METHODS: The D-PRISM study was a multinational, survey-based investigation to assess the diagnosis and treatment of pneumonia in the ICU. A self-administered online questionnaire was distributed to intensive care clinicians from 72 countries between September to November 2022. The questionnaire included sections on professional profiles, current clinical practice in diagnosing and managing CAP, HAP, and VAP, and the availability of microbiology diagnostic tests. Multivariable analysis using multiple regression analysis was used to assess the relationship between reported antibiotic duration and organisational variables collected in the study.
RESULTS: A total of 1296 valid responses were collected from ICU clinicians, spread between low-and-middle income (LMIC) and high-income countries (HIC), with LMIC respondents comprising 51% of respondents. There is heterogeneity across the diagnostic processes, including clinical assessment, where 30% (389) did not consider radiological evidence essential to diagnose pneumonia, variable collection of microbiological samples, and use and practice in bronchoscopy. Microbiological diagnostics were least frequently available in low and lower-middle-income nation settings. Modal intended antibiotic treatment duration was 5-7 days for all types of pneumonia. Shorter durations of antibiotic treatment were associated with antimicrobial stewardship (AMS) programs, high national income status, and formal intensive care training.
CONCLUSIONS: This study highlighted variations in clinical practice and diagnostic capabilities for pneumonia, particularly issues with access to diagnostic tools in LMICs were identified. There is a clear need for improved adherence to existing guidelines and standardized approaches to diagnosing and treating pneumonia in the ICU. Trial registration As a survey of current practice, this study was not registered. It was reviewed and endorsed by the European Society of Intensive Care Medicine.
OBJECTIVES: This study used nationally representative samples from the Global School-based Student Health Survey (GSHS) (2010-2019) to determine the frequency of toothbrushing among school-going students (N = 266,113) in 72 countries.
MATERIAL AND METHODS: The country-specific sample size ranged from 130 in Tokelau to 25,408 in Malaysia. The outcome variable was the frequency of brushing or cleaning teeth once daily within the past 30 days prior to the survey. Bivariate analysis was conducted following a descriptive study to determine the frequency of toothbrushing or cleaning across different age groups (≤12, 13, 14, 15, ≥16 years), sexes, World Health Organization (WHO) regions, and gross domestic product (GDP) per capita quintiles.
RESULTS: The overall proportion of males to females in the sample was 50.9:49.1. In 45 countries or territories (62.5%), the proportion of participants who reported brushing their teeth at least once a day was above 90%. Participants from 10 countries or territories (13.9%) reported never or rarely brushing their teeth. In 69 countries or territories (95.8%), male students were more likely than female students to never or rarely brush their teeth. The highest rate of individuals who never or rarely brush their teeth (32.1%) was reported in the Eastern Mediterranean Region. In comparison, the Region of the Americas had the highest frequency of brushing twice or more daily (82.9%).
CONCLUSIONS: Educational interventions focused on dental health implemented in schools and aimed at early adolescents have the potential to promote the formation of healthy habits, which may lead to improved well-being over both short and long terms.
METHODS: We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29,000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.
FINDINGS: We estimated that 6·3 million (95% UI 6·0-6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1-18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6-177·4) in Guinea-Bissau to 2·3 (1·8-2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.
INTERPRETATION: Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.
FUNDING: Bill & Melinda Gates Foundation, US Agency for International Development.
METHOD: Data were obtained from 36 members of COSMIC, representing 28 countries across 6 continents (HICs: Australia, Canada, Faroe Islands, France, Germany, Greece, Italy, Japan, Netherlands, South Korea, Spain, Sweden, & USA; LMICs: Brazil, China, Cuba, Dominican Republic, Ecuador, Indonesia, Malaysia, Mexico, Nigeria, Peru, Philippines, Republic of Congo, & Tanzania). For each member study, we calculated incidence rates for all-cause dementia. Findings from 14 studies, with a consensus diagnosis are presented in the results. Using an Item Response Theory approach, we are currently calculating a comparable incidence rate for those studies without a consensus diagnosis.
RESULT: Consistent with previous trends, incidence rates (per 100 person-years) increased with age, from 65-70 years-old to 85-90 years-old, for both males (i.e., Republic of Congo, 4.41 to 19.57; France, 0.46 to 3.89; USA, 0.17 to 3.22; Spain, 0.31 to 4.22; 65-70 & 85-90 cohorts respectively) and females (i.e., Republic of Congo, 3.57 to 15.31; France, 0.45 to 3.72; USA, 0.22 to 4.25; Spain, 0.36 to 4.96; 65-70 & 85-90 cohorts respectively). There were no sex differences in incidence rates in younger age groups (60-65). Among older age groups, however, women tended to have higher incidence rates than men, in some countries (Faroe Islands, Germany, Sweden, and USA).
CONCLUSION: Geographical differences in dementia incidence rates likely represent inherent variation among countries, beyond methodological considerations. We are working to expand the range of studies and regions for which we calculate dementia incidence rates. This involves the development of approaches to classify and harmonise incident dementia in studies lacking consensus diagnoses. Doing so will bolster LMIC representation.
METHODS: Age-standardised rates per 100,000 population for prevalence, annual incidence and YLDs were compared across regions and countries, as well as the socio-demographic index (SDI). Trends were expressed as percentage changes (PC) and estimates were reported with uncertainty intervals (UI).
RESULTS: Globally, in 2021, the age-standardised rates per 100,000 population for the prevalence of hepatitis B, hepatitis C, MASLD and cirrhosis and other chronic liver diseases were 3583.6 (95%UI 3293.6-3887.7), 1717.8 (1385.5-2075.3), 15018.1 (13756.5-16361.4) and 20302.6 (18845.2-21791.9) respectively. From 2010 to 2021, the PC in age-standardised prevalence rates were-20.4% for hepatitis B, -5.1% for hepatitis C, +11.2% for MASLD and + 2.6% for cirrhosis and other chronic liver diseases. Over the same period, the PC in age-standardized incidence rates were -24.7%, -6.8%, +3.2%, and +3.0%, respectively. Generally, negative associations, but with fluctuations, were found between age-standardised prevalence rates for hepatitis B, hepatitis C, cirrhosis and other chronic liver diseases and the SDI at a global level. However, MASLD prevalence peaked at moderate SDI levels.
CONCLUSIONS: The global burden of chronic liver diseases remains substantial. Hepatitis B and C have decreased in prevalence and incidence in the last decade, while MASLD, cirrhosis and other chronic liver diseases have increased, necessitating targeted public health strategies and resource allocation.
METHODS: An electronic search was conducted using PubMed, Embase and Google Scholar search engines, to retrieve data on malocclusion prevalence for both mixed and permanent dentitions, up to December 2016.
RESULTS: Out of 2,977 retrieved studies, 53 were included. In permanent dentition, the global distributions of Class I, Class II, and Class III malocclusion were 74.7% [31 - 97%], 19.56% [2 - 63%] and 5.93% [1 - 20%], respectively. In mixed dentition, the distributions of these malocclusions were 73% [40 - 96%], 23% [2 - 58%] and 4% [0.7 - 13%]. Regarding vertical malocclusions, the observed deep overbite and open bite were 21.98% and 4.93%, respectively. Posterior crossbite affected 9.39% of the sample. Africans showed the highest prevalence of Class I and open bite in permanent dentition (89% and 8%, respectively), and in mixed dentition (93% and 10%, respectively), while Caucasians showed the highest prevalence of Class II in permanent dentition (23%) and mixed dentition (26%). Class III malocclusion in mixed dentition was highly prevalent among Mongoloids.
CONCLUSION: Worldwide, in mixed and permanent dentitions, Angle Class I malocclusion is more prevalent than Class II, specifically among Africans; the least prevalent was Class III, although higher among Mongoloids in mixed dentition. In vertical dimension, open bite was highest among Mongoloids in mixed dentition. Posterior crossbite was more prevalent in permanent dentition in Europe.
