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  • Khattab, Ayman; Jylha, Kaisa; Hakala, Tomi; Aalto, Mikko; Malima, Robert; Kisinza, William; Honkala, Markku; Nousiainen, Pertti; Meri, Seppo (2017)
    Background: Mosquitoes are vectors for many diseases such as malaria. Insecticide-treated bed nets and indoor residual spraying of insecticides are the principal malaria vector control tools used to prevent malaria in the tropics. Other interventions aim at reducing man-vector contact. For example, house screening provides additive or synergistic effects to other implemented measures. We used commercial screen materials made of polyester, polyethylene or polypropylene to design novel mosquito screens that provide remarkable additional benefits to those commonly used in house screening. The novel design is based on a double screen setup made of a screen with 3D geometric structures parallel to a commercial mosquito screen creating a trap between the two screens. Owing to the design of the 3D screen, mosquitoes can penetrate the 3D screen from one side but cannot return through the other side, making it a unidirectional mosquito screen. Therefore, the mosquitoes are trapped inside the double screen system. The permissiveness of both sides of the 3D screens for mosquitoes to pass through was tested in a wind tunnel using the insectary strain of Anopheles stephensi. Results: Among twenty- five tested 3D screen designs, three designs from the cone, prism, or cylinder design groups were the most efficient in acting as unidirectional mosquito screens. The three cone-,prism-, and cylinder-based screens allowed, on average, 92, 75 and 64% of Anopheles stephensi mosquitoes released into the wind tunnel to penetrate the permissive side and 0, 0 and 6% of mosquitoes to escape through the non-permissive side, respectively. Conclusions: A cone- based 3D screen fulfilled the study objective. It allowed capturing 92% of mosquitoes within the double screen setup inside the wind tunnel and blocked 100% from escaping. Thus, the cone- based screen effectively acted as a unidirectional mosquito screen. This 3D screen-based trap design could therefore be used in house screening as a means of avoiding infective bites and reducing mosquito population size.
  • Vidilaseris, Keni; Kiriazis, Alexandros; Turku, Ainoleena; Khattab, Ayman Abdelnaby Shaaban; Johansson, Niklas G; Leino, Teppo Olavi; Kiuru, Paula Sinikka; Boije af Gennäs, Per Gustav; Meri, Seppo Kalevi; Yli-Kauhaluoma, Jari Tapani; Xhaard, Henri Guillaume Michel; Goldman, Adrian (2019)
    Membrane-bound pyrophosphatases are homodimeric integral membrane proteins that hydrolyze pyrophosphate into orthophosphates, coupled to the active transport of protons or sodium ions across membranes. They are important in the life cycle of bacteria, archaea, plants, and parasitic protists, but no homologous proteins exist in vertebrates, making them a promising drug target. Here, we report the first nonphosphorus allosteric inhibitor of the thermophilic bacterium Thermotoga maritima membrane-bound pyrophosphatase and its bound structure together with the substrate analog imidodiphosphate. The unit cell contains two protein homodimers, each binding a single inhibitor dimer near the exit channel, creating a hydrophobic clamp that inhibits the movement of beta-strand 1-2 during pumping, and thus prevents the hydrophobic gate from opening. This asymmetry of inhibitor binding with respect to each homodimer provides the first clear structural demonstration of asymmetry in the catalytic cycle of membrane-bound pyrophosphatases.
  • Kiyuka, Patience Kerubo; Meri, Seppo; Khattab, Ayman (2020)
    The malaria parasite has for long been thought to escape host complement attack as a survival strategy. However, it was only recently that complement evasion mechanisms of the parasite were described. Simultaneously, the role of complement in antibody-mediated naturally acquired and vaccine-induced protection against malaria has also been reported. Such findings should be considered in future vaccine design, given the current need to develop more efficacious vaccines against malaria. Parasite antigens derived from molecules mediating functions crucial for parasite survival, such as complement evasion, or parasite antigens against which antibody responses lead to an efficient complement attack could present new candidates for vaccines. In this review, we discuss recent findings on complement evasion by the malaria parasites and the emerging role of complement in antibody-mediated protection against malaria. We emphasize that immune responses to vaccines based on complement inhibitors should not only induce complement-activating antibodies but also neutralize the escape mechanisms of the parasite.
