55 research outputs found
Learning About Ares I from Monte Carlo Simulation
This paper addresses Monte Carlo simulation analyses that are being conducted to understand the behavior of the Ares I launch vehicle, and to assist with its design. After describing the simulation and modeling of Ares I, the paper addresses the process used to determine what simulations are necessary, and the parameters that are varied in order to understand how the Ares I vehicle will behave in flight. Outputs of these simulations furnish a significant group of design customers with data needed for the development of Ares I and of the Orion spacecraft that will ride atop Ares I. After listing the customers, examples of many of the outputs are described. Products discussed in this paper include those that support structural loads analysis, aerothermal analysis, flight control design, failure/abort analysis, determination of flight performance reserve, examination of orbit insertion accuracy, determination of the Upper Stage impact footprint, analysis of stage separation, analysis of launch probability, analysis of first stage recovery, thrust vector control and reaction control system design, liftoff drift analysis, communications analysis, umbilical release, acoustics, and design of jettison systems
The Bane of the Ancients: A Software Adaptation of the Tabletop Role-Playing Adventure
This project is the adaptation of a tabletop role-playing experience into an interactive computer program, with an emphasis on effective storytelling, world-building, combat, and player choice. The story provided by the customer, āThe Bane of the Ancientsā, was initially designed within the Dungeon Crawl Classics framework. Translation of this design into a digital format required many creative and technical additions to the original concept, including sound and art design, music composition, world building and structuring, and development of interaction mechanics and physics. The digital experience was built on top of the Godot engine for its ease of adoption in regards with the chosen style. The software utilizes a top-down art style to convey storytelling and interactive elements. The development of the software followed an agile development cycle with two-week sprints to allow for flexibility and efficiency while working closely with the customer. The scope of our prototype was limited to the first act of the written story so that sufficient time and resources can be devoted to implementing all requested features
Population-based germline breast cancer gene association studies and meta-analysis to inform wider mainstream testing
Breast cancer; Mainstream genetic testing; Multigene panel testingCĆ”ncer de mama; Pruebas genĆ©ticas convencionales; Prueba de panel multigĆ©nicoCĆ ncer de mama; Proves genĆØtiques convencionals; Prova de panell multigĆØnicBackground
Germline genetic testing, previously restricted to familial and young-onset breast cancer, is now offered increasingly broadly to patients with āpopulation-typeā breast cancer in mainstream oncology clinics, with wide variation in the genes included.
Patients and methods
Weighted meta-analysis was carried out for three population-based caseācontrol studies (BRIDGES, CARRIERS and UK Biobank) comprising in total 101ā397 women with breast cancer and 312ā944 women without breast cancer, to quantify 37 putative breast cancer susceptibility genes (BCSGs) for the frequency of pathogenic variants (PVs) in unselected, āpopulation-typeā breast cancer cases and their association with breast cancer and its subtypes.
Results
Meta-analysed odds ratios (ORs) and frequencies of PVs in āpopulation-typeā breast cancer cases were generated for BRCA1 (OR 8.73, 95% confidence interval (CI) 7.47-10.20; 1 in 101), BRCA2 (OR 5.68, 95% CI 5.13-6.30; 1 in 68) and PALB2 (OR 4.30, 95% CI 3.68-5.03; 1 in 187). For both CHEK2 (OR 2.40, 95% CI 2.21-2.62; 1 in 73) and ATM (OR 2.16, 95% CI 1.93-2.41; 1 in 132) subgroup analysis showed a stronger association with oestrogen receptor-positive disease. The magnitude of association and frequency of PVs were low for RAD51C (OR 1.53, 95% CI 1.29-2.04; 1 in 913), RAD51D (OR 1.76, 95% CI 1.29-2.41; 1 in 1079) and BARD1 (OR 2.34, 95% CI 1.85-2.97; 1 in 672); frequencies and associations were higher when the analysis was restricted to triple-negative breast cancers. The PV frequency in āpopulation-typeā breast cancer cases was very low for āsyndromicā BCSGs TP53 (1 in 1844), STK11 (1 in 11ā525), CDH1 (1 in 2668), PTEN (1 in 3755) and NF1 (1 in 1470), with metrics of association also modest ranging from OR 3.62 (95% CI 1.98-6.61) for TP53 down to OR 1.60 (95% CI 0.48-5.30) for STK11.
