| 1. |
- Micah, Angela E., et al.
(author)
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Tracking development assistance for health and for COVID-19 : a review of development assistance, government, out-of-pocket, and other private spending on health for 204 countries and territories, 1990-2050
- 2021
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In: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 398:10308, s. 1317-1343
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Research review (peer-reviewed)abstract
- Background The rapid spread of COVID-19 renewed the focus on how health systems across the globe are financed, especially during public health emergencies. Development assistance is an important source of health financing in many low-income countries, yet little is known about how much of this funding was disbursed for COVID-19. We aimed to put development assistance for health for COVID-19 in the context of broader trends in global health financing, and to estimate total health spending from 1995 to 2050 and development assistance for COVID-19 in 2020. Methods We estimated domestic health spending and development assistance for health to generate total health-sector spending estimates for 204 countries and territories. We leveraged data from the WHO Global Health Expenditure Database to produce estimates of domestic health spending. To generate estimates for development assistance for health, we relied on project-level disbursement data from the major international development agencies' online databases and annual financial statements and reports for information on income sources. To adjust our estimates for 2020 to include disbursements related to COVID-19, we extracted project data on commitments and disbursements from a broader set of databases (because not all of the data sources used to estimate the historical series extend to 2020), including the UN Office of Humanitarian Assistance Financial Tracking Service and the International Aid Transparency Initiative. We reported all the historic and future spending estimates in inflation-adjusted 2020 US$, 2020 US$ per capita, purchasing-power parity-adjusted US$ per capita, and as a proportion of gross domestic product. We used various models to generate future health spending to 2050. Findings In 2019, health spending globally reached $8. 8 trillion (95% uncertainty interval [UI] 8.7-8.8) or $1132 (1119-1143) per person. Spending on health varied within and across income groups and geographical regions. Of this total, $40.4 billion (0.5%, 95% UI 0.5-0.5) was development assistance for health provided to low-income and middle-income countries, which made up 24.6% (UI 24.0-25.1) of total spending in low-income countries. We estimate that $54.8 billion in development assistance for health was disbursed in 2020. Of this, $13.7 billion was targeted toward the COVID-19 health response. $12.3 billion was newly committed and $1.4 billion was repurposed from existing health projects. $3.1 billion (22.4%) of the funds focused on country-level coordination and $2.4 billion (17.9%) was for supply chain and logistics. Only $714.4 million (7.7%) of COVID-19 development assistance for health went to Latin America, despite this region reporting 34.3% of total recorded COVID-19 deaths in low-income or middle-income countries in 2020. Spending on health is expected to rise to $1519 (1448-1591) per person in 2050, although spending across countries is expected to remain varied. Interpretation Global health spending is expected to continue to grow, but remain unequally distributed between countries. We estimate that development organisations substantially increased the amount of development assistance for health provided in 2020. Continued efforts are needed to raise sufficient resources to mitigate the pandemic for the most vulnerable, and to help curtail the pandemic for all. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.
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| 2. |
- Ademuyiwa, Adesoji O., et al.
(author)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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In: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Journal article (peer-reviewed)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 8. |
- Kocarnik, J. M., et al.
(author)
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Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019 A Systematic Analysis for the Global Burden of Disease Study 2019
- 2022
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In: Jama Oncology. - : American Medical Association (AMA). - 2374-2437 .- 2374-2445. ; 8:3, s. 420-488
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Journal article (peer-reviewed)abstract
- IMPORTANCE The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. OBJECTIVE To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. EVIDENCE REVIEW The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). FINDINGS In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3%(95% UI, 20.3%-32.3%) increase in new cases, a 20.9%(95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4%(1.1%-1.8%) in the low SDI quintile to 5.7%(4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and YDALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. CONCLUSIONS AND RELEVANCE The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.
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| 9. |
- Uddin, Amad, et al.
(author)
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Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity
- 2022
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In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 13
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Journal article (peer-reviewed)abstract
- We employed a comprehensive approach of target-based virtual high-throughput screening to find potential hits from the ZINC database of natural compounds against cysteine proteases falcipain-2 and falcipain-3 (FP2 and FP3). Molecular docking studies showed the initial hits showing high binding affinity and specificity toward FP2 were selected. Furthermore, the enzyme inhibition and surface plasmon resonance assays were performed which resulted in a compound ZINC12900664 (ST72) with potent inhibitory effects on purified FP2. ST72 exhibited strong growth inhibition of chloroquine-sensitive (3D7; EC50 = 2.8 µM) and chloroquine-resistant (RKL-9; EC50 = 6.7 µM) strains of Plasmodium falciparum. Stage-specific inhibition assays revealed a delayed and growth defect during parasite growth and development in parasites treated with ST72. Furthermore, ST72 significantly reduced parasite load and increased host survival in a murine model infected with Plasmodium berghei ANKA. No Evans blue staining in ST72 treatment indicated that ST72 mediated protection of blood–brain barrier integrity in mice infected with P. berghei. ST72 did not show any significant hemolysis or cytotoxicity against human HepG2 cells suggesting a good safety profile. Importantly, ST72 with CQ resulted in improved growth inhibitory activity than individual drugs in both in vitro and in vivo studies.