METHODS: In this study, systematic review and meta-analysis have been conducted on the previous studies focused on the prevalence of the Dupuytren disease. The search keywords were Prevalence, Prevalent, Epidemiology, Dupuytren Contracture, Dupuytren and Incidence. Subsequently, SID, MagIran, ScienceDirect, Embase, Scopus, PubMed and Web of Science databases and Google Scholar search engine were searched without a lower time limit and until June 2020. In order to analyse reliable studies, the stochastic effects model was used and the I2 index was applied to test the heterogeneity of the selected studies. Data analysis was performed within the Comprehensive Meta-Analysis Software version 2.0.
RESULTS: By evaluating 85 studies (10 in Asia, 56 in Europe, 2 in Africa and 17 studies in America) with a total sample size of 6628506 individuals, the prevalence of Dupuytren disease in the world is found as 8.2% (95% CI 5.7-11.7%). The highest prevalence rate is reported in Africa with 17.2% (95% CI 13-22.3%). According to the subgroup analysis, in terms of underlying diseases, the highest prevalence was obtained in patients with type 1 diabetes with 34.1% (95% CI 25-44.6%). The results of meta-regression revealed a decreasing trend in the prevalence of Dupuytren disease by increasing the sample size and the research year (P < 0.05).
CONCLUSION: The results of this study show that the prevalence of Dupuytren disease is particularly higher in alcoholic patients with diabetes. Therefore, the officials of the World Health Organization should design measures for the prevention and treatment of this disease.
METHODS: To answer this demand, the Health Equity Assessment Toolkit (HEAT), was developed between 2014 and 2016. The software, which contains the World Health Organization's Health Equity Monitor database, allows the assessment of inequalities within a country using over 30 reproductive, maternal, newborn and child health indicators and five dimensions of inequality (economic status, education, place of residence, subnational region and child's sex, where applicable).
RESULTS/CONCLUSION: HEAT was beta-tested in 2015 as part of ongoing capacity building workshops on health inequality monitoring. This is the first and only application of its kind; further developments are proposed to introduce an upload data feature, translate it into different languages and increase interactivity of the software. This article will present the main features and functionalities of HEAT and discuss its relevance and use for health inequality monitoring.
METHODS: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.
FINDINGS: 292,982 (95% UI 261,017-327,792) maternal deaths occurred in 2013, compared with 376,034 (343,483-407,574) in 1990. The global annual rate of change in the MMR was -0·3% (-1·1 to 0·6) from 1990 to 2003, and -2·7% (-3·9 to -1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0·4% (0·2-0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1-1262·8) in South Sudan to 2·4 (1·6-3·6) in Iceland.
INTERPRETATION: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.
FUNDING: Bill & Melinda Gates Foundation.
METHODS: Various databases were used to search relevant articles since 1995. Studies included were cohort and cross-sectional studies, all patients with dengue infection and must report the number of death or case fatality rate. The Joanna Briggs Institute appraisal checklist was used to evaluate the risk of bias of the full-texts. The studies were grouped according to the classification adopted: WHO 1997 and WHO 2009. Meta-regression was employed using a logistic transformation (log-odds) of the case fatality rate. The result of the meta-regression was the adjusted case fatality rate and odds ratio on the explanatory variables.
RESULTS: A total of 77 studies were included in the meta-regression analysis. The case fatality rate for all studies combined was 1.14% with 95% confidence interval (CI) of 0.82-1.58%. The combined (unadjusted) case fatality rate for 69 studies which adopted WHO 1997 dengue case classification was 1.09% with 95% CI of 0.77-1.55%; and for eight studies with WHO 2009 was 1.62% with 95% CI of 0.64-4.02%. The unadjusted and adjusted odds ratio of case fatality using WHO 2009 dengue case classification was 1.49 (95% CI: 0.52, 4.24) and 0.83 (95% CI: 0.26, 2.63) respectively, compared to WHO 1997 dengue case classification. There was an apparent increase in trend of case fatality rate from the year 1992-2016. Neither was statistically significant.
CONCLUSIONS: The WHO 2009 dengue case classification might have no effect towards the case fatality rate although the adjusted results indicated a lower case fatality rate. Future studies are required for an update in the meta-regression analysis to confirm the findings.
OBJECTIVE: To estimate mortality due to firearm injury deaths from 1990 to 2016 in 195 countries and territories.
DESIGN, SETTