satellite for future missions.

Aim This study aims (1) to quantify the broad-scale patterns of functional diversity and life-history strategies of freshwater fish in relation to environmental variation across Australian river basins and (2) to identify key life-history traits associated with species extinction risk in order to determine how fish communities and extinction-prone species may respond to future environmental change. Location One hundred and twenty-three river basins across eastern Australia. Methods Based on 10 key life-history traits for 194 freshwater fish we used a novel analytical approach to quantify multivariate life-history indices in relation to environmental variation within a spatio-phylogenetic framework. We assessed the utility of our analytical framework by contrasting final models against all candidate models, both with and without an eigenvector filtering procedure, and quantified the degree of autocorrelation in all model residuals. Results Temperature, habitat heterogeneity/availability, flow variability and primary productivity accounted for between 55 and 80% of the variation in life-history indices. Best-performing models were all derived from the addition of spatial and phylogenetic covariates to the analytical framework which consistently produced more parsimonious final models with higher explanatory power and insignificant levels of autocorrelation in the model residuals. Main conclusion The life-history functional diversity of fish assemblages and the composition of life-history strategies across Australian river basins is in part determined by environmental variability, stability and seasonality, highlighting both the importance of environmentally driven community assembly processes and the potential changes to freshwater fish biodiversity in response to climate change. A spatio-phylogenetic analytical framework is a key component in the effective management of autocorrelation in ecological data and the derivation of more rigorous trait–environment relationships.

Dryland rivers in arid and semi-arid regions drain approximately one-third of the Earth's land area, yet basic aspects of their ecology are poorly documented and many are threatened by excessive water use leading to alterations of the flow regime. Management of dryland rivers imperilled by changes to the flow regime requires quantitative hydro-ecological relationships and models to support environmental flow restoration strategies and to define ecological response indicators for assessment of trends in ecological health. Fish living in dryland rivers experience highly variable levels of food resources associated with 'boom and bust' productivity patterns driven by highly irregular episodes of rainfall, runoff and floodplain inundation followed by busts associated with drying of remnant aquatic habitats. To cope with variable food resource levels, fish store energy as fat during productivity booms, enabling them to breed later or to survive through extended periods of limited food resources. This study tracked temporal patterns of body condition and recruitment success of the four most abundant fish species in two Australian dryland river systems with contrasting patterns of flow variability, Cooper Creek and the Moonie River. We found consistent responses to flow magnitude and timing for body condition and/or recruitment success in Cooper Creek but fewer responses in the Moonie River. Results suggest that the fish metrics and relationships to flow established for Cooper Creek may apply in similar dryland rivers exhibiting clear boom and bust patterns, whereas the Moonie River results could be applicable to rivers with less variable flow patterns and fewer spells of zero flows. Our study demonstrates that simple, non-destructive methods based on fish length and weight provide useful biological indicators of response to flow variability provided that care is taken with species selection and that hydro-ecological relationships are calibrated for each contrasting type of hydrologic regime.

Effective environmental flow management depends on identification of ecologically-relevant flow attributes to maintain or restore flows in the context of other natural and human influences on stream ecosystems. This study in subtropical eastern Australia identified associations of fish with climatic and flow gradients, catchment topography, reach geology, habitat structure and land use across 20 catchments. Land-use patterns and associated stressors accounted for very little variation in fish assemblage structure. Of the 35 fish species analysed, 24 were strongly associated with gradients in mean daily flows and their variability, baseflow, number of zero-flow days and high-flow pulses, magnitude of the 1-year annual return interval flood and the constancy and predictability of monthly flows. The finding that 22 species (benthic and pelagic) were associated with gradients of antecedent low-flow hydrology indicates that these species (or functional trait groups) should be the focus of further analysis to explore hydro-ecological relationships in systems with regulated flow regimes.

