Lessons Learned from Deploying an Analytical Task Management Database

Defining requirements, missions, technologies, and concepts for space exploration involves multiple levels of organizations, teams of people with complementary skills, and analytical models and simulations. Analytical activities range from filling a To-Be-Determined (TBD) in a requirement to creating animations and simulations of exploration missions. In a program as large as returning to the Moon, there are hundreds of simultaneous analysis activities. A way to manage and integrate efforts of this magnitude is to deploy a centralized database that provides the capability to define tasks, identify resources, describe products, schedule deliveries, and generate a variety of reports. This paper describes a web-accessible task management system and explains the lessons learned during the development and deployment of the database. Through the database, managers and team leaders can define tasks, establish review schedules, assign teams, link tasks to specific requirements, identify products, and link the task data records to external repositories that contain the products. Data filters and spreadsheet export utilities provide a powerful capability to create custom reports. Import utilities provide a means to populate the database from previously filled form files. Within a four month period, a small team analyzed requirements, developed a prototype, conducted multiple system demonstrations, and deployed a working system supporting hundreds of users across the aeros pace community. Open-source technologies and agile software development techniques, applied by a skilled team enabled this impressive achievement. Topics in the paper cover the web application technologies, agile software development, an overview of the system's functions and features, dealing with increasing scope, and deploying new versions of the system

Ephrin/Eph receptor interaction facilitates macrophage recognition of differentiating human erythroblasts

Erythropoiesis is one of the most efficient cellular processes in the human body producing approximately 2.5 million red blood cells every second. This process occurs in a bone marrow niche comprised of a central resident macrophage surrounded by differentiating erythroblasts, termed an erythroblastic island. It is not known what initially attracts the macrophage to erythroblasts to form these islands. The ephrin/EPH receptor family are known to regulate heterophilic cell-cell adhesion. We find that human VCAM1+ and VCAM1- bone marrow macrophages and in vitro cultured macrophages are ephrin-B2 positive, whereas differentiating human erythroblasts express EPHB4, EPHB6 and EPHA4. Furthermore, we detect a rise in integrin activation on erythroblasts at the stage at which the cells bind which is independent of EPH receptor presence. Using a live cell imaging assay, we show that specific inhibitory peptides or shRNA depletion of EPHB4 cause a significant reduction in the ability of macrophages to interact with erythroblasts but does not affect integrin activation. This study demonstrates for the first time that EPHB4 expression is required on erythroblasts to facilitate the initial recognition and subsequent interaction with macrophages, alongside the presence of active integrins

Early evaluation of the Children and Young People's Mental Health Trailblazer programme:a rapid mixed-methods study

BACKGROUND: The Children and Young People’s Mental Health Trailblazer programme is funding the creation of new mental health support teams to work in schools and further education colleges. Mental health support teams directly support children and young people with ‘mild to moderate’ mental health problems and work with school and college staff to promote well-being for all. A new workforce of education mental health practitioners is being trained for the teams. OBJECTIVE(S): The National Institute for Health and Care Research Birmingham, RAND and Cambridge Evaluation Rapid Evaluation Centre and Policy Innovation and Evaluation Research Unit undertook an early evaluation of the Trailblazer programme to examine the development, implementation and early progress of mental health support teams in the programme’s first 25 ‘Trailblazer’ sites. DESIGN: A mixed-methods evaluation, comprising three work packages: 1. Establishing the baseline and understanding the development and early impacts of the Trailblazer sites, including two rounds of surveys with key informants and participating education settings in all 25 sites. 2. More detailed research in five purposively selected Trailblazer sites, including interviews with a range of stakeholders and focus groups with children and young people. 3. Scoping and developing options for a longer-term assessment of the programme’s outcomes and impacts. Fieldwork was undertaken between November 2020 and February 2022. The University of Birmingham Institute for Mental Health Youth Advisory Group was involved throughout the study, including co-producing the focus groups with children and young people. RESULTS: Substantial progress had been made implementing the programme, in challenging circumstances, and there was optimism about what it had the potential to achieve. The education mental health practitioner role had proven popular, but sites reported challenges in retaining education mental health practitioners, and turnover left mental health support teams short-staffed and needing to re-recruit. Education settings welcomed additional mental health support and reported positive early outcomes, including staff feeling more confident and having faster access to advice about mental health issues. At the same time, there were concerns about children who had mental health problems that were more serious than ‘mild to moderate’ but not serious enough to be accepted for specialist help, and that the interventions offered were not working well for some young people. Mental health support teams were generally spending more time supporting children with mental health problems than working with education settings to develop ‘whole school’ approaches to mental health and well-being, and service models in some sites appeared to be more clinically oriented, with a strong focus on mental health support teams’ therapeutic functions. LIMITATIONS: Despite efforts to maximise participation, survey response rates were relatively low and some groups were less well represented than others. We were not able to gather sufficiently detailed data to develop a typology of Trailblazer sites, as was planned. CONCLUSIONS: Key lessons for future programme implementation include: - Whether mental health support teams should expand support to children and young people with more complex and serious mental health problems. - How to keep the twin aims of prevention and early intervention in balance. - How to retain education mental health practitioners once trained. FUTURE WORK: The findings have important implications for the design of a longer-term impact evaluation of the programme, which is due to commence in summer 2023

Glucocorticoids induce differentiation of monocytes towards macrophages that share functional and phenotypical aspects with erythroblastic island macrophages

The classical central macrophage found in erythroblastic islands plays an important role in erythroblast differentiation, proliferation and enucleation in the bone marrow. Convenient human in vitro models to facilitate the study of erythroid-macrophage interactions are desired. Recently, we demonstrated that cultured monocytes/macrophages enhance in vitro erythropoiesis by supporting hematopoietic stem and progenitor cell survival. Herein, we describe that these specific macrophages also support erythropoiesis. Human monocytes cultured in serum-free media supplemented with stem cell factor, erythropoietin, lipids and dexamethasone differentiate towards macrophages expressing CD16, CD163, CD169, CD206, CXCR4 and the phagocytic TAM-receptor family. Phenotypically, they resemble both human bone marrow and fetal liver resident macrophages. This differentiation is dependent on glucocorticoid receptor activation. Proteomic studies confirm that glucocorticoid receptor activation differentiates monocytes to anti-inflammatory tissue macrophages with a M2 phenotype, termed GC-macrophages. Proteins involved in migration, tissue residence and signal transduction/receptor activity are upregulated whilst lysosome and hydrolase activity GO-categories are downregulated. Functionally, we demonstrate that GC-macrophages are highly mobile and can interact to form clusters with erythroid cells of all differentiation stages and phagocytose the expelled nuclei, recapitulating aspects of erythroblastic islands. In conclusion, glucocorticoid-directed monocyte differentiation to macrophages represents a convenient model system to study erythroid-macrophage interactions

A Two-cohort Phase I Study of Weekly Oxaliplatin and Gemcitabine, Then Oxaliplatin, Gemcitabine, and Erlotinib During Radiotherapy for Unresectable Pancreatic Carcinoma

Gemcitabine is a potent radiosensitizer. When combined with standard radiotherapy (XRT) the gemcitabine dose must be reduced to about 10% of its conventional dose. Oxaliplatin and erlotinib also have radiosensitizing properties. In vitro, oxaliplatin and gemcitabine have demonstrated synergy. We aimed to determine the maximum tolerated dose of oxaliplatin and gemcitabine with concurrent XRT, then oxaliplatin, gemcitaibine and erlotinib with XRT in the treatment of locally advanced and low volume metastatic pancreatic or biliary cancer

A phase I trial of everolimus in combination with 5-FU/LV, mFOLFOX6 and mFOLFOX6 plus panitumumab in patients with refractory solid tumors

This phase I study investigated the safety, dose limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered 1) in combination with 5-fluourouracil with leucovorin (5-FU/LV), 2) with mFOLFOX6 (5-FU/LV + Oxaliplatin), and 3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors

Evaluation of US Hospital Episode Spending for Acute Inpatient Conditions After the Patient Protection and Affordable Care Act.

Importance: Under the Patient Protection and Affordable Care Act (ACA), US hospitals were exposed to a number of reforms intended to reduce spending, many of which, beginning in 2012, targeted acute care hospitals and often focused on specific diagnoses (eg, acute myocardial infarction, heart failure, and pneumonia) for Medicare patients. Other provisions enacted in the ACA and under budget sequestration (beginning in 2013) mandated Medicare fee cuts. Objective: To evaluate the association between the enactment of ACA reforms and 30-day price-standardized hospital episode spending. Design, Setting, and Participants: This policy evaluation included index discharges between January 1, 2008, and August 31, 2015, from a national random 20% sample of Medicare beneficiaries. Data analysis was performed from February 1, 2019 to July 8, 2020. Exposure: Payment reforms after passage of the ACA. Main Outcomes and Measures: 30-day price-standardized episode payments. Three alternative estimation approaches were used to evaluate the association between reforms following the ACA and episode spending: (1) a difference-in-difference (DID) analysis among acute care hospitals, comparing spending for diagnoses commonly targeted by ACA programs with nontargeted diagnoses; (2) a DID analysis comparing acute care hospitals and critical access hospitals (not exposed to reforms); and (3) a generalized synthetic control analysis, comparing acute care and critical access hospitals. Supplemental analysis examined the degree to which Medicare fee cuts contributed to spending reductions. Results: A total of 7 634 242 index discharges (4 525 630 [59.2%] female patients; mean [SD] age, 79.31 [8.02] years) were included. All 3 approaches found that reforms following the ACA were associated with a significant reduction in episode spending. The DID estimate comparing targeted and untargeted diagnoses suggested that reforms following the ACA were associated with a -$431 (95$492 to -$369; -2.87$1232 (95% CI, -$1488 to -$965; -10.12%) change in total episode spending, amounting in a total annual savings of $5.68 billion. Cuts to Medicare fees accounted for most of these savings. Conclusions and Relevance: In this policy evaluation, the ACA was associated with large reductions in US hospital episode spending

A Phase I Study of Bortezomib in Combination With Standard 5-Fluorouracil and External-Beam Radiation Therapy for the Treatment of Locally Advanced or Metastatic Rectal Cancer

Standard therapy for stage II/III rectal cancer consists of a fluoropyrimidine and radiation therapy followed by surgery. Preclinical data demonstrated that bortezomib functions as a radiosensitizer in colorectal cancer models. The purpose of this study was to determine the maximum tolerated dose (MTD) of bortezomib in combination with chemotherapy and radiation