  • Dieleman, Joseph; Campbell, Madeline; Chapin, Abigail; Eldrenkamp, Erika; Fan, Victoria Y.; Haakenstad, Annie; Kates, Jennifer; Liu, Yingying; Matyasz, Taylor; Micah, Angela; Reynolds, Alex; Sadat, Nafis; Schneider, Matthew T.; Sorensen, Reed; Evans, Tim; Evans, David; Kurowski, Christoph; Tandon, Ajay; Abbas, Kaja M.; Abera, Semaw Ferede; Kiadaliri, Aliasghar Ahmad; Ahmed, Kedir Yimam; Ahmed, Muktar Beshir; Alam, Khurshid; Alizadeh-Navaei, Reza; Alkerwi, Ala'a; Amini, Erfan; Ammar, Walid; Amrock, Stephen Marc; Antonio, Carl Abelardo T.; Atey, Tesfay Mehari; Avila-Burgos, Leticia; Awasthi, Ashish; Barac, Aleksandra; Alberto Bernal, Oscar; Beyene, Addisu Shunu; Beyene, Tariku Jibat; Birungi, Charles; Bizuayehu, Habtamu Mellie; Breitborde, Nicholas J. K.; Cahuana-Hurtado, Lucero; Estanislao Castro, Ruben; Catalia-Lopez, Ferran; Dalal, Koustuv; Dandona, Lalit; Dandona, Rakhi; de Jager, Pieter; Dharmaratne, Samath D.; Dubey, Manisha; Meretoja, Atte; Global Burden Dis Hlth Financing (2017)
    Background An adequate amount of prepaid resources for health is important to ensure access to health services and for the pursuit of universal health coverage. Previous studies on global health financing have described the relationship between economic development and health financing. In this study, we further explore global health financing trends and examine how the sources of funds used, types of services purchased, and development assistance for health disbursed change with economic development. We also identify countries that deviate from the trends. Methods We estimated national health spending by type of care and by source, including development assistance for health, based on a diverse set of data including programme reports, budget data, national estimates, and 964 National Health Accounts. These data represent health spending for 184 countries from 1995 through 2014. We converted these data into a common inflation-adjusted and purchasing power-adjusted currency, and used non-linear regression methods to model the relationship between health financing, time, and economic development. Findings Between 1995 and 2014, economic development was positively associated with total health spending and a shift away from a reliance on development assistance and out-of-pocket (OOP) towards government spending. The largest absolute increase in spending was in high-income countries, which increased to purchasing power-adjusted $5221 per capita based on an annual growth rate of 3.0%. The largest health spending growth rates were in upper-middle-income (5.9) and lower-middle-income groups (5.0), which both increased spending at more than 5% per year, and spent $914 and $267 per capita in 2014, respectively. Spending in low-income countries grew nearly as fast, at 4.6%, and health spending increased from $51 to $120 per capita. In 2014, 59.2% of all health spending was financed by the government, although in low-income and lower-middle-income countries, 29.1% and 58.0% of spending was OOP spending and 35.7% and 3.0% of spending was development assistance. Recent growth in development assistance for health has been tepid; between 2010 and 2016, it grew annually at 1.8%, and reached US$37.6 billion in 2016. Nonetheless, there is a great deal of variation revolving around these averages. 29 countries spend at least 50% more than expected per capita, based on their level of economic development alone, whereas 11 countries spend less than 50% their expected amount. Interpretation Health spending remains disparate, with low-income and lower-middle-income countries increasing spending in absolute terms the least, and relying heavily on OOP spending and development assistance. Moreover, tremendous variation shows that neither time nor economic development guarantee adequate prepaid health resources, which are vital for the pursuit of universal health coverage.
  • Johansson, Niklas G; Dreano, Loic; Vidilaseris, Keni; Khattab, Ayman; Liu, Jianing; Lasbleiz, Arthur; de Castro Ribeiro, Orquidea Marilia; Kiriazis, Alexandros; Boije af Gennäs, Gustav; Meri, Seppo; Goldman, Adrian; Yli-Kauhaluoma, Jari; Xhaard, Henri (2021)
    Inhibition of membrane-bound pyrophosphatase (mPPase) with small molecules offer a new approach in the fight against pathogenic protozoan parasites. mPPases are absent in humans, but essential for many protists as they couple pyrophosphate hydrolysis to the active transport of protons or sodium ions across acidocalcisomal membranes. So far, only few nonphosphorus inhibitors have been reported. Here, we explore the chemical space around previous hits using a combination of screening and synthetic medicinal chemistry, identifying compounds with low micromolar inhibitory activities in the Thermotoga maritima mPPase test system. We furthermore provide early structure-activity relationships around a new scaffold having a pyrazolo[1,5-a]pyrimidine core. The most promising pyrazolo[1,5-a]pyrimidine congener was further investigated and found to inhibit Plasmodium falciparum mPPase in membranes as well as the growth of P. falciparum in an ex vivo survival assay.
  • Cuadros, Juan; Perez-Tanoira, Ramon; Prieto-Perez, Laura; Martin-Martin, Ines; Berzosa, Pedro; Gonzalez, Vicenta; Tisiano, Gebre; Balcha, Seble; Manuel Ramos, Jose; Gorgolas, Miguel (2015)
    Background In up to one third of the hospitals in some rural areas of Africa, laboratory services in malaria diagnosis are limited to microscopy by thin film, as no capability to perform thick film exists (gold standard in terms of sensitivity for malaria diagnosis). A new rapid molecular malaria diagnostic test called Loop-mediated isothermal DNA amplification (LAMP) has been recently validated in clinical trials showing exceptional sensitivity and specificity features. It could be a reliable diagnostic tool to be implemented without special equipment or training. Objective The objective of this proof of concept study was to confirm the feasibility of using LAMP technique for diagnosis of malaria in a rural Ethiopian hospital with limited resources. Methodology/Principal Findings This study was carried out in Gambo General Hospital, West Arsi Province (Ethiopia), from November 1st to December 31st 2013. A total of 162 patients with a non-focal febrile syndrome were investigated. The diagnostic capability (sensitivity, specificity, positive predictive and negative predictive values) of rapid malaria tests and microscopy by thin film was evaluated in comparison with LAMP. Eleven (6.79%) out of the 162 patients with fever and suspected malaria, tested positive for LAMP, 3 (1.85%) for rapid malaria tests and none of the eleven cases was detected by thin film microscopy. Conclusions/Significance LAMP can be performed in basic rural laboratories without the need for specialized infrastructure and it may set a reliable tool for malaria control to detect a low level parasitemia.
  • Choi, Jaeyoung; Kim, Ki-Tae; Jeon, Jongbum; Wu, Jiayao; Song, Hyeunjeong; Asiegbu, Fred O.; Lee, Yong-Hwan (2014)
  • Naghavi, Mohsen; Abajobir, Amanuel Alemu; Abbafati, Cristiana; Abbas, Kaja M.; Abd-Allah, Foad; Abera, Semaw Ferede; Aboyans, Victor; Adetokunboh, Olatunji; Arnlov, Johan; Afshin, Ashkan; Agrawal, Anurag; Kiadaliri, Aliasghar Ahmad; Ahmadi, Alireza; Ahmed, Muktar Beshir; Aichour, Amani Nidhal; Aichour, Ibtihel; Aichour, Miloud Taki Eddine; Aiyar, Sneha; Al-Eyadhy, Ayman; Alahdab, Fares; Al-Aly, Ziyad; Alam, Khurshid; Alam, Noore; Alam, Tahiya; Alene, Kefyalew Addis; Ali, Syed Danish; Alizadeh-Navaei, Reza; Alkaabi, Juma M.; Alkerwi, Ala'a; Alla, Francois; Allebeck, Peter; Allen, Christine; Al-Raddadi, Rajaa; Alsharif, Ubai; Altirkawi, Khalid A.; Alvis-Guzman, Nelson; Amare, Azmeraw T.; Amini, Erfan; Ammar, Walid; Amoako, Yaw Ampem; Anber, Nahla; Andersen, Hjalte H.; Andrei, Catalina Liliana; Androudi, Sofia; Ansari, Hossein; Kivimaki, Mika; Lallukka, Tea; Meretoja, Atte; Meretoja, Tuomo J.; Weiderpass, Elisabete; GBD 2016 Causes Death Collaborato (2017)
    Background Monitoring levels and trends in premature mortality is crucial to understanding how societies can address prominent sources of early death. The Global Burden of Disease 2016 Study (GBD 2016) provides a comprehensive assessment of cause-specific mortality for 264 causes in 195 locations from 1980 to 2016. This assessment includes evaluation of the expected epidemiological transition with changes in development and where local patterns deviate from these trends. Methods We estimated cause-specific deaths and years of life lost (YLLs) by age, sex, geography, and year. YLLs were calculated from the sum of each death multiplied by the standard life expectancy at each age. We used the GBD cause of death database composed of: vital registration (VR) data corrected for under-registration and garbage coding; national and subnational verbal autopsy (VA) studies corrected for garbage coding; and other sources including surveys and surveillance systems for specific causes such as maternal mortality. To facilitate assessment of quality, we reported on the fraction of deaths assigned to GBD Level 1 or Level 2 causes that cannot be underlying causes of death (major garbage codes) by location and year. Based on completeness, garbage coding, cause list detail, and time periods covered, we provided an overall data quality rating for each location with scores ranging from 0 stars (worst) to 5 stars (best). We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to generate estimates for each location, year, age, and sex. We assessed observed and expected levels and trends of cause-specific deaths in relation to the Socio-demographic Index (SDI), a summary indicator derived from measures of average income per capita, educational attainment, and total fertility, with locations grouped into quintiles by SDI. Relative to GBD 2015, we expanded the GBD cause hierarchy by 18 causes of death for GBD 2016. Findings The quality of available data varied by location. Data quality in 25 countries rated in the highest category (5 stars), while 48, 30, 21, and 44 countries were rated at each of the succeeding data quality levels. Vital registration or verbal autopsy data were not available in 27 countries, resulting in the assignment of a zero value for data quality. Deaths from non-communicable diseases (NCDs) represented 72.3% (95% uncertainty interval [UI] 71.2-73.2) of deaths in 2016 with 19.3% (18.5-20.4) of deaths in that year occurring from communicable, maternal, neonatal, and nutritional (CMNN) diseases and a further 8.43% (8.00-8.67) from injuries. Although age-standardised rates of death from NCDs decreased globally between 2006 and 2016, total numbers of these deaths increased; both numbers and age-standardised rates of death from CMNN causes decreased in the decade 2006-16-age-standardised rates of deaths from injuries decreased but total numbers varied little. In 2016, the three leading global causes of death in children under-5 were lower respiratory infections, neonatal preterm birth complications, and neonatal encephalopathy due to birth asphyxia and trauma, combined resulting in 1.80 million deaths (95% UI 1.59 million to 1.89 million). Between 1990 and 2016, a profound shift toward deaths at older ages occurred with a 178% (95% UI 176-181) increase in deaths in ages 90-94 years and a 210% (208-212) increase in deaths older than age 95 years. The ten leading causes by rates of age-standardised YLL significantly decreased from 2006 to 2016 (median annualised rate of change was a decrease of 2.89%); the median annualised rate of change for all other causes was lower (a decrease of 1.59%) during the same interval. Globally, the five leading causes of total YLLs in 2016 were cardiovascular diseases; diarrhoea, lower respiratory infections, and other common infectious diseases; neoplasms; neonatal disorders; and HIV/AIDS and tuberculosis. At a finer level of disaggregation within cause groupings, the ten leading causes of total YLLs in 2016 were ischaemic heart disease, cerebrovascular disease, lower respiratory infections, diarrhoeal diseases, road injuries, malaria, neonatal preterm birth complications, HIV/AIDS, chronic obstructive pulmonary disease, and neonatal encephalopathy due to birth asphyxia and trauma. Ischaemic heart disease was the leading cause of total YLLs in 113 countries for men and 97 countries for women. Comparisons of observed levels of YLLs by countries, relative to the level of YLLs expected on the basis of SDI alone, highlighted distinct regional patterns including the greater than expected level of YLLs from malaria and from HIV/AIDS across sub-Saharan Africa; diabetes mellitus, especially in Oceania; interpersonal violence, notably within Latin America and the Caribbean; and cardiomyopathy and myocarditis, particularly in eastern and central Europe. The level of YLLs from ischaemic heart disease was less than expected in 117 of 195 locations. Other leading causes of YLLs for which YLLs were notably lower than expected included neonatal preterm birth complications in many locations in both south Asia and southeast Asia, and cerebrovascular disease in western Europe. Interpretation The past 37 years have featured declining rates of communicable, maternal, neonatal, and nutritional diseases across all quintiles of SDI, with faster than expected gains for many locations relative to their SDI. A global shift towards deaths at older ages suggests success in reducing many causes of early death. YLLs have increased globally for causes such as diabetes mellitus or some neoplasms, and in some locations for causes such as drug use disorders, and conflict and terrorism. Increasing levels of YLLs might reflect outcomes from conditions that required high levels of care but for which effective treatments remain elusive, potentially increasing costs to health systems. Copyright (C) The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
  • Hay, Simon I.; Abajobir, Amanuel Alemu; Abate, Kalkidan Hassen; Abbafati, Cristiana; Abbas, Kaja M.; Abd-Allah, Foad; Abdulle, Abdishakur M.; Abebo, Teshome Abuka; Abera, Semaw Ferede; Aboyans, Victor; Abu-Raddad, Laith J.; Ackerman, Ilana N.; Adedeji, Isaac A.; Adetokunboh, Olatunji; Afshin, Ashkan; Aggarwal, Rakesh; Agrawal, Sutapa; Agrawal, Anurag; Kiadaliri, Aliasghar Ahmad; Ahmed, Muktar Beshir; Aichour, Amani Nidhal; Aichour, Ibtihel; Aichour, Miloud Taki Eddine; Aiyar, Sneha; Akinyemiju, Tomi F.; Akseer, Nadia; Al Lami, Faris Hasan; Alahdab, Fares; Al-Aly, Ziyad; Alam, Khurshid; Alam, Noore; Alam, Tahiya; Alasfoor, Deena; Alene, Kefyalew Addis; Ali, Raghib; Alizadeh-Navaei, Reza; Alkaabi, Juma M.; Alkerwi, Ala'a; Alla, Francois; Allebeck, Peter; Allen, Christine; Al-Maskari, Fatma; AlMazroa, Mohammad AbdulAziz; Al-Raddadi, Rajaa; Alsharif, Ubai; Kivimaki, Mika; Lallukka, Tea; Meretoja, Atte; Meretoja, Tuomo J.; Weiderpass, Elisabete; GBD 2016 DALYs HALE Collaborators (2017)
    Background Measurement of changes in health across locations is useful to compare and contrast changing epidemiological patterns against health system performance and identify specific needs for resource allocation in research, policy development, and programme decision making. Using the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we drew from two widely used summary measures to monitor such changes in population health: disability-adjusted life-years (DALYs) and healthy life expectancy (HALE). We used these measures to track trends and benchmark progress compared with expected trends on the basis of the Socio-demographic Index (SDI). Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2016. We calculated DALYs by summing years of life lost and years of life lived with disability for each location, age group, sex, and year. We estimated HALE using age-specific death rates and years of life lived with disability per capita. We explored how DALYs and HALE differed from expected trends when compared with the SDI: the geometric mean of income per person, educational attainment in the population older than age 15 years, and total fertility rate. Findings The highest globally observed HALE at birth for both women and men was in Singapore, at 75.2 years (95% uncertainty interval 71.9-78.6) for females and 72.0 years (68.8-75.1) for males. The lowest for females was in the Central African Republic (45.6 years [42.0-49.5]) and for males was in Lesotho (41.5 years [39.0-44.0]). From 1990 to 2016, global HALE increased by an average of 6.24 years (5.97-6.48) for both sexes combined. Global HALE increased by 6.04 years (5.74-6.27) for males and 6.49 years (6.08-6.77) for females, whereas HALE at age 65 years increased by 1.78 years (1.61-1.93) for males and 1.96 years (1.69-2.13) for females. Total global DALYs remained largely unchanged from 1990 to 2016 (-2.3% [-5.9 to 0.9]), with decreases in communicable, maternal, neonatal, and nutritional (CMNN) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). The exemplars, calculated as the five lowest ratios of observed to expected age-standardised DALY rates in 2016, were Nicaragua, Costa Rica, the Maldives, Peru, and Israel. The leading three causes of DALYs globally were ischaemic heart disease, cerebrovascular disease, and lower respiratory infections, comprising 16.1% of all DALYs. Total DALYs and age-standardised DALY rates due to most CMNN causes decreased from 1990 to 2016. Conversely, the total DALY burden rose for most NCDs; however, age-standardised DALY rates due to NCDs declined globally. Interpretation At a global level, DALYs and HALE continue to show improvements. At the same time, we observe that many populations are facing growing functional health loss. Rising SDI was associated with increases in cumulative years of life lived with disability and decreases in CMNN DALYs offset by increased NCD DALYs. Relative compression of morbidity highlights the importance of continued health interventions, which has changed in most locations in pace with the gross domestic product per person, education, and family planning. The analysis of DALYs and HALE and their relationship to SDI represents a robust framework with which to benchmark location-specific health performance. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform health policies, health system improvement initiatives, targeted prevention efforts, and development assistance for health, including financial and research investments for all countries, regardless of their level of sociodemographic development. The presence of countries that substantially outperform others suggests the need for increased scrutiny for proven examples of best practices, which can help to extend gains, whereas the presence of underperforming countries suggests the need for devotion of extra attention to health systems that need more robust support. Copyright (C) The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
  • Vos, Theo; Allen, Christine; Arora, Megha; Barber, Ryan M.; Bhutta, Zulfiqar A.; Brown, Alexandria; Carter, Austin; Casey, Daniel C.; Charlson, Fiona J.; Chen, Alan Z.; Coggeshall, Megan; Cornaby, Leslie; Dandona, Lalit; Dicker, Daniel J.; Dilegge, Tina; Erskine, Holly E.; Ferrari, Alize J.; Fitzmaurice, Christina; Fleming, Tom; Forouzanfar, Mohammad H.; Fullman, Nancy; Gething, Peter W.; Goldberg, Ellen M.; Graetz, Nicholas; Haagsma, Juanita A.; Johnson, Catherine O.; Kassebaum, Nicholas J.; Kawashima, Toana; Kemmer, Laura; Khalil, Ibrahim A.; Kinfu, Yohannes; Kyu, Hmwe H.; Leung, Janni; Liang, Xiaofeng; Lim, Stephen S.; Lopez, Alan D.; Lozano, Rafael; Marczak, Laurie; Mensah, George A.; Mokdad, Ali H.; Naghavi, Mohsen; Nguyen, Grant; Nsoesie, Elaine; Olsen, Helen; Pigott, David M.; Pinho, Christine; Lallukka, Tea; Meretoja, Atte; Meretoja, Tuomo J.; Weiderpass, Elisabete; GBD 2015 Dis Injury Incidence (2016)
    Background Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015. Methods We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60 900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index [SDI]) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores. Findings We generated 9.3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year. In 2015, two causes had acute incidences in excess of 1 billion: upper respiratory infections (17.2 billion, 95% uncertainty interval [UI] 15.4-19.2 billion) and diarrhoeal diseases (2.39 billion, 2.30-2.50 billion). Eight causes of chronic disease and injury each affected more than 10% of the world's population in 2015: permanent caries, tension-type headache, iron-deficiency anaemia, age-related and other hearing loss, migraine, genital herpes, refraction and accommodation disorders, and ascariasis. The impairment that affected the greatest number of people in 2015 was anaemia, with 2.36 billion (2.35-2.37 billion) individuals affected. The second and third leading impairments by number of individuals affected were hearing loss and vision loss, respectively. Between 2005 and 2015, there was little change in the leading causes of years lived with disability (YLDs) on a global basis. NCDs accounted for 18 of the leading 20 causes of age-standardised YLDs on a global scale. Where rates were decreasing, the rate of decrease for YLDs was slower than that of years of life lost (YLLs) for nearly every cause included in our analysis. For low SDI geographies, Group 1 causes typically accounted for 20-30% of total disability, largely attributable to nutritional deficiencies, malaria, neglected tropical diseases, HIV/AIDS, and tuberculosis. Lower back and neck pain was the leading global cause of disability in 2015 in most countries. The leading cause was sense organ disorders in 22 countries in Asia and Africa and one in central Latin America; diabetes in four countries in Oceania; HIV/AIDS in three southern sub-Saharan African countries; collective violence and legal intervention in two north African and Middle Eastern countries; iron-deficiency anaemia in Somalia and Venezuela; depression in Uganda; onchoceriasis in Liberia; and other neglected tropical diseases in the Democratic Republic of the Congo. Interpretation Ageing of the world's population is increasing the number of people living with sequelae of diseases and injuries. Shifts in the epidemiological profile driven by socioeconomic change also contribute to the continued increase in years lived with disability (YLDs) as well as the rate of increase in YLDs. Despite limitations imposed by gaps in data availability and the variable quality of the data available, the standardised and comprehensive approach of the GBD study provides opportunities to examine broad trends, compare those trends between countries or subnational geographies, benchmark against locations at similar stages of development, and gauge the strength or weakness of the estimates available. Copyright (C) The Author(s). Published by Elsevier Ltd.
  • Malaria Genomic Epidemiology Net; Band, Gavin; Le, Quang Si; Clarke, Geraldine M.; Kivinen, Katja; Spencer, Chris C. A. (2019)
    The human genetic factors that affect resistance to infectious disease are poorly understood. Here we report a genome-wide association study in 17,000 severe malaria cases and population controls from 11 countries, informed by sequencing of family trios and by direct typing of candidate loci in an additional 15,000 samples. We identify five replicable associations with genome-wide levels of evidence including a newly implicated variant on chromosome 6. Jointly, these variants account for around one-tenth of the heritability of severe malaria, which we estimate as -23% using genome-wide genotypes. We interrogate available functional data and discover an erythroid-specific transcription start site underlying the known association in ATP2B4, but are unable to identify a likely causal mechanism at the chromosome 6 locus. Previously reported HLA associations do not replicate in these samples. This large dataset will provide a foundation for further research on thegenetic determinants of malaria resistance in diverse populations.
  • Bakka, Haakon; Vanhatalo, Jarno; Illian, Janine B.; Simpson, Daniel; Rue, Havard (2019)
    The classical tools in spatial statistics are stationary models, like the Matern field. However, in some applications there are boundaries, holes, or physical barriers in the study area, e.g. a coastline, and stationary models will inappropriately smooth over these features, requiring the use of a non-stationary model. We propose a new model, the Barrier model, which is different from the established methods as it is not based on the shortest distance around the physical barrier, nor on boundary conditions. The Barrier model is based on viewing the Matern correlation, not as a correlation function on the shortest distance between two points, but as a collection of paths through a Simultaneous Autoregressive (SAR) model. We then manipulate these local dependencies to cut off paths that are crossing the physical barriers. To make the new SAR well behaved, we formulate it as a stochastic partial differential equation (SPDE) that can be discretised to represent the Gaussian field, with a sparse precision matrix that is automatically positive definite. The main advantage with the Barrier model is that the computational cost is the same as for the stationary model. The model is easy to use, and can deal with both sparse data and very complex barriers, as shown in an application in the Finnish Archipelago Sea. Additionally, the Barrier model is better at reconstructing the modified Horseshoe test function than the standard models used in R-INLA. (C) 2019 Elsevier B.V. All rights reserved.
  • Behrens, Ron H.; Carroll, Bernadette; Hellgren, Urban; Visser, Leo G.; Siikamaki, Heli; Vestergaard, Lasse S.; Calleri, Guido; Jaenisch, Thomas; Myrvang, Bjorn; Gascon, Joaquim; Hatz, Christoph (2010)