Background NHL is the most common hematological malignancy. Among a heterogeneous group of NHLs, 85-90% are of B-cell origin and include follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and several other B-NHLs. Anti-CD20 Abs in combination with chemotherapy are the standard of care for the treatment of B-NHLs; however, despite initial responses, many patients relapse, often with progressively shorter response durations in subsequent lines of therapy and poor outcome. REGN1979 is a CD20 x CD3 bispecific IgG4 Ab that binds to CD3+ T-cells and CD20+ B-cells, targeting CD20+ tumor cells via T-cell-mediated cytotoxicity. An ongoing Phase 1 study in patients with B-cell malignancies is evaluating the safety, tolerability, and efficacy of REGN1979 as monotherapy (NCT02290951). Preliminary data from the Phase 1 study showed broad antitumor activity with REGN1979 in heavily pretreated R/R B-NHL patients, including some with progression after prior chimeric antigen receptor T (CAR T)-cell therapy. REGN1979 has been tolerated at doses up to 320 mg weekly, with no observed dose limiting toxicities. These data informed the dosage regimen of the current Phase 2 study. Methods This open-label, multi-center, Phase 2 study (NCT03888105) is evaluating the efficacy and safety of REGN1979 in six disease-specific cohorts, each comprising a single arm with independent parallel enrollment: patients with R/R FL Grade 1-3a after ≥2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent; patients with R/R DLBCL after ≥2 prior lines of systemic therapy (patients in this cohort may not have received prior CAR T-cell therapy); patients with R/R DLBCL after CAR T-cell therapy failure; patients with MCL that have relapsed after or are refractory to Bruton's tyrosine kinase (BTK) inhibitor therapy (patients with R/R MCL who have demonstrated intolerance to BTK inhibitor therapy may also be enrolled); patients with R/R MZL that have relapsed after or are refractory to ≥1 prior line of systemic therapy; patients with R/R other B-NHL subtypes, excluding Waldenström macroglobulinemia, after ≥1 prior line of systemic therapy including an anti-CD20 antibody. The initial screening period of up to 28 days is followed by a weekly dosing period where REGN1979 is administered in gradually increasing doses to achieve target nominal dose by Week 4 and continued through Week 12. Patients then receive REGN1979 every two weeks for up to 86 weeks (total treatment period of 98 weeks). The post-treatment follow-up period will continue for up to 96 weeks after the last dose of study treatment. Approximately 481 patients will be enrolled at sites across the US, Canada, Europe, and the Asia-Pacific region. Key eligibility criteria are: age ≥18 years; ≥1 bi-dimensionally measurable nodal lesion of ≥1.5 cm; Eastern Cooperative Oncology Group performance status of 0 or 1; and adequate bone marrow and hepatic functions. Key exclusion criteria include primary central nervous system (CNS) lymphoma or involvement by non-primary CNS NHL; treatment with systemic anti-lymphoma therapy within five half-lives or 28 days prior to first administration of REGN1979; and history of allogeneic hematopoietic stem cell transplantation. The primary endpoint for each disease-specific cohort is objective response rate (ORR) according to the Lugano Classification of response in malignant lymphoma by independent central review. Secondary endpoints include complete response (CR) rate, progression-free survival, duration of response, disease control rate (DCR), duration of disease control, overall survival; incidence and severity of treatment-emergent adverse events; patient-reported outcomes; pharmacokinetics; and immunogenicity responses. The primary endpoint, ORR, will be summarized along with a two-sided 95% confidence interval (CI). Other efficacy endpoints, such as CR rate and DCR, will be summarized using the same approach as for ORR. The time to event endpoints will be summarized, where appropriate, by median and the corresponding 95% CI using the Kaplan-Meier method. The study is recruiting in FL grade 1-3a cohort and recruitment in other disease-specific cohorts is planned. Disclosures Topp: Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Duell:Regeneron Pharmaceuticals, Inc.: Research Funding. Li:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Jankovic:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Lowy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Sternberg:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Adriaens:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Peterman:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ambati:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Bannerji:AbbVie, Inc: Consultancy, travel support; Celgene: Consultancy; Pharmacyclics: Other: travel support; Pharmacyclics: Other: travel support; Gilead: Other: travel support; Gilead: Other: travel support; AbbVie, Inc: Consultancy; Merck: Other: travel support, Patents & Royalties: IP rights; Celgene: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Merck: Other: travel support, Patents & Royalties: IP rights. OffLabel Disclosure: The abstract outlines data on the use of REGN1979 in a Phase 1 trial in patients with relapsed/refractory B-cell non-Hodgkin lymphoma and describes the design of a Phase 2 trial in a similar patient population.