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| 10. |
- Afzal, Mohammad, 1987-, et al.
(author)
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A formulation of the Jacobian matrixfor 3D numerical friction contact model applied to turbine blade shroud contact
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In: Journal of Sound and Vibration. - 0022-460X .- 1095-8568.
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Journal article (other academic/artistic)abstract
- An analytical expression is formulated to compute the Jacobian matrix for 3D friction contact modelling that eciently evaluates the matrix while computing the friction contact forces in the time domain by means of the alternate frequency time domain approach. The developed expression is successfully used for thecalculation of the friction damping on a turbine blade with shroud contact interface having an arbitrary 3Drelative displacement. The analytical expression drastically reduces the computation time of the Jacobian matrix with respect to the classical finite dierence method, with many points at the contact interface. Therefore,it also significantly reduces the overall computation time for the solution of the equations of motion,since the formulation of the Jacobian matrix is the most time consuming step in solving the large set of nonlinear algebraic equations when a finite dierence approach is employed. The equations of motion are formulated in the frequency domain using the multiharmonic balance method to accurately capture the nonlinear contact forces and displacements. Moreover, the equations of motion of the full turbine blade model are reduced to a single sector model by exploiting the concept of cyclic symmetry boundary condition for aperiodic structure. Implementation of the developed scheme in solving the equations of motion is proved to be effective and significant reduction in time is achieved without loss of accuracy.
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| 11. |
- Afzal, Mohammad, 1987-, et al.
(author)
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Adaptive control of normal load at the friction interface of bladed disks using giant magnetostrictive material
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In: Journal of Vibration and Control. - 1077-5463 .- 1741-2986.
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Journal article (other academic/artistic)abstract
- A novel application of magnetostrictive actuators in underplatform dampers of bladed disks is proposed for adaptive control of the normal load at the friction interface in order to achieve the desired friction damping in the structure. Friction damping in a bladed disk depends on many parameters such as rotational speed, engine excitation order, nodal diameter, contact stiffness, friction coefficient and normal contact load. However, all these parameters have a fixed value at an operating point. On the other hand, the ability to vary some of these parameters such as the normal contact load is desirable in order to obtain an optimum damping in the bladed disk at different operating conditions. Under the influence of an external magnetic field, magnetostrictive materials develop an internal strain that can be exploited to vary the normal contact load at the friction interface, which makes them a potentially good candidate for this application. A commercially available magnetostrictive alloy, Terfenol-D is considered in this analysis that is capable of providing magnetostrain up to 0.002 under prestress and a blocked force over 1500 N. A linearized model of the magnetostrictive material, which is accurate enough for a DC application, is employed to compute the output displacement and the blocked force of the actuator. A nonlinear finite element contact analysis is performed to compute the normal contact load between the blade platform and the underplatform damper as a result of magnetostrictive actuation. The contact analysis is performed for different mounting configurations of the actuator and the obtained results are discussed. The proposed solution is potentially applicable to adaptively control vibratory stresses in bladed disks and consequently to reduce failure due to high-cycle fatigue. Finally, the practical challenges in employing magnetostrictive actuators in underplatform dampers are discussed.
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| 12. |
- Afzal, Mohammad, 1987-, et al.
