Identification of a putative anti-rheumatoid arthritis molecule by virtual screening

Purpose: To propose an improved chemical skeleton whose scaffolds could be used for the design of future thymidylate synthase (TS)-inhibitors against rheumatoid arthritis. Methods: The drug discovery platform, ‘MCULE’, was employed for inhibitor-screening. The ‘methotrexate-interaction site’ in the crystal (PDB ID 5X66) was used as a target. One ‘RO5 violation’ was permitted. A maximum of ‘10 rotatable bonds’ and ‘100 diverse molecules’ were also allowed in the protocol. The ‘threshold similarity cut off’ was 0.7. The input values describing the remaining parameters were kept as ‘default’. The ‘Open Babel Linear Fingerprint’ was used for the analyses of molecular descriptors, followed by ADME-check. Results: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidine corresponding to the MCULE ID-7590816301-0-93 exhibited the overall best binding with TS. The free energy of binding was -8.6 kcal/mol. A total of 17 amino acid residues were significant for the binding interactions. Importantly, 9 residues were common to methotrexate binding. It satisfied pertinent ADME conditions. Conclusion: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidinemay emerge as a potent seed molecule for TS-inhibitor design in the context of rheumatoid arthritis. It has satisfied pertinent ADME features. However, there is need for further wet laboratory validation. Keywords: Anti-rheumatoid arthritis, Inhibitor design, Methotrexate, Seed molecule, Thymidylate synthase, Virtual screenin

Molecular interaction of 4-amino-N’-(benzoyloxy)-N-(2,4- dimethylphenyl)-1,2,5-oxadiazole-3-carboximidamide with the methotrexate binding site of human DHFR, and its implication in rheumatoid arthritis

Purpose: To identify an improved lead molecule for the human dihydrofolate reductase (DHFR) inhibition that ‘sits’ in the same binding cavity as methotrexate by high throughput computationalscreening.Methods: The 3-D structure of the DHFR binding site was examined using ‘CASTp3.0’. Structure based in silico screening of about 5 million drug candidates housed in the MCULE database was performed. The obtained molecule-hits were ranked in accordance with their VINA scores, made to pass through drug-likeness filters, ΔG cut-off criterion, toxicity-checker and finally ‘zero RO5 criterion’.Results: The ‘top molecule’, namely, 4-amino-N'-(benzoyloxy)-N-(2,4-dimethylphenyl)-1,2,5-oxadiazole- 3-carboximidamide, displayed robust binding with human DHFR through 21 amino acid residues (ΔG = - 9.6 kcal/mol) while 10 of these residues were the same as those displayed by ‘methotrexate binding interactions’. It passed through relevant drug screening filters including the ‘Toxicity Checker’.Conclusion: This research work describes the molecular interaction of human DHFR with an improved lead molecule named, 4-amino- N’-(benzoyloxy)-N-(2,4-dimethylphenyl)-1,2,5-oxadiazole-3- carboximidamide, with a ΔG of -9.6 kcal/mol, thus satisfying adequate ADME features for further in vitro and in vivo validation in the context of rheumatoid arthritis. Keywords: Dihydrofolate reductase, In silico screening, Methotrexate, Rheumatoid arthritis, DHF

The association between hypertension and other cardiovascular risk factors among non-diabetic Saudis adults-A cross sectional study

Population specific associations between cardiovascular disease with various risk factors including pre-hypertension and hypertension were reported. We aimed to investigate the association of higher than optimal blood pressure with measures of dysglycemia, dyslipidemia, and markers of inflammation in non-diabetic Saudi adults hoping to improve current Saudi guidelines to prevent cardiovascular disease. Volunteers were recruited randomly from public healthcare centers in Jeddah. Demographic information, blood pressure (BP), and anthropometric measurements were taken. Fasting blood samples were drawn, then again following 1-hour oral glucose tolerance test. Glycated hemoglobin, fasting plasma glucose (FPG), lipid profile, highly sensitive C- reactive protein, gamma glutamyl transferase, and 1-hour plasma glucose were measured. Complete data was found for 742 men and 592 women. Pre-hypertension was found in 47.2% of men, and 24.7% of women, while 15.1% of men, and 14.6% of women were hypertensive. Means of measured variables differed significantly between normotensive, pre-hypertensive, and hypertensive groups of men and women in gender specific manner. Association between measured variables and elevated BP, and hypertension were assessed using logistic regression models. After adjustment for age, body mass index and waist circumference, elevated blood pressure was associated with elevated triglycerides in men, while hypertension was significantly associated with elevated fasting plasma glucose, total cholesterol, triglycerides, low density lipoprotein- cholesterol, and low high density lipoprotein- cholesterol in men, and elevated triglycerides, and total cholesterol in women. Therefore, it is strongly recommended to measure lipid profile, specifically TG, for all diagnosed pre-hypertensive and hypertensive patients in addition to FPG for men.Peer reviewe

Injury burden in individuals aged 50 years or older in the Eastern Mediterranean region, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019

BackgroundInjury poses a major threat to health and longevity in adults aged 50 years or older. The increased life expectancy in the Eastern Mediterranean region warrants a further understanding of the ageing population's inevitable changing health demands and challenges. We aimed to examine injury-related morbidity and mortality among adults aged 50 years or older in 22 Eastern Mediterranean countries. MethodsDrawing on data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we categorised the population into adults aged 50–69 years and adults aged 70 years and older. We examined estimates for transport injuries, self-harm injuries, and unintentional injuries for both age groups, with sex differences reported, and analysed the percentage changes from 1990 to 2019. We reported injury-related mortality rates and disability-adjusted life-years (DALYs). The Socio-demographic Index (SDI) and the Healthcare Access and Quality (HAQ) Index were used to better understand the association of socioeconomic factors and health-care system performance, respectively, with injuries and health status in older people. Healthy life expectancy (HALE) was compared with injury-related deaths and DALYs and to the SDI and HAQ Index to understand the effect of injuries on healthy ageing. Finally, risk factors for injury deaths between 1990 and 2019 were assessed. 95% uncertainty intervals (UIs) are given for all estimates. FindingsEstimated injury mortality rates in the Eastern Mediterranean region exceeded the global rates in 2019, with higher injury mortality rates in males than in females for both age groups. Transport injuries were the leading cause of deaths in adults aged 50–69 years (43·0 [95% UI 31·0–51·8] per 100 000 population) and in adults aged 70 years or older (66·2 [52·5–75·5] per 100 000 population), closely followed by conflict and terrorism for both age groups (10·2 [9·3–11·3] deaths per 100 000 population for 50–69 years and 45·7 [41·5–50·3] deaths per 100 000 population for ≥70 years). The highest annual percentage change in mortality rates due to injury was observed in Afghanistan among people aged 70 years or older (400·4% increase; mortality rate 1109·7 [1017·7–1214·7] per 100 000 population). The leading cause of DALYs was transport injuries for people aged 50–69 years (1798·8 [1394·1–2116·0] per 100 000 population) and unintentional injuries for those aged 70 years or older (2013·2 [1682·2–2408·7] per 100 000 population). The estimates for HALE at 50 years and at 70 years in the Eastern Mediterranean region were lower than global estimates. Eastern Mediterranean countries with the lowest SDIs and HAQ Index values had high prevalence of injury DALYs and ranked the lowest for HALE at 50 years of age and HALE at 70 years. The leading injury mortality risk factors were occupational exposure in people aged 50–69 years and low bone mineral density in those aged 70 years or older. InterpretationInjuries still pose a real threat to people aged 50 years or older living in the Eastern Mediterranean region, mainly due to transport and violence-related injuries. Dedicated efforts should be implemented to devise injury prevention strategies that are appropriate for older adults and cost-effective injury programmes tailored to the needs and resources of local health-care systems, and to curtail injury-associated risk and promote healthy ageing. FundingBill & Melinda Gates Foundation.We acknowledge the Bill & Melinda Gates Foundation for funding this study

Mortality, morbidity, and hospitalisations due to influenza lower respiratory tract infections, 2017: an analysis for the global burden of disease study 2017

Although the burden of influenza is often discussed in the context of historical pandemics and the threat of future pandemics, every year a substantial burden of lower respiratory tract infections (LRTIs) and other respiratory conditions (like chronic obstructive pulmonary disease) are attributable to seasonal influenza. The Global Burden of Disease Study (GBD) 2017 is a systematic scientific effort to quantify the health loss associated with a comprehensive set of diseases and disabilities. In this Article, we focus on LRTIs that can be attributed to influenza. Methods: We modelled the LRTI incidence, hospitalisations, and mortality attributable to influenza for every country and selected subnational locations by age and year from 1990 to 2017 as part of GBD 2017. We used a counterfactual approach that first estimated the LRTI incidence, hospitalisations, and mortality and then attributed a fraction of those outcomes to influenza. Findings: Influenza LRTI was responsible for an estimated 145 000 (95% uncertainty interval [UI] 99 000–200 000) deaths among all ages in 2017. The influenza LRTI mortality rate was highest among adults older than 70 years (16·4 deaths per 100 000 [95% UI 11·6–21·9]), and the highest rate among all ages was in eastern Europe (5·2 per 100 000 population [95% UI 3·5–7·2]). We estimated that influenza LRTIs accounted for 9 459 000 (95% UI 3 709 000–22 935 000) hospitalisations due to LRTIs and 81 536 000 hospital days (24 330 000–259 851 000). We estimated that 11·5% (95% UI 10·0–12·9) of LRTI episodes were attributable to influenza, corresponding to 54 481 000 (38 465 000–73 864 000) episodes and 8 172 000 severe episodes (5 000 000–13 296 000). Interpretation: This comprehensive assessment of the burden of influenza LRTIs shows the substantial annual effect of influenza on global health. Although preparedness planning will be important for potential pandemics, health loss due to seasonal influenza LRTIs should not be overlooked, and vaccine use should be considered. Efforts to improve influenza prevention measures are needed. Funding: Bill & Melinda Gates Foundation

The prevalence of diabetes and prediabetes in the adult population of Jeddah, Saudi Arabia- a community-based survey

BACKGROUND: Type 2 (T2DM) is believed to be common in Saudi Arabia, but data are limited. In this population survey, we determined the prevalence of T2DM and prediabetes. MATERIALS AND METHODS: A representative sample among residents aged ≥ 18 years of the city of Jeddah was obtained comprising both Saudi and non-Saudi families (N = 1420). Data on dietary, clinical and socio-demographic characteristics were collected and anthropometric measurements taken. Fasting plasma glucose and glycated hemoglobin (HbA1c) were used to diagnose diabetes and prediabetes employing American Diabetes Association criteria. Multiple logistic regression analysis was used to identify factors associated with T2DM. RESULTS: Age and sex standardized prevalence of prediabetes was 9.0% (95% CI 7.5-10.5); 9.4% (7.1-11.8) in men and 8.6% (6.6-10.6) in women. For DM it was 12.1% (10.7-13.5); 12.9% (10.7-13.5) in men and 11.4% (9.5-13.3) in women. The prevalence based on World Population as standard was 18.3% for DM and 11.9% for prediabetes. The prevalence of DM and prediabetes increased with age. Of people aged ≥50 years 46% of men and 44% of women had DM. Prediabetes and DM were associated with various measures of adiposity. DM was also associated with and family history of dyslipidemia in women, cardiovascular disease in men, and with hypertension, dyslipidemia and family history of diabetes in both sexes. DISCUSSION: Age was the strongest predictor of DM and prediabetes followed by obesity. Of people aged 50 years or over almost half had DM and another 10-15% had prediabetes leaving only a small proportion of people in this age group with normoglycemia. Since we did not use an oral glucose tolerance test the true prevalence of DM and prediabetes is thus likely to be even higher than reported here. These results demonstrate the urgent need to develop primary prevention strategies for type 2 diabetes in Saudi Arabia

Global, regional, and national burden of chronic kidney disease, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, −1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, −1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI

Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

© 2020 Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages. Methods: Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (≥65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0–100 based on the 2·5th and 97·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—we estimated additional population equivalents with UHC effective coverage from 2018 to 2023. Findings: Globally, performance on the UHC effective coverage index improved from 45·8 (95% uncertainty interval 44·2–47·5) in 1990 to 60·3 (58·7–61·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2·6% [1·9–3·3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010–2019 relative to 1990–2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach $1398 pooled health spending per capita (US$ adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388·9 million (358·6–421·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3·1 billion (3·0–3·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968·1 million [903·5–1040·3]) residing in south Asia. Interpretation: The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all people—the ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how close—or how far—all populations are in benefiting from UHC. Funding: Bill & Melinda Gates Foundation

Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations : a systematic analysis from the Global Burden of Disease Study 2016

Background A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. Methods Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. Findings In 2016, HAQ Index performance spanned from a high of 97.1 (95% UI 95.8-98.1) in Iceland, followed by 96.6 (94.9-97.9) in Norway and 96.1 (94.5-97.3) in the Netherlands, to values as low as 18.6 (13.1-24.4) in the Central African Republic, 19.0 (14.3-23.7) in Somalia, and 23.4 (20.2-26.8) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91.5 (89.1-936) in Beijing to 48.0 (43.4-53.2) in Tibet (a 43.5-point difference), while India saw a 30.8-point disparity, from 64.8 (59.6-68.8) in Goa to 34.0 (30.3-38.1) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4.8-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20.9-point to 17.0-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17.2-point to 20.4-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. Interpretation GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle-SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view and subsequent provision of quality health care for all populations. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: A systematic analysis from the Global Burden of Disease Study 2016

Copyright © 2018 The Author(s). Published by Elsevier Ltd. Background A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. Methods Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. Findings In 2016, HAQ Index performance spanned from a high of 97·1 (95% UI 95·8-98·1) in Iceland, followed by 96·6 (94·9-97·9) in Norway and 96·1 (94·5-97·3) in the Netherlands, to values as low as 18·6 (13·1-24·4) in the Central African Republic, 19·0 (14·3-23·7) in Somalia, and 23·4 (20·2-26·8) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91·5 (89·1-93·6) in Beijing to 48·0 (43·4-53·2) in Tibet (a 43·5-point difference), while India saw a 30·8-point disparity, from 64·8 (59·6-68·8) in Goa to 34·0 (30·3-38·1) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4·8-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20·9-point to 17·0-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17·2-point to 20·4-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. Interpretation GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle- SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage hinges upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view - and subsequent provision - of quality health care for all populations