Background REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce Fc binding. Engaging both targets results in CD20-specific, local T-cell activation and cytotoxicity, a mechanism of action distinct from standard anti-CD20 Abs. Dose escalation is complete and a recommended Ph 2 dose has been determined. We report Ph 1 safety and efficacy results of REGN1979 in patients (pts) with R/R B-NHL previously treated with anti-CD20 Abs, including pts with progressive disease after anti-CD19 CAR T-cell (CAR T) therapy. Methods Primary objectives are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives are to assess antitumor activity, pharmacokinetics (PK), and pharmacodynamics. Eligible pts with R/R B-NHL must have received prior CD20-directed therapy. Treatment consists of 12 weekly intravenous doses of REGN1979 followed by every 2-week dosing for 12 doses (36 weeks total). Results As of June 3, 2019, 96 pts (diffuse large cell B-cell lymphoma [DLBCL] [n=53], follicular lymphoma [FL] grade [Gr] 1-3a [n=25], mantle cell lymphoma [n=6], marginal zone lymphoma [n=6], or other [FL Gr 3b, FL unknown, FL ungraded, or Waldenström macroglobulinemia ] [n=6]) were treated with REGN1979 0.03-320 mg and received a median of 9 doses (range 1-24). Pts had a median of 3 prior lines of therapy (range 1-11); 12 pts with prior CAR T therapy were included in the safety analysis of which 6 were included in the efficacy analysis. Twenty-four pts remain on treatment; 18 completed treatment; 54 discontinued early (35 due to progressive disease [PD]). No pts with B-NHL experienced a DLT. The most common treatment-emergent adverse events (AEs) were pyrexia (n=74), CRS (n=55), chills (n=49), infections and infestations (n=47), fatigue (n=36), increased C-reactive protein (n=32), and anemia (n=32). Seven pts experienced Gr 3 CRS. The severity of CRS symptoms declined through optimized pre-medication even with REGN1979 dose escalation. Most common Gr 3 or 4 AEs were anemia (n=19), decreased lymphocytes/lymphopenia (n=19), infections and infestations (n=18), decreased neutrophils/neutropenia (n=17), and hypophosphatemia/decreased blood phosphorus (n=16). No pts had seizures or grade 4/5 neurologic AEs. Gr 3 neurologic AEs included depressed level of consciousness (unrelated), somnolence, and syncope (n=1 each). Neurological events were transient and none required permanent treatment termination. Five pts discontinued due to AEs: Gr 3 hemolysis; Gr 3 fatigue; Gr 2 and Gr 3 pneumonia; and Gr 3 neck abscess (1 each). Eleven pts died on study: PD (n=6), gastric perforation (n=1), cardiac arrest (n=1), lung infection (n=1), multi-organ failure (n=1), pneumonia (n=1). The Table and Figure show efficacy and duration of response for R/R DLBCL by dose level. Pts who had opportunity for response assessment at Week 12 were included in the analysis of response. Emerging data suggest increasing efficacy with higher doses in R/R DLBCL, with 5 of 8 pts treated at 80/160/320 mg achieving CR; at these doses 2 of 3 pts achieved CR after failure of CAR T therapy. Data also suggest increasing efficacy with increasing doses in R/R FL, but maximum efficacy appears to be achieved at lower doses than in DLBCL; in pts with FL Gr 1-3a treated at ≥5 mg, the ORR was 93% (13/14), and the CR rate was 71.4% (10/14). REGN1979 concentrations in serum increased linearly with dose during the first five weeks. Elevated levels of serum cytokines were observed, mostly in week 1, and no correlation was observed with clinical efficacy. Immunohistological analysis of malignant lymph node tissue demonstrated that pts with high and low CD20 expression achieved clinical response. Relapse among responders was seen with either maintenance or loss of CD20 expression, suggesting antigen-dependent and independent disease escape mechanisms. Conclusions/Summary Tolerability of REGN1979 has been demonstrated at doses up to the final dose level of 320 mg weekly, with no observed DLTs in pts with B-NHL. No pts discontinued due to neurologic AE. Activity was observed broadly in heavily pretreated R/R B-NHL pts treated with REGN1979. With increasing dose, more resistant tumors such as R/R DLBCL are showing benefit, even in pts with prior CAR T therapy failure. Based on these efficacy findings, a global Ph 2 study is underway to evaluate REGN1979 monotherapy in R/R FL Gr 1-3a, R/R DLBCL, and other R/R B-NHL subtypes. Disclosures Bannerji: AbbVie, Inc: Consultancy, travel support; Gilead: Other: travel support; Gilead: Other: travel support; Pharmacyclics: Other: travel support; Merck: Other: travel support, Patents & Royalties: IP rights; AbbVie, Inc: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Celgene: Consultancy; Celgene: Consultancy; Merck: Other: travel support, Patents & Royalties: IP rights; Pharmacyclics: Other: travel support. Allan:Acerta Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie company: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Arnason:Celgene/Juno: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Brown:AstraZeneca: Consultancy; Acerta Pharma: Consultancy; Morphosys: Other: Data safety monitoring boards ; Sun Pharmaceuticals, Inc: Research Funding; Sun: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Teva: Honoraria; Sunesis: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Janssen: Honoraria; Invectys: Other: other; Loxo: Consultancy, Research Funding; Novartis: Consultancy; Octapharma: Consultancy; Kite: Consultancy, Research Funding; Dynamo Therapeutics: Consultancy; Catapult Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharma: Research Funding; Janssen: Research Funding; Merck: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cell Medica, Ltd: Consultancy; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stanford University: Employment, Equity Ownership; Regeneron: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Seattle Genetics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Mayo Clinic Rochester: Employment. O'Brien:Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Astellas: Consultancy; Celgene: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; Verastem: Consultancy; Sunesis: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; TG Therapeutics: Consultancy, Research Funding. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Duell:Regeneron Pharmaceuticals, Inc.: Research Funding. Martin:I-MAB: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; Teneobio: Consultancy. Charnas:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ambati:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Adriaens:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ufkin:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhu:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Li:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Gasparini:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ibrahim:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Jankovic:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Fiaschi:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Aina:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhang:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Deering:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Hamon:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Thurston:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Murphy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Weinreich:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Yancopoulos:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Lowy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Sternberg:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Topp:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The data described in the abstract will report on use REGN1979 in a Phase 1 clinical trial of patients with B-NHL.

Background Engaging PWID in HCV treatment and monitoring for reinfection is critical to eliminate HCV and improve health in people who use drugs. However, PWID are often marginalized and can be difficult to engage and retain in care. The collocation of HCV treatment with buprenorphine to treat opioid use disorder (OUD) may improve visit adherence in this population. Methods ANCHOR is a single-center study evaluating treatment of HCV in PWID with chronic HCV, OUD, and IDU. Participants receive sofosbuvir/velpatasvir x12 weeks and are offered collocated buprenorphine. HCV visits occur at weeks 4, 12, 24, 48, 72 and 96. Results At screening, the 100 enrolled patients were predominantly male (76%), black (93%), middle-aged (median 57years), injected opioids daily or more (58%), and were not on OAT (67%). Fifty-five (55%) patients were initiated on collocated buprenorphine at some point after day 0. Being on collocated buprenorphine at the time of HCV visit was associated with increased likelihood of visit attendance at weeks 12 (P = 0.002), 24 (P = 0.01), 48 (P = 0.02), 72 (P = 0.003), and 96 (P = 0.04). For patients who attended study visits, being on collocated buprenorphine was associated with a shorter time between planned visit and actual visit at weeks 12 (P = 0.03), 24 (P = 0.04), and 48 (P = 0.04). When looking at patients not on collocated buprenorphine, being on noncollocated opioid agonist therapy vs. not being on OUD treatment did not impact visit adherence. Conclusion Evidence-based treatment of HCV and OUD are critical to improving health in PWID. The collocation of HCV treatment with office-based buprenorphine may improve adherence to visits and visit timing, especially in long-term follow-up. Infectious disease providers should offer collocated buprenorphine as a tool to improve long-term outcomes and engagement in this high-risk population. Disclosures All Authors: No reported Disclosures.

Background People who inject drugs (PWID) have significant morbidity and mortality associated with hepatitis C (HCV); however, harms associated with ongoing injecting drug use (IDU)—such as opioid overdose—may pose a more imminent risk, and often are not addressed as part of HCV treatment. Naloxone distribution is a simple, evidenced-based strategy to reduce mortality associated with opioid overdose. Methods ANCHOR is a single-center study embedded in an urban harm-reduction program evaluating treatment of HCV in PWID with chronic HCV, opioid use disorder (OUD), and IDU. Participants received HCV treatment and were offered collocated buprenorphine. At each study visit, patients self-reported experienced and witnessed overdose and were offered naloxone. Results The 100 enrolled participants are predominantly male (75%), median 57 years, black (93%) and inject opioids at least daily (58%). At baseline, 65% had ever experienced overdose, 91% had ever witnessed an overdose, and 35% had ever administered naloxone. Between day 0 and week 48, 15 patients (15%) experienced overdose; of which, 4 (4%) were fatal. The rate of experienced overdose was 15 overdoses per 100 person-years. In addition, 59 (59%) patients witnessed at least one overdose between day 0 and week 48. Seventy-three patients were dispensed naloxone at least once, and of those who witnessed an overdose, 48 (81%) administered naloxone. Nineteen (40%) patients who administered naloxone had never used naloxone before starting HCV treatment. Conclusion PWID with HCV, OUD, and ongoing IDU have high rates of personal and witnessed overdose during and after HCV treatment. Dispensing naloxone at HCV-related visits is highly acceptable among PWID, and results in high rates of naloxone utilization. To reduce morbidity and mortality in patients and their communities, ID providers should complement treatment of infections by prescribing naloxone for patients with OUD, ideally as part of a comprehensive package of harm reduction and OUD treatment. Disclosures All Authors: No reported Disclosures.

Summary The Lake Eyre Basin in central Australia is one of the world's last unregulated dryland river systems. To facilitate future research in this area, the relationships between total length, standard length, and wet weight for 10 widespread, large-bodied freshwater fish species are presented. All linear relationships were strong (r2 > 0.90) and values of the exponent b of the length–weight relationships ranged from 2.786 to 3.336. These results provide novel baseline data for species in this area.

Summary The biogeography of freshwater fish is determined in part by large-scale filters such as phylogenetic history, the spatial arrangement of catchments and environmental variability. Species are filtered from the regional pool if they possess a combination of functional traits enabling them to persist in the local environment. This article aims to quantify the relative importance of these large-scale filters in determining spatial variation in freshwater fish life-history traits and functional trait composition of Australian river basins. We developed a database of 10 life-history traits for 141 native freshwater fish species and compiled species distribution data for 123 river basins across the Australian continent. In order to partition the variation in the representation of life-history trait into unique and overlapping components, we also quantified the degree of phylogenetic relatedness among species, the geographical arrangement of river basins throughout the landscape and 12 broad-scale environmental factors. We then related life-history trait composition to gradients of environmental variation by constrained multivariate ordination and simple linear regression. Our explanatory matrices accounted for 86.8% of the total variation in life-history trait composition at the river basin scale, of which 59.4% could be attributed to phylogeny and spatially structured environmental variation. This component represents the overlap among the broad-scale filtering processes of phylogenetic history, spatial autocorrelation and environmental variability in accounting for the distribution of life-history traits across Australian river basins. Our analysis showed strong associations between suites of life-history traits that define generation time and reproductive output and a strong climate–hydrological gradient across the landscape. We also showed significant correlations between specific environmental variables and a number of key life-history traits that highlight the importance of trait-mediated environmental filters at broad spatial scales. This study advances our conceptual understanding of broad-scale community assembly theory and has revealed trait–environment relationships at scales relevant to restoration and conservation of aquatic biodiversity. Our study provides greater insight into the determinants of spatial variation in fish species distributions and potentially addresses key scientific challenges, such as understanding how fish communities are assembled, and identifies the potential threats to, and responses of, these communities caused by environmental change.