(author)
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Adaptive control of normal load at the friction interface of bladed disks using giant magnetostrictive material
- 2020
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In: Journal of Intelligent Materials Systems and Structures. - : SAGE Publications. - 1045-389X .- 1530-8138. ; 31:8, s. 1111-1125
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Journal article (peer-reviewed)abstract
- A novel application of magnetostrictive actuators in underplatform dampers of bladed disks is proposed for adaptive control of the normal load at the friction interface to achieve the desired friction damping in the structure. Friction damping in a bladed disk depends on operating parameters, such as rotational speed, engine excitation order, nodal diameter normal contact load, and contact interface parameters, such as contact stiffness and friction coefficient. The operating parameters have a fixed value, whereas the contact interface parameters vary in an unpredictable way at an operating point. However, the ability to vary some of these parameters such as the normal contact load in a controlled manner is desirable to attain an optimum damping in the bladed disk at different operating conditions. Under the influence of an external magnetic field, magnetostrictive materials develop an internal strain that can be exploited to vary the normal contact load at the friction interface, which makes them a potentially good candidate for this application. A commercially available magnetostrictive alloy, Terfenol-D is considered in this analysis that is capable of providing magnetostrain up to 2 × 10-3 under prestress and a blocked force over 1500 N. A linearized model of the magnetostrictive material, which is accurate enough for a direct current application, is employed to compute the output force of the actuator. A nonlinear finite element contact analysis is performed to compute the normal contact load between the blade platform and the underplatform damper as a result of magnetostrictive actuation. The nonlinear contact analysis is performed for different actuator mounting configurations and the obtained results are discussed. The proposed solution is potentially applicable to adaptively control vibratory stresses in bladed disks and consequently to reduce failure due to high-cycle fatigue. Finally, the practical challenges in employing magnetostrictive actuators in underplatform dampers are discussed.
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| 13. |
- Afzal, Mohammad, et al.
(author)
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An analytical calculation of the Jacobian matrix for 3D friction contact model applied to turbine blade shroud contact
- 2016
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In: Computers & structures. - : Elsevier. - 0045-7949 .- 1879-2243. ; 177, s. 204-217
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Journal article (peer-reviewed)abstract
- An analytical expression is formulated to compute the Jacobian matrix for 3D friction contact modeling that efficiently evaluates the matrix while computing the friction contact forces in the time domain by means of the alternate frequency time domain approach. The developed expression is successfully used for the calculation of the friction damping on a turbine blade with shroud contact interface having an arbitrary 3D relative displacement. The analytical expression drastically reduces the computation time of the Jacobian matrix with respect to the classical finite difference method, with many points at the contact interface. Therefore, it also significantly reduces the overall computation time for the solution of the equations of motion, since the formulation of the Jacobian matrix is the most time consuming step in solving the large set of nonlinear algebraic equations when a finite difference approach is employed. The equations of motion are formulated in the frequency domain using the multiharmonic balance method to accurately capture the nonlinear contact forces and displacements. Moreover, the equations of motion of the full turbine blade model are reduced to a single sector model by exploiting the concept of cyclic symmetry boundary condition for a periodic structure. Implementation of the developed scheme in solving the equations of motion is proved to be effective and significant reduction in time is achieved without loss of accuracy.
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| 14. |
- Afzal, Mohammad, 1987-, et al.
(author)
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Numerical analysis of multiple friction contacts in bladed disks
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In: International Journal of Mechanical Sciences. - 0020-7403 .- 1879-2162.
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Journal article (other academic/artistic)abstract
- The damping potential of multiple friction contacts in a bladed disk, tip shroud and strip damper is investigated, showing that friction damping effectiveness can be potentially increased by using multiple friction contact interfaces. Friction damping depends on many parameters such as rotational speed, engine excitation order and mode family and therefore it is not possible to damp all the critical resonances using a single friction contact interface. For example, a strip damper is more effective for the low nodal diameters, where blade/disk coupling is strong. The equations of motion of the bladed disk with multiple friction contacts are derived in the frequency domain for a cyclic structure with rotating excitations and a highly accurate method is used to generate the frequency response function (FRF) matrix. Furthermore, a finite element contact analysis is performed to compute the normal contact load and the contact area of the shroud interface at operating rotational speed. The multiharmonic balance method is employed in combination with the alternate frequency time domain method to find the approximate steady state periodic solution. A low-pressure turbine bladed disk is considered and the effect of the engine excitation level, strip mass, thickness and the accuracy of FRF matrix on the nonlinear response curve are investigated in detail.
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| 15. |
- Afzal, Mohammad, et al.
(author)
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Numerical analysis of multiple friction contacts in bladed disks
- 2018
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In: International Journal of Mechanical Sciences. - : Elsevier. - 0020-7403 .- 1879-2162. ; 137, s. 224-237
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Journal article (peer-reviewed)abstract
- The damping potential of multiple friction contacts in a bladed disk is investigated. Friction contacts at tip shrouds and strip dampers are considered. It is shown that friction damping effectiveness can be potentially increased by using multiple friction contact interfaces. Friction damping depends on many parameters such as rotational speed, engine excitation order and mode family and therefore it is not possible to damp all the critical resonances using a single kind of friction contact interface. For example, a strip damper is more effective for the low nodal diameters, where blade/disk coupling is strong. The equations of motion of the bladed disk with multiple friction contacts are derived in the frequency domain for a cyclic structure with rotating excitations. A highly accurate method is used to generate the frequency response function (FRF) matrix. Furthermore, a finite element contact analysis is performed to compute the normal contact load and the contact area of the shroud interface at operating rotational speed. The multiharmonic balance method is employed in combination with the alternate frequency time domain method to find the steady state periodic solution. A low-pressure turbine bladed disk is considered and the effect of the engine excitation level, strip mass, thickness and the accuracy of FRF matrix on the nonlinear response curve are investigated in detail.
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| 16. |
- Afzal, Mohammad, 1987-
(author)
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Numerical modelling and analysis of friction contact for turbine blades
- 2015
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Licentiate thesis (other academic/artistic)abstract
- High cycle fatigue failure of turbine and compressor blades due to resonance in the operating frequency range is one of the main problems in the design of gas turbine engines. To suppress excessive vibrations in the blades and prevent high cycle fatigue, dry friction dampers are used by the engine manufacturers. However, due to the nonlinear nature of friction contact, analysis of such systems becomes complicated.This work focuses on the numerical modelling of friction contact and a 3D friction contact model is developed. To reduce the computation time in the Newton-iteration steps, a method to compute the Jacobian matrix in parallel to the contact forces is proposed. The developed numerical scheme is successfully applied on turbine blades with shroud contact having an arbitrary 3D relative displacement. The equations of motion are formulated in the frequency domain using the multiharmonic balance method to accurately capture the nonlinear contact forces and displacements. Moreover, the equations of motion of the full turbine blade model are reduced to a single sector model by exploiting the concept of the cyclic symmetry boundary condition for a periodic structure.The developed 3D coupled numerical contact model is compared with a 3D contact model having uncoupled tangential motion and drawback of the uncoupled contact model is discussed. Furthermore, presence of higher harmonics in the nonlinear contact forces is analyzed and their effect on the excitation of the different harmonic indices (nodal diameters) of the bladed disk are systematically presented. Moreover, due to the quasi-analytical computation of the Jacobian matrix, the developed scheme is proved to be effective in solving the equations of motion and significant reduction in time is achieved without loss of accuracy.
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| 17. |
- Afzal, Mohammad, 1987-
(author)
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On efficient and adaptive modelling of friction damping in bladed disks
- 2017
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Doctoral thesis (other academic/artistic)abstract
- This work focuses on efficient modelling and adaptive control of friction damping in bladed disks. To efficiently simulate the friction contact, a full-3D time-discrete contact model is reformulated and an analytical expression for the Jacobian matrix is derived that reduces the computation time drastically with respect to the classical finite difference method. The developed numerical solver is applied on bladed disks with shroud contact and the advantage of full-3D contact model compared to a quasi-3D contact model is presented. The developed numerical solver is also applied on bladed disks with strip damper and multiple friction contacts and obtained results are discussed. Furthermore, presence of higher harmonics in the nonlinear contact forces is analyzed and their effect on the excitation of the different nodal diameters of the bladed disk are systematically presented. The main parameters that influence the effectiveness of friction damping in bladed disks are engine excitation order, contact stiffnesses, friction coefficient, relative motion at the friction interface and the normal contact load. Due to variation in these parameters during operation, the obtained friction damping in practice may differ from the optimum value. Therefore, to control the normal load adaptively that will lead to an optimum damping in the system despite these variations, use of magnetostrictive actuator is proposed. The magnetostrictive material that develops an internal strain under the influence of an external magnetic field is employed to increase and decrease the normal contact load. A linearized model of the magnetostrictive actuator is used to characterize the magnetoelastic behavior of the actuator. A nonlinear static contact analysis of the bladed disk reveals that a change of normal load more than 700 N can be achieved using a reasonable size of the actuator. This will give a very good control on friction damping once applied in practice.
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| 18. |
- Afzal, Zeeshan, 1991-, et al.
(author)
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A Wireless Intrusion Detection System for 802.11 networks
- 2016
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In: PROCEEDINGS OF THE 2016 IEEE INTERNATIONAL CONFERENCE ON WIRELESS COMMUNICATIONS, SIGNAL PROCESSING AND NETWORKING (WISPNET). - : IEEE. - 9781467393386 ; , s. 828-834
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Conference paper (peer-reviewed)abstract
- Wireless local area networks (WLANs) deployment is increasing rapidly. At the same time, WLANs have become an attractive target for many potential attackers. In spite of that, the de facto standard used to implement most WLANs (IEEE 802.11) has what appear to be residual vulnerabilities related to identity spoofing. In this paper, a pragmatic study of two common attacks on the standard is conducted. These attacks are then implemented on test beds to learn attack behavior. Finally, novel attack signatures and techniques to detect these attacks are devised and implemented in a proof of concept Wireless Intrusion Detection System (WIDS).
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| 19. |
- Alvarez, E. M., et al.
(author)
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The global burden of adolescent and young adult cancer in 2019: a systematic analysis for the Global Burden of Disease Study 2019
- 2022
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In: Lancet Oncology. - : Elsevier BV. - 1470-2045. ; 23:1, s. 27-52
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Journal article (peer-reviewed)abstract
- Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.
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| 20. |
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| 21. |
- Aneja, Babita, et al.
(author)
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Design and development of Isatin-triazole hydrazones as potential inhibitors of microtubule affinity-regulating kinase 4 for the therapeutic management of cell proliferation and metastasis
- 2019
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 163, s. 840-852
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Journal article (peer-reviewed)abstract
- Microtubule affinity-regulating kinase 4 (MARK4) is a potential drug target as the same is found to be over expressed in several types of cancers. In search of effective MARK4 inhibitors, we have synthesized and characterized Isatin-triazole hydrazones (9a-i) and evaluated their inhibitory potential. Of all the compounds, 9g showed better binding affinity and enzyme inhibition potential in sub micromolar range. Human serum albumin (HSA) binding assay suggested an easy transportation of 9g in blood stream due to its binding affinity. In vitro anticancer studies performed on MCF-7, MDA-MB-435s and HepG2 cells using 9g showed inhibition of cell proliferation and cell migration. Further, 9g induces apoptosis in these cancerous cells, with IC50 values of 6.22, 9.94 and 8.14 mu M, respectively. Putatively, 9g seems to cause oxidative stress resulting in apoptosis. Functional assay of 9g with a panel of 26 kinases showed MARK4 specific profile. In conclusion, 9g seems to possess an effective inhibitory potential towards MARK4 adding an additional repertoire to anticancer therapeutics.
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| 22. |
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| 23. |
- Bryazka, D., et al.
(author)
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Population-level risks of alcohol consumption by amount, geography, age, sex, and year: a systematic analysis for the Global Burden of Disease Study 2020
- 2022
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In: Lancet. - 0140-6736. ; 400:10347, s. 185-235
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Journal article (peer-reviewed)abstract
- Background The health risks associated with moderate alcohol consumption continue to be debated. Small amounts of alcohol might lower the risk of some health outcomes but increase the risk of others, suggesting that the overall risk depends, in part, on background disease rates, which vary by region, age, sex, and year. Methods For this analysis, we constructed burden-weighted dose-response relative risk curves across 22 health outcomes to estimate the theoretical minimum risk exposure level (TMREL) and non-drinker equivalence (NDE), the consumption level at which the health risk is equivalent to that of a non-drinker, using disease rates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020 for 21 regions, including 204 countries and territories, by 5-year age group, sex, and year for individuals aged 15-95 years and older from 1990 to 2020. Based on the NDE, we quantified the population consuming harmful amounts of alcohol. Findings The burden-weighted relative risk curves for alcohol use varied by region and age. Among individuals aged 15-39 years in 2020, the TMREL varied between 0 (95% uncertainty interval 0-0) and 0.603 (0.400-1.00) standard drinks per day, and the NDE varied between 0.002 (0-0) and 1.75 (0.698-4.30) standard drinks per day. Among individuals aged 40 years and older, the burden-weighted relative risk curve was J-shaped for all regions, with a 2020 TMREL that ranged from 0.114 (0-0.403) to 1.87 (0.500-3.30) standard drinks per day and an NDE that ranged between 0.193 (0-0.900) and 6.94 (3.40-8.30) standard drinks per day. Among individuals consuming harmful amounts of alcohol in 2020, 59.1% (54.3-65.4) were aged 15-39 years and 76.9% (7.0-81.3) were male. Interpretation There is strong evidence to support recommendations on alcohol consumption varying by age and location. Stronger interventions, particularly those tailored towards younger individuals, are needed to reduce the substantial global health loss attributable to alcohol. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.
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| 24. |
- Flannick, Jason, et al.
(author)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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In: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Journal article (peer-reviewed)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 25. |
- Fuchsberger, Christian, et al.
(author)
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The genetic architecture of type 2 diabetes
- 2016
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Journal article (peer-reviewed)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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