Conclusions
These metrics reflecting āpopulation-typeā breast cancer will be informative in defining the appropriate gene set as we continue to expand to germline testing to an increasingly unselected group of breast cancer cases.This work was supported by CG-MAVE, Cancer Research UK Programme Award [grant number EDDPGM-Nov22/100004 to CT funding CFR and SA] and the Canadian Institutes of Health Research [grant number FDN-148390 to WDF]. MT was supported by the NIHR Cambridge Biomedical Research Centre (grant number NIHR203312). HH was supported by the NIHR Exeter Biomedical Research Centre (grant number NIHR203320)
Prostate cancer detection through unbiased capture of methylated cell-free DNA
Funding: Cancer Research UK, CRUK Career Development Fellowship, University of Cambridge W.D. Armstrong Trust Fund, John Black Prostate Cancer Foundation Young Investigator Award. This research was also supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).Prostate cancer screening using prostate-specific antigen (PSA) has been shown to reduce mortality but with substantial overdiagnosis, leading to unnecessary biopsies. The identification of a highly specific biomarker using liquid biopsies, represents an unmet need in the diagnostic pathway for prostate cancer. In this study, we employed a method that enriches for methylated cell-free DNA fragments coupled with a machine learning algorithm which enabled the detection of metastatic and localized cancers with AUCs of 0.96 and 0.74, respectively. The model also detected 51.8% (14/27) of localized and 88.7% (79/89) of patients with metastatic cancer in an external dataset. Furthermore, we show that the differentially methylated regions reflect epigenetic and transcriptomic changes at the tissue level. Notably, these regions are significantly enriched for biologically relevant pathways associated with the regulation of cellular proliferation and TGF-beta signaling. This demonstrates the potential of circulating tumor DNA methylation for prostate cancer detection and prognostication.Peer reviewe
Cryogenic Optical Performance of a Lightweighted Mirror Assembly for Future Space Astronomical Telescopes: Correlating Optical Test Results and Thermal Optical Model
A 43cm diameter stacked core mirror demonstrator was interferometrically tested at room temperature down to 250 degrees Kelvin for thermal deformation. The 2.5m radius of curvature spherical mirror assembly was constructed by low temperature fusing three abrasive waterjet core sections between two CNC pocket milled face sheets. The 93% lightweighted Corning ULE mirror assembly represents the current state of the art for future UV, optical, near IR space telescopes. During the multiple thermal test cycles, test results of interferometric test, thermal IR images of the front face were recorded in order to validate thermal optical model
Identification of Anti-Malarial Compounds as Novel Antagonists to Chemokine Receptor CXCR4 in Pancreatic Cancer Cells
Despite recent advances in targeted therapies, patients with pancreatic adenocarcinoma continue to have poor survival highlighting the urgency to identify novel therapeutic targets. Our previous investigations have implicated chemokine receptor CXCR4 and its selective ligand CXCL12 in the pathogenesis and progression of pancreatic intraepithelial neoplasia and invasive pancreatic cancer; hence, CXCR4 is a promising target for suppression of pancreatic cancer growth. Here, we combined in silico structural modeling of CXCR4 to screen for candidate anti-CXCR4 compounds with in vitro cell line assays and identified NSC56612 from the National Cancer Institute's (NCI) Open Chemical Repository Collection as an inhibitor of activated CXCR4. Next, we identified that NSC56612 is structurally similar to the established anti-malarial drugs chloroquine and hydroxychloroquine. We evaluated these compounds in pancreatic cancer cells in vitro and observed specific antagonism of CXCR4-mediated signaling and cell proliferation. Recent in vivo therapeutic applications of chloroquine in pancreatic cancer mouse models have demonstrated decreased tumor growth and improved survival. Our results thus provide a molecular target and basis for further evaluation of chloroquine and hydroxychloroquine in pancreatic cancer. Historically safe in humans, chloroquine and hydroxychloroquine appear to be promising agents to safely and effectively target CXCR4 in patients with pancreatic cancer
Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990ā2019 : A systematic analysis for the Global Burden of Disease Study 2019
Background
Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages.
Methods
Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (ā„65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0ā100 based on the 2Ā·5th and 97Ā·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion targetā1 billion more people benefiting from UHC by 2023āwe estimated additional population equivalents with UHC effective coverage from 2018 to 2023.
Findings
Globally, performance on the UHC effective coverage index improved from 45Ā·8 (95% uncertainty interval 44Ā·2ā47Ā·5) in 1990 to 60Ā·3 (58Ā·7ā61Ā·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2Ā·6% [1Ā·9ā3Ā·3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010ā2019 relative to 1990ā2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0Ā·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388Ā·9 million (358Ā·6ā421Ā·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3Ā·1 billion (3Ā·0ā3Ā·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968Ā·1 million [903Ā·5ā1040Ā·3]) residing in south Asia.
Interpretation
The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all peopleāthe ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how closeāor how farāall populations are in benefiting from UHC
Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990ā2019: a systematic analysis for the Global Burden of Disease Study 2019
Background
Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages.
Methods
Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (ā„65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0ā100 based on the 2Ā·5th and 97Ā·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion targetā1 billion more people benefiting from UHC by 2023āwe estimated additional population equivalents with UHC effective coverage from 2018 to 2023.
Findings
Globally, performance on the UHC effective coverage index improved from 45Ā·8 (95% uncertainty interval 44Ā·2ā47Ā·5) in 1990 to 60Ā·3 (58Ā·7ā61Ā·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2Ā·6% [1Ā·9ā3Ā·3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010ā2019 relative to 1990ā2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0Ā·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388Ā·9 million (358Ā·6ā421Ā·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3Ā·1 billion (3Ā·0ā3Ā·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968Ā·1 million [903Ā·5ā1040Ā·3]) residing in south Asia.
Interpretation
The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all peopleāthe ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how closeāor how farāall populations are in benefiting from UHC
Burden of disease scenarios for 204 countries and territories, 2022ā2050: a forecasting analysis for the Global Burden of Disease Study 2021
Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2Ā·5th and 97Ā·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60Ā·1% [95% UI 56Ā·8ā63Ā·1] of DALYs were from CMNNs in 2022 compared with 35Ā·8% [31Ā·0ā45Ā·0] in 2050) and south Asia (31Ā·7% [29Ā·2ā34Ā·1] to 15Ā·5% [13Ā·7ā17Ā·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33Ā·8% (27Ā·4ā40Ā·3) to 41Ā·1% (33Ā·9ā48Ā·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20Ā·1% (15Ā·6ā25Ā·3) of DALYs due to YLDs in 2022 to 35Ā·6% (26Ā·5ā43Ā·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15Ā·4% (13Ā·5ā17Ā·5) compared with the reference scenario, with decreases across super-regions ranging from 10Ā·4% (9Ā·7ā11Ā·3) in the high-income super-region to 23Ā·9% (20Ā·7ā27Ā·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5Ā·2% [3Ā·5ā6Ā·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23Ā·2% [20Ā·2ā26Ā·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2Ā·0% [ā0Ā·6 to 3Ā·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions