Prospectus, April 7, 1999

https://spark.parkland.edu/prospectus_1999/1011/thumbnail.jp

Prospectus, April 21, 1999

https://spark.parkland.edu/prospectus_1999/1013/thumbnail.jp

Galileo mission planning for Low Gain Antenna based operations

The Galileo mission operations concept is undergoing substantial redesign, necessitated by the deployment failure of the High Gain Antenna, while the spacecraft is on its way to Jupiter. The new design applies state-of-the-art technology and processes to increase the telemetry rate available through the Low Gain Antenna and to increase the information density of the telemetry. This paper describes the mission planning process being developed as part of this redesign. Principal topics include a brief description of the new mission concept and anticipated science return (these have been covered more extensively in earlier papers), identification of key drivers on the mission planning process, a description of the process and its implementation schedule, a discussion of the application of automated mission planning tool to the process, and a status report on mission planning work to date. Galileo enhancements include extensive reprogramming of on-board computers and substantial hard ware and software upgrades for the Deep Space Network (DSN). The principal mode of operation will be onboard recording of science data followed by extended playback periods. A variety of techniques will be used to compress and edit the data both before recording and during playback. A highly-compressed real-time science data stream will also be important. The telemetry rate will be increased using advanced coding techniques and advanced receivers. Galileo mission planning for orbital operations now involves partitioning of several scarce resources. Particularly difficult are division of the telemetry among the many users (eleven instruments, radio science, engineering monitoring, and navigation) and allocation of space on the tape recorder at each of the ten satellite encounters. The planning process is complicated by uncertainty in forecast performance of the DSN modifications and the non-deterministic nature of the new data compression schemes. Key mission planning steps include quantifying resource or capabilities to be allocated, prioritizing science observations and estimating resource needs for each, working inter-and intra-orbit trades of these resources among the Project elements, and planning real-time science activity. The first major mission planning activity, a high level, orbit-by-orbit allocation of resources among science objectives, has already been completed; and results are illustrated in the paper. To make efficient use of limited resources, Galileo mission planning will rely on automated mission planning tools capable of dealing with interactions among time-varying downlink capability, real-time science and engineering data transmission, and playback of recorded data. A new generic mission planning tool is being adapted for this purpose

Selective Impairment of TH17-Differentiation and Protection against Autoimmune Arthritis after Overexpression of BCL2A1 in T Lymphocytes

The inhibition of apoptotic cell death in T cells through the dysregulated expression of BCL2 family members has been associated with the protection against the development of different autoimmune diseases. However, multiple mechanisms were proposed to be responsible for such protective effect. The purpose of this study was to explore the effect of the Tcell overexpression of BCL2A1, an anti-apoptotic BCL2 family member without an effect on cell cycle progression, in the development of collagen-induced arthritis. Our results demonstrated an attenuated development of arthritis in these transgenic mice. The protective effect was unrelated to the suppressive activity of regulatory T cells but it was associated with a defective activation of p38 mitogen-activated protein kinase in CD4+ cells after in vitro TCR stimulation. In addition, the in vitro and in vivo TH17 differentiation were impaired in BCL2A1 transgenic mice. Taken together, we demonstrated here a previously unknown role for BCL2A1 controlling the activation of CD4+ cells and their differentiation into pathogenic proinflammatory TH17 cells and identified BCL2A1 as a potential target in the control of autoimmune/inflammatory diseases

Bcl-2-regulated cell death signalling in the prevention of autoimmunity

Cell death mediated through the intrinsic, Bcl-2-regulated mitochondrial apoptosis signalling pathway is critical for lymphocyte development and the establishment of central and maintenance of peripheral tolerance. Defects in Bcl-2-regulated cell death signalling have been reported to cause or correlate with autoimmunity in mice and men. This review focuses on the role of Bcl-2 family proteins implicated in the development of autoimmune disorders and their potential as targets for therapeutic intervention

Paediatric Strategy Forum for medicinal product development of DNA damage response pathway inhibitors in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration

DNA damage response inhibitors have a potentially important therapeutic role in paediatric cancers; however, their optimal use, including patient selection and combination strategy, remains unknown. Moreover, there is an imbalance between the number of drugs with diverse mechanisms of action and the limited number of paediatric patients available to be enrolled in early-phase trials, so prioritisation and a strategy are essential. While PARP inhibitors targeting homologous recombination-deficient tumours have been used primarily in the treatment of adult cancers with BRCA1/2 mutations, BRCA1/2 mutations occur infrequently in childhood tumours, and therefore, a specific response hypothesis is required. Combinations with targeted radiotherapy, ATR inhibitors, or antibody drug conjugates with DNA topoisomerase I inhibitor-related warheads warrant evaluation. Additional monotherapy trials of PARP inhibitors with the same mechanism of action are not recommended. PARP1-specific inhibitors and PARP inhibitors with very good central nervous system penetration also deserve evaluation. ATR, ATM, DNA-PK, CHK1, WEE1, DNA polymerase theta and PKMYT1 inhibitors are early in paediatric development. There should be an overall coordinated strategy for their development. Therefore, an academia/industry consensus of the relevant biomarkers will be established and a focused meeting on ATR inhibitors (as proof of principle) held. CHK1 inhibitors have demonstrated activity in desmoplastic small round cell tumours and have a potential role in the treatment of other paediatric malignancies, such as neuroblastoma and Ewing sarcoma. Access to CHK1 inhibitors for paediatric clinical trials is a high priority. The three key elements in evaluating these inhibitors in children are (1) innovative trial design (design driven by a clear hypothesis with the intent to further investigate responders and non-responders with detailed retrospective molecular analyses to generate a revised or new hypothesis); (2) biomarker selection and (3) rational combination therapy, which is limited by overlapping toxicity. To maximally benefit children with cancer, investigators should work collaboratively to learn the lessons from the past and apply them to future studies. Plans should be based on the relevant biology, with a focus on simultaneous and parallel research in preclinical and clinical settings, and an overall integrated and collaborative strategy

Role of BIM in Type I diabetes

The BCL-2 family of proteins consists of approximately twenty members that function in the stress pathway of apoptosis. Interactions between anti-apoptotic and pro-apoptotic member proteins determine cell fate. Over the years, it has become evident that the interplay between BCL-2 family members affects more than just apoptosis, but also other processes such as proliferation and intracellular calcium signaling. BIM is a pro-apoptotic BCL-2 family member protein that functions in the process of negative selection to delete self-reactive lymphocytes and in clonal contraction following clearance of pathogens. Its role in the apoptosis of self-reactive lymphocytes is believed to be important for the prevention of autoimmunity. Studies with non-obese diabetic mice (NOD) indicate that a defect in BIM expression contributes to Type I diabetes (TID) development in NOD mice. Through studies into TID, we have discovered that BIM deficiency actually prevents TID development. Although BIM knockout mice have more self-reactive T cells than control mice, using limiting dilution analysis we show that the actual “effective frequency” of (β-cell-specific T cells able to respond to antigen is significantly lower. Through analysis of BIM-deficient T cells, we show that BIM plays a role in T cell proliferation and activation. BIM-deficient T cells are defective in TCR-induced intracellular calcium efflux, which results in decreased IL-2 production due to improper NFAT activation. Although BIM knockout mice may have more self-reactive T cells, they are not as “effectively” activated as T cells in wildtype mice when exposed to antigen

Three Essays on Healthcare Provider Behavior

This dissertation consists of three essays Essay 1 In recent years, the physician practice landscape has been characterized by a shift away from small, single specialty physician practices and towards larger, more integrated providers. Responses to this trend have been mixed, with some hailing it as a cost saving cure-all and others warning about the dangers of increased market power and the potential for anti-competitive behavior. This trade-off has been debated by health care professionals, economists and government agencies in boardrooms, academia and courts. The discussion of integration has been impeded by a failure to carefully define terms and distinguish between two distinct components of integration: administrative and behavioral. Administrative, or financial, integration happens when providers merge, or hospitals purchase physician practices. This type of integration is associated with increased bargaining power and higher reimbursements. Furthermore, through profit sharing, financial integration can create an incentive for providers to refer patients to other specialists for more tests or more care, some of which may be unnecessary. In contrasts, behavioral integration refers to doctors working together and coordinating care. It has been associated with decreased waste and more efficient care. Previous work has often used measures of administrative integration, such as the share of physician practices owned by hospitals, to proxy for behavioral integration. Those modeling decisions are understandable as, up to this point, a metric which separately captures behavioral integration in a systematic way has not existed. The lack of a metric has been a hurdle to evaluating these two components separately. In this paper, I use Medicare data on physician patient sharing patterns to develop metrics that capture physician practice integration at the behavioral level. I compare these behavioral integration metrics to a more standard organizational level integration metric. The low correlation, only 0.30, demonstrates that these metrics are distinct. Using all these metrics, I examine the impact of these two types of physician integration on the utilization of medical care. With national data over time, I use changes in integration and utilization within regions to estimate how the different types of integration impact the ability to provide quality care at a low cost, which I refer to as efficiency. As a model of physician behavior predicts, I find that behavioral integration reduces cost while improving quality. In contrasts, financial integration appears to increase cost without having an impact on quality. These results are robust to different measures of behavioral integration and different identification strategies. Essay 2 When health care providers and managed care organizations (MCOs) bargain, the main tool providers have is the threat to refuse to be in the MCO’s network. In fact, anecdotal evidence indicates that a major mechanism that practices employ to maximize profits in the face of differing insurer reimbursements, limited capacity and stochastic demand is to choose insurers discriminately. Providers do not accept patients from every MCO, however, providers do not exclusively accept the most profitable MCO. In this paper, I apply these institutional facts to a Nash cooperative bargaining framework to develop a bargaining model that explicitly models the provider’s disagreement point with the MCOs. In doing this, I am able to solve analytically [Don’t split infinitives] for the interdependence of prices between MCOs and add to previous bargaining models by making the value of a MCO to a provider more explicit. This model shows the impact of MCO market structure on prices. By introducing provider capacity constraints, I am able to model two important provider-side considerations: the risk capacity will be unused, and the risk that a low-paying patient will displace a higher-paying patient. Neither of these two effects have been previously captured in the bargaining literature, which typically has featured marginal costs as the limiting factor for providers contracting with MCOs. I also show how predictions in my model match empirical observations and estimates from other work. I demonstrate a strong negative association between MCOs’ market power and negotiated prices, and show that the degree of market level price differences predicted by this model is similar to what has been observed. Finally, recent empirical work has found that that price increases for Medicare are positively associated with private MCOs’ prices and that this impact is stronger in areas with more concentrated insurers, and areas in which Medicare patients represent a larger share of the market. My model analytically makes these predictions and can explain the underlying mechanisms. Essay 3 This paper examines how primary care providers (PCPs) change their referral patterns to specialists after they join a Medicare Shared Savings Program Accountable Care Organization (ACO). We find that primary-care providers respond differently to ACO formation depending on the degree to which the providers have a pre-existing relationship with specialists in the ACO. Relatively speaking, the smaller the previous PCP-specialist relationship, the bigger the response. We also find that primary-care providers without a pre-existing relationship with ACO specialists make up a large share of the ACOs PCPs and referrals. PCPs that sent a large share of referrals to specialists that join an ACO in the years prior to ACO formation decrease the number of patient they refer to those specialists