As space missions grow more complex, engineers must rely increasingly on multi-satellite operations to accomplish various mission objectives. Several concepts have emerged for autonomous robotic servicing and assembly of orbiting assets which rely on close proximity operation of independently controlled elements. These architectures are inherently associated with increased levels of mission risk. Consequently, mission architects often rely on pre-flight testing for risk mitigation. Unfortunately, this process historically has led to the development of dedicated testbeds that provide risk reduction for a limited number of mission architectures. This paper describes an extension to the Synchronized Position Hold Engage Reorient Experimental Satellites (SPHERES) facility that allows for unprecedented reconfigurability. This SPHERES extension incorporates hardware and software that can enable TRL6 verification of control algorithms for classes of missions through ground, simulation, and flight testing. The SPHERES facility, consisting of two sets of three identical satellites located at both the MIT Space Systems Laboratory and on the International Space Station (ISS), is being upgraded to include six SPHERES Docking Ports (SDPs) and two SPHERES Halo multi-port expansion structures. The docking ports allow two SDP-equipped elements to dock with each other, and the Halo structures allow for a Halo-equipped satellite to operate up to six peripherals simultaneously through the inclusion of six identical electromechanical expansion ports. This hardware is available for testing on the ground with 3-DOF air carriage systems and aboard the ISS in its 6-DOF long duration microgravity environment. The SPHERES simulation environment, a high-fidelity model of the satellites in 6-DOF, is also being upgraded to include these hardware expansions. This paper describes the design of the hardware and software upgrades, and the expected testbed capabilities they will create. It details how this unique facility enables comprehensive testing to determine the behavior characteristics of future robotic servicing and assembly missions and the interactions between multiple satellites operating in close proximity. A sequence of planned, incremental test sessions aboard the ISS is also described to demonstrate the process by which ground, simulation, and flight testing can be combined constructively to reduce risks associated with these multi-satellite architectures. Results from ground, simulation, and reduced gravity aircraft environments are shown in support of the planned ISS operations.

The ecology of dryland rivers is driven by their highly variable hydrology, particularly flooding regimes, whereby intermittent floods typically generate ‘booms’ of primary and secondary productivity, including massive fish production. We tested these concepts in the Moonie River, Australia, using the percichthyid, Macquaria ambigua, a dryland river species known to display pronounced ‘boom and bust’ abundance patterns in response to floodplain inundation followed by extended periods of low to no channel flow. We expected that body condition (as measured by whole body lipid content) and biomass of M. ambigua would be related to prey biomass, and that these factors would all ‘spike’ following widespread flooding. Instead we found more subtle responses. There were ‘booms’ in biomass of Macrobrachium and zooplankton, two important food items, whereas M. ambigua maintained relatively low but sustained lipid and biomass levels following flooding. It appears that instead of a ‘boom’ in fish biomass, abundant invertebrate food resources and sustained lipid levels contributed to high survivorship of this species during the ‘bust’ period over cool dry months.

Catadromous fish species often use elevated flows to migrate from freshwater to downstream spawning grounds. However, in regulated river systems, artificial barriers and flow alteration can disrupt movement cues, affecting fish migration. Using a combination of acoustic telemetry, passive integrated transponder (PIT) tags and gonad maturity data, we assessed the migratory timing and flow requirements for downstream spawning migrations and upstream dispersal in two co-occurring mullet species in the Logan River, eastern Australia. Over 4 years, 141 adult sea mullet (Mugil cephalus) and 28 adult pinkeye mullet (Trachystoma petardi) were implanted with acoustic transmitters and broad-scale movements tracked using an array of 49 acoustic receivers. Juvenile upstream dispersal was monitored using implanted PIT tags and readers deployed in weir fishways. Sea mullet and pinkeye mullet undertook large-scale downstream migrations from February to March. Movements past weirs only occurred once sufficient flow had occurred and, in the case of pinkeye mullet, when gonads were mature. In contrast, juvenile dispersal into upstream habitats occurred primarily between November and April on low flows. This study advances our understanding of bidirectional movement ecology and flow requirements of two co-occurring mullet species to inform environmental flow management (e.g. to facilitate fish passage) in a regulated river system.

Introduction REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce Fc binding. Engaging both targets results in CD20-specific, local T-cell activation and cytotoxicity, a mechanism of action distinct from standard anti-CD20 Abs. We report updated promising efficacy results of a Phase 1 trial of REGN1979 in patients (pts) with relapsed/refactory (R/R) B-NHL previously treated with anti-CD20 Abs. Methods The primary objectives of the study are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives include assessment of preliminary antitumor activity, pharmacokinetics (PK), and pharmacodynamics. Eligible pts with R/R NHL must have received at least 1 prior CD20-directed therapy. Treatment consists of 12 weekly doses of REGN1979 followed by every 2 week dosing for 12 doses for a total of 36 weeks. Guidelines are provided for management of cytokine release syndrome (CRS) and include steroids and/or tocilizumab at investigator discretion. Results As of June 1, 2018, 54 pts with B-NHL were treated with REGN1979 monotherapy: DLBCL (pt number [n]=30), FL (n=16), MCL (n=5), MZL (n=2), and WM (n=1). The median number of prior regimens was 3 (range, 1-11); 41 pts were refractory to their last prior systemic therapy, 18 had bulky disease, and 6 had prior HSCT. Pts were treated with REGN1979 0.03-27 mg and received a median of 7 (range, 1-24) doses. Eight pts remain on treatment, 13 completed treatment, and 33 discontinued therapy prior to the planned 36 wks (majority [n=22] due to progressive disease [PD]). There have been no DLTs to date. The most common treatment-related treatment-emergent adverse events (TR-TEAEs) included infusion-related reactions (IRR) or CRS; 26 pts experienced CRS (Grade 1-2, n=23; Grade 3, n=3) with a median duration of CRS of 2 (range 1-15) days. Six pts received tocilizumab. The severity of CRS symptoms declined through optimized pre-medication even with REGN1979 dose escalation. Other common Grade ≥3 TR-TEAEs were lymphocytopenia/ decreased lymphocyte count (n=8); neutropenia/ decreased neutrophil count (n=7); and thrombocytopenia/ decreased platelet count, hypotension, hypophosphatemia, and anemia (each n=3). Seventeen pts experienced a nervous system event including headache, dizziness, paraesthesia, dysgeusia, and peripheral neuropathy with no Grade ≥3 events; no neurologic event required termination of study drug. Seven pts died on study: PD (n=5), gastric perforation (n=1), and cardiac arrest (n=1). TEAEs leading to premature discontinuation of REGN1979 were Grade 3 fatigue (n=1), Grade 3 hemolysis (n=1), and Grade 2 pyrexia/Grade 2 tachycardia (n=1). Among 27 pts treated with REGN1979 ≥5 mg (dose associated with tumor killing in pre-clinical data), the overall response rate (ORR) was 55.6% (5 complete response [CR] and 10 partial response [PR]; Table/Figure). Responses were seen in 7/7 FL Grade 1-3a pts (5 CR, 2 PR), 6/15 DLBCL pts (all PR), 2/2 MCL pts (all PR). At 18 mg and 27 mg of REGN1979, 4 of 4 pts with DLBCL had best response of PR. Post data cut-off, 1 pt with a DLBCL best response of PR converted to CR. PK and pharmacodynamic assessments suggest that for pts treated with REGN1979 5-18 mg, best exposures in the first 3 weeks appear to linearly increase with dose. In pts treated with up to REGN1979 18 mg, a maximum mean Ctrough of 1.6 mcg/mL was observed in the first 3 weeks of weekly dosing. Studies of peripheral blood biomarkers demonstrated depletion of peripheral B lymphocytes, transient margination of circulating T-cells, and elevated circulating cytokines following REGN1979 dosing. Increased peak cytokine levels (IL-6, IL-10, and TNF-alpha) were observed in pts with CRS. Immunohistological analysis of malignant lymph node tissue demonstrated a decrease of CD20 expression in responding pts; among the responders, subsequent relapse was associated with either maintenance of CD20 expression or further CD20 loss, suggesting antigen-dependent and independent disease escape mechanisms. Conclusions REGN1979 displays efficacy and an acceptable safety profile in pts with R/R B-NHL. Most TR-TEAEs were IRR/CRS and have been well managed with supportive care. No significant neurological toxicity has been observed. At doses of 5-27 mg of REGN1979, the preliminary ORR was 100% in pts with FL Grade 1-3a and 40.0% in pts with DLBCL. This promising efficacy warrants further clinical investigation. Disclosures Bannerji: Regeneron Pharmaceuticals, Inc.: Consultancy; AbbVie, Inc.: Consultancy. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy. Advani:Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Janssen Pharmaceutical: Other: Institutional Research Support; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Millenium: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Infinity: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Cell Medica: Other: Consultancy/Advisory Role; Agensys: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Kura: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Autolus: Other: Consultancy/Advisory Role; AstraZeneca: Other: Consultancy/Advisory Role. Brown:Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Pharmacyclics: Consultancy; Celgene: Consultancy; Genentech: Consultancy; TG Therapeutics: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Abbvie: Consultancy; Gilead: Consultancy, Research Funding; Sun Pharmaceutical Industries: Research Funding; Sunesis: Consultancy; Loxo: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Invectys: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy; Boehringer: Consultancy. Allan:Genentech: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Celldex: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. O'Brien:Kite Pharma: Research Funding; Aptose Biosciences Inc.: Consultancy; Pharmacyclics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Astellas: Consultancy; Sunesis: Consultancy, Research Funding; Alexion: Consultancy; Amgen: Consultancy; TG Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; Janssen: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding. Chavez:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Humanigen: Consultancy. Lowy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Charnas:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Sternberg:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ambati:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Adriaens:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ufkin:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Yan:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Li:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Navarro:Regeneron Pharmaceuticals, Inc.: Employment. Gasparini:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Jankovic:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Fiaschi:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhang:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Hamon:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Thurston:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Topp:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding.

Background People who inject drugs (PWID) have an increased risk for HIV, and HCV infection may foreshadow HIV acquisition in current epidemics. Studies of PWID have demonstrated a desire to obtain HCV treatment; however, use of pre-exposure prophylaxis (PrEP) in this population has not been well studied. Methods The ANCHOR study is an ongoing single-center study evaluating treatment of HCV in PWID. Enrolled patients have chronic HCV, opioid use disorder, and inject opioids. Patients are treated with sofosbuvir/velpatasvir and offered PrEP. Patients complete baseline community health worker (CHW)-administered surveys, physician assessment of PrEP eligibility, and are offered PrEP uptake. Results Of 89 enrolled patients, 49 (55%) met CDC criteria for PrEP, and 21 (24%) patients started PrEP. Reasons for not starting PrEP are in Figure 1. Though most patients are black (n = 82, 92.1%) and heterosexual (n = 81, 91%), these patients were less likely to start PrEP (P = 0.0068 and P = 0.0283, respectively). Baseline interest in starting PrEP was correlated with uptake (P = 0.0023), however, self-identifying as high-risk for HIV acquisition or meeting CDC criteria for PrEP were not. Though more patients endorsed sharing of injection equipment to a CHW than a physician (17% vs. 7%), endorsement to a physician rather than CHW was associated with starting PrEP (P = 0.0307). To date, 13 (62%) patients discontinued PrEP, 7 (54%) due to side effects. Conclusion Preliminary results of the ANCHOR study support that engagement in HCV care provides an opportunity for PWID to participate in PrEP intake; however, we found relatively low uptake in these patients, despite over half meeting CDC criteria. Our findings highlight the importance of counseling by physicians for initiation of PrEP, and suggest that improved communication between CHW and physician regarding risk behaviors could improve uptake. These data also reinforce that patients must be counseled and managed for side effects in order to retain them in care. Given the increasing opioid epidemic in the United States, more consideration needs to be given regarding how to incorporate PrEP into care, and how to effectively target and improve interest in PrEP for high-risk populations with poor uptake, including minorities and PWID. Disclosures C. Gross, Merck, Pfizer, Johnson and Johnson: Shareholder, stock. E. Rosenthal, Gilead Sciences, Merck: Grant Investigator, Grant recipient.

Kalman Filters have been used as a means of estimation in the aerospace field for decades. By offering both vector modeling and recursive processing, these filters can be used to estimate state vectors. These state estimates rely on input data from sensors which may become available at irregular intervals. A past sensor measurement, for example, may arrive after the estimate for a time step has been computed using the other sensor data. In this paper, we introduce a general solution to update the Kalman filter with the outof-sequence measurements (OOSM) based on the fixed-lag smoother (FLS). It is able to generate a new state estimation at OOSM time using two adjacent estimations in FLS so that these OOSMs can be incorporated into future state estimates for improved accuracy. An inductive proof is presented to show the derivation and application of the new algorithm, called the Augmented Fixed-Lag Smoother.

Multidisciplinary system design optimization is performed to determine an optimal on-orbit satellite assembly mission architecture. Modern satellite assembly and launch systems rely on monolithic launches of complete satellites. There are many benefits, however, that may be attained through deviating from the status quo. Launching robotic, on-orbit assemble-able satellite modules increases the number of launches, but since each is launch is of a smaller satellite, the net launch costs can be decreased. Additionally, the price per pound of satellite launches can be decreased through ride-share programs with other missions. Spacecraft versatility is increased when not restricted to the selected launch vehicle payload weight capacity and geometric envelope by instead relying on reconfiguration once in orbit to achieve a final operational configuration. To facilitate the realization of these and other benefits, this paper addresses the architecture of an on-orbit assembly mission that requires an assembly satellite(s) to rendezvous with customer modules and assemble them into a complete satellite in the desired final orbit. A model of this assembly mission is created which calculates costs over the whole multi-assembly mission lifetime of one through five assembler satellites and the downtime which customer satellites experience while on orbit waiting for assembly to be complete. Five design variables are identified for this model, namely, the number of assembler satellites, the number of modules each assembler can manipulate at once, the starting location of each assembler, the autonomy level of the assemblers, and type of transfer orbits utilized by the assemblers. By varying these five aspects of the mission, an optimization is carried out which seeks to minimize total cost of the assembler mission and downtime of the customer satellites while holding to certain parameters and meeting constraints. This paper presents the problem, a simulation of the problem, the optimization methodology, and the results of that optimization.

The production of pigments during industrial fermentations is undesirable, and expensive purification steps are often required to remove colored compounds from anticipated commercial products. We observed that a recombinant Bacillus subtilis strain synthesizing the heterologous polysaccharide hyaluronic acid (HA) produced copious amounts of a red pigment with biochemical properties characteristic of pulcherrimin, a previously characterized iron-binding pyrazine compound. An apigmented B. subtilis mutant was isolated following chemical mutagenesis and compared to its parent strain using DNA microarray transcriptome analysis. Among the genes whose transcription was significantly (p < 0.05) altered in the apigmented mutant, yvmC, and cypX were selected as likely pulcherrimin biosynthetic genes on the basis of in silico bioinformatics examination which suggested that the yvmC gene product contains a putative phosphopantetheine domain characteristic of some cyclic peptide synthases, and the cypX gene encodes a...

Multiple herpes simplex virus type 1 functions control translation by regulating phosphorylation of the initiation factor eIF2 on its alpha subunit. Both of the two known regulators, the γ 1 34.5 and Us11 gene products, are produced late in the viral life cycle, although the γ 1 34.5 gene is expressed prior to the γ 2 Us11 gene, as γ 2 genes require viral DNA replication for their expression while γ 1 genes do not. The γ 1 34.5 protein, through a GADD34-related domain, binds a cellular phosphatase (PP1α), maintaining pools of active, unphosphorylated eIF2. Infection of a variety of cultured cells with a γ 1 34.5 mutant virus results in the accumulation of phosphorylated eIF2α and the inhibition of translation prior to the completion of the viral lytic program. Ectopic, immediate-early Us11 expression prevents eIF2α phosphorylation and the inhibition of translation observed in cells infected with a γ 1 34.5 mutant by inhibiting activation of the cellular kinase PKR and the subsequent phosphorylation of eIF2α; however, a requirement for the Us11 protein, produced in its natural context as a γ 2 polypeptide, remains to be demonstrated. To determine if Us11 regulates late translation, we generated two Us11 null viruses. In cells infected with a Us11 mutant, elevated levels of activated PKR and phosphorylated eIF2α were detected, viral translation rates were reduced 6- to 7-fold, and viral replication was reduced 13-fold compared to replication in cells infected with either wild-type virus or a virus in which the Us11 mutation was repaired. This establishes that the Us11 protein is critical for proper late translation rates. Moreover, it demonstrates that the shutoff of protein synthesis observed in cells infected with a γ 1 34.5 mutant virus, previously ascribed solely to the γ 1 34.5 mutation, actually results from the combined loss of γ 1 34.5 and Us11 functions, as the γ 2 Us11 mRNA is not translated in cells infected with a γ 1 34.5 mutant.

Context Present-day distribution records show that Oxyeleotris lineolata (sleepy cod) has colonised many ephemeral streams and refugial waterholes of the Cooper Creek catchment in the Lake Eyre Basin within a decade of the first record or capture. When introduced to new habitats outside its natural range, this species is considered to be a serious conservation risk to native fish species. Aims The present study aims to document the transport, establishment, colonisation and integration of O. lineolata in the Lake Eyre Basin, and quantify its impact on native fish assemblages. Methods Fish samples were taken annually in 21 waterholes between 2011 and 2016, by using a combination of single- and double-winged fyke nets. We collected novel diet and life-history information from 242 O. lineolata individuals across their known distribution. Key results Abundance, length distribution and life-history information suggested a ‘colonising front’ moving downstream, across state jurisdictional boundaries and into the Coongie Lakes Ramsar site. Oxyeleotris lineolata diet is most similar to that of two native generalist invertivore–piscivores and preys on several native fish species. With a derived longevity in excess of 15 years and a life-history strategy that combines batch spawning, high fecundity and parental care (i.e. high juvenile survivorship), there is real potential for O. lineolata to dominate fish assemblages in waterholes that provide refuge for native fishes during dry periods. Conclusions The present study showed that O. lineolata has the potential to negatively influence native fish assemblages through both competition and predation in refugial waterholes. Eradication of O. lineolata from the Cooper Creek catchment in central Australia is highly unlikely, given its widespread distribution, the remoteness of the receiving landscape and a current lack of resources to monitor spread and attempt eradication at the moving front of the Cooper Creek population. Implications Achieving greater awareness of the potential impacts of introducing or spreading non-native species is an important first step towards preserving the native fish fauna of the Lake Eyre Basin. Further research is warranted to fully understand the current and potential future distribution of O. lineolata in the basin, its biological and ecological requirements, and influence on native fish species and assemblages.