An Analysis of Missile Systems Cost Growth and Implementation of Acquisition Reform Initiatives Using a Hybrid Adjusted Cost Growth Model

This thesis examined cost growth in Department of Defense (DoD) missile systems from 1991 to 2001 using Selected Acquisition Report (SAR) data with a hybrid adjusted cost growth (ACG) model. In addition, an analysis of acquisition reform initiatives during the treatment period was conducted to determine if reform efforts impacted missile system cost growth. A pre-reform (1 January 1991 to 31 December 1996) period and post reform (1 January 1997 to 31 December 2001) period was subjectively developed to compare the mean annual ACG during each period for statistical differences. The hybrid ACG model outlined in this thesis may aid program managers and other interested parties in determining weapon systems cost growth, and the conclusion drawn from analyzing current acquisition initiatives may assist DoD leadership in assessing reform effectiveness on reducing cost growth. This research effort analyzed 135 SARs for 21 missile systems that reported a Milestone II baseline during the treatment period. Adjusted Cost Growth (ACG) calculations revealed that missile systems from 1 January 1991 to 31 December 2001 averaged 28 percent cost growth annually. The acquisition reform analysis included 76 SARs from 20 programs during the pre-reform period and 59 SARs from 13 programs in the post-reform period. A small sample t-test was used to compare the annual means of the two periods and revealed that at a 0.05 significance level, the annual average ACG for the post-reform period was higher than the annual average ACG of the pre-reform period

Hubble Space Telescope Near-Ultraviolet Spectroscopy of Bright CEMP-s Stars

We present an elemental-abundance analysis, in the near-ultraviolet (NUV) spectral range, for the bright carbon-enhanced metal-poor (CEMP) stars HD196944 (V = 8.40, [Fe/H] = -2.41) and HD201626 (V = 8.16, [Fe/H] = -1.51), based on data acquired with the Space Telescope Imaging Spectrograph (STIS) on the Hubble Space Telescope. Both of these stars belong to the sub-class CEMP-s, and exhibit clear over-abundances of heavy elements associated with production by the slow neutron-capture process. HD196944 has been well-studied in the optical region, but we are able to add abundance results for six species (Ge, Nb, Mo, Lu, Pt, and Au) that are only accessible in the NUV. In addition, we provide the first determination of its orbital period, P=1325 days. HD201626 has only a limited number of abundance results based on previous optical work -- here we add five new species from the NUV, including Pb. We compare these results with models of binary-system evolution and s-process element production in stars on the asymptotic giant branch, aiming to explain their origin and evolution. Our best-fitting models for HD 196944 (M1,i = 0.9Mo, M2,i = 0.86Mo, for [Fe/H]=-2.2), and HD 201626 (M1,i = 0.9Mo , M2,i = 0.76Mo , for [Fe/H]=-2.2; M1,i = 1.6Mo , M2,i = 0.59Mo, for [Fe/H]=-1.5) are consistent with the current accepted scenario for the formation of CEMP-s stars.Comment: 25 pages, 13 figures; accepted for publication in Ap

Quantifying risks and interventions that have affected the burden of lower respiratory infections among children younger than 5 years: an analysis for the Global Burden of Disease Study 2017

Background Despite large reductions in under-5 lower respiratory infection (LRI) mortality in many locations, the pace of progress for LRIs has generally lagged behind that of other childhood infectious diseases. To better inform programmes and policies focused on preventing and treating LRIs, we assessed the contributions and patterns of risk factor attribution, intervention coverage, and sociodemographic development in 195 countries and territories by drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) LRI estimates. Methods We used four strategies to model LRI burden: the mortality due to LRIs was modelled using vital registration data, demographic surveillance data, and verbal autopsy data in a predictive ensemble modelling tool; the incidence of LRIs was modelled using population representative surveys, health-care utilisation data, and scientific literature in a compartmental meta-regression tool; the attribution of risk factors for LRI mortality was modelled in a counterfactual framework; and trends in LRI mortality were analysed applying changes in exposure to risk factors over time. In GBD, infectious disease mortality, including that due to LRI, is among HIV-negative individuals. We categorised locations based on their burden in 1990 to make comparisons in the changing burden between 1990 and 2017 and evaluate the relative percent change in mortality rate, incidence, and risk factor exposure to explain differences in the health loss associated with LRIs among children younger than 5 years. Findings In 2017, LRIs caused 808 920 deaths (95% uncertainty interval 747 286–873 591) in children younger than 5 years. Since 1990, there has been a substantial decrease in the number of deaths (from 2 337 538 to 808 920 deaths; 65·4% decrease, 61·5–68·5) and in mortality rate (from 362·7 deaths [330·1–392·0] per 100 000 children to 118·9 deaths [109·8–128·3] per 100 000 children; 67·2% decrease, 63·5–70·1). LRI incidence declined globally (32·4% decrease, 27·2–37·5). The percent change in under-5 mortality rate and incidence has varied across locations. Among the risk factors assessed in this study, those responsible for the greatest decrease in under-5 LRI mortality between 1990 and 2017 were increased coverage of vaccination against Haemophilus influenza type b (11·4% decrease, 0·0–24·5), increased pneumococcal vaccine coverage (6·3% decrease, 6·1–6·3), and reductions in household air pollution (8·4%, 6·8–9·2). Interpretation Our findings show that there have been substantial but uneven declines in LRI mortality among countries between 1990 and 2017. Although improvements in indicators of sociodemographic development could explain some of these trends, changes in exposure to modifiable risk factors are related to the rates of decline in LRI mortality. No single intervention would universally accelerate reductions in health loss associated with LRIs in all settings, but emphasising the most dominant risk factors, particularly in countries with high case fatality, can contribute to the reduction of preventable deaths

Approximation Techniques for Stochastic Analysis of Biological Systems

There has been an increasing demand for formal methods in the design process of safety-critical synthetic genetic circuits. Probabilistic model checking techniques have demonstrated significant potential in analyzing the intrinsic probabilistic behaviors of complex genetic circuit designs. However, its inability to scale limits its applicability in practice. This chapter addresses the scalability problem by presenting a state-space approximation method to remove unlikely states resulting in a reduced, finite state representation of the infinite-state continuous-time Markov chain that is amenable to probabilistic model checking. The proposed method is evaluated on a design of a genetic toggle switch. Comparisons with another state-of-art tool demonstrates both accuracy and efficiency of the presented method

Quantifying risks and interventions that have affected the burden of lower respiratory infections among children younger than 5 years: an analysis for the Global Burden of Disease Study 2017

Background: Despite large reductions in under-5 lower respiratory infection (LRI) mortality in many locations, the pace of progress for LRIs has generally lagged behind that of other childhood infectious diseases. To better inform programmes and policies focused on preventing and treating LRIs, we assessed the contributions and patterns of risk factor attribution, intervention coverage, and sociodemographic development in 195 countries and territories by drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) LRI estimates.Research reported in this publication was supported by the Bill & Melinda Gates Foundation. AA acknowledges support by the Department of Science and Technology, Government of India (New Delhi, India) through the INSPIRE Faculty program. SA acknowledges the International Centre for Casemix and Clinical Coding, the Faculty of Medicine, National University of Malaysia, and the Department of Health Policy and Management, Faculty of Public Health, Kuwait University for the approval and support to participate in this research project. ABad acknowledges support from the Public Health Agency of Canada. ABar acknowledges support for research from the Project of Ministry of Education, Science and Technology of the Republic of Serbia (number III45005). FC acknowledges funding support from Foundation for Science and Technology/Minister of Science, Technology, and Higher Education through national funds (UID/MULTI/04378/2019 and UID/QUI/50006/2019). AJC acknowledges support by the Health Effects Institute, Boston, MA, USA. MMSM acknowledges the support from the Ministry of Education, Science and Technological Development, Republic of Serbia (Contract number 175087). AMS was supported by the Egyptian Fulbright Mission Program (EFMP). RS-S acknowledges support from Applied and Environmental Sciences University (Bogota, Colombia). AS acknowledges support from Health Data Research UK

Quantifying risks and interventions that have affected the burden of diarrhoea among children younger than 5 years: an analysis of the Global Burden of Disease Study 2017

Background Many countries have shown marked declines in diarrhoeal disease mortality among children younger than 5 years. With this analysis, we provide updated results on diarrhoeal disease mortality among children younger than 5 years from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) and use the study’s comparative risk assessment to quantify trends and effects of risk factors, interventions, and broader sociodemographic development on mortality changes in 195 countries and territories from 1990 to 2017. Methods This analysis for GBD 2017 had three main components. Diarrhoea mortality was modelled using vital registration data, demographic surveillance data, and verbal autopsy data in a predictive, Bayesian, ensemble modelling tool; and the attribution of risk factors and interventions for diarrhoea were modelled in a counterfactual framework that combines modelled population-level prevalence of the exposure to each risk or intervention with the relative risk of diarrhoea given exposure to that factor. We assessed the relative and absolute change in diarrhoea mortality rate between 1990 and 2017, and used the change in risk factor exposure and sociodemographic status to explain differences in the trends of diarrhoea mortality among children younger than 5 years. Findings Diarrhoea was responsible for an estimated 533 768 deaths (95% uncertainty interval 477 162–593145) among children younger than 5 years globally in 2017, a rate of 78·4 deaths (70·1–87·1) per 100000 children. The diarrhoea mortality rate ranged between countries by over 685 deaths per 100000 children. Diarrhoea mortality per 100000 globally decreased by 69·6% (63·1–74·6) between 1990 and 2017. Among the risk factors considered in this study, those responsible for the largest declines in the diarrhoea mortality rate were reduction in exposure to unsafe sanitation (13·3% decrease, 11·2–15·5), childhood wasting (9·9% decrease, 9·6–10·2), and low use of oral rehydration solution (6·9% decrease, 4·8–8·4). Interpretation Diarrhoea mortality has declined substantially since 1990, although there are variations by country. Improvements in sociodemographic indicators might explain some of these trends, but changes in exposure to risk factors—particularly unsafe sanitation, childhood growth failure, and low use of oral rehydration solution—appear to be related to the relative and absolute rates of decline in diarrhoea mortality. Although the most effective interventions might vary by country or region, identifying and scaling up the interventions aimed at preventing and protecting against diarrhoea that have already reduced diarrhoea mortality could further avert many thousands of deaths due to this illness.SMA acknowledges the International Centre for Casemix and Clinical Coding, Faculty of Medicine, National University of Malaysia and Department of Health Policy and Management, Faculty of Public Health, Kuwait University for their approval and support to participate in this research project. AsA acknowledges funding support from the Department of Science and Technology, Government of India through the INSPIRE faculty scheme. AlaB acknowledges support from the Public Health Agency of Canada. AleB acknowledges support for research from the Project of Ministry of Education, Science and Technology of the Republic of Serbia (number III45005). FC acknowledges funding support from Foundation for Science and Technology/Minister of Science, Technology, and Higher Education through national funds (UID/MULTI/04378/2019 and UID/ QUI/50006/2019). AMS was supported by the Egyptian Fulbright Mission Program. MMSM acknowledges the support from the Ministry of Education, Science and Technological Development, Republic of Serbia (Contract No. 175087). AS acknowledges support from Health Data Research UK

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis.

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium

ABSTRACT Background Advanced-stage mycosis fungoides (MF)/Sezary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. Patients and methods This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). Results Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. Conclusion This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach

IFN-λ3, not IFN-λ4, likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis

Genetic variation in the IFNL3-IFNL4 (interferon-λ3-interferon-λ4) region is associated with hepatic inflammation and fibrosis. Whether IFN-λ3 or IFN-λ4 protein drives this association is not known. We demonstrate that hepatic inflammation, fibrosis stage, fibrosis progression rate, hepatic infiltration of immune cells, IFN-λ3 expression, and serum sCD163 levels (a marker of activated macrophages) are greater in individuals with the IFNL3-IFNL4 risk haplotype that does not produce IFN-λ4, but produces IFN-λ3. No difference in these features was observed according to genotype at rs117648444, which encodes a substitution at position 70 of the IFN-λ4 protein and reduces IFN-λ4 activity, or between patients encoding functionally defective IFN-λ4 (IFN-λ4-Ser70) and those encoding fully active IFN-λ4-Pro70. The two proposed functional variants (rs368234815 and rs4803217) were not superior to the discovery SNP rs12979860 with respect to liver inflammation or fibrosis phenotype. IFN-λ3 rather than IFN-λ4 likely mediates IFNL3-IFNL4 haplotype-dependent hepatic inflammation and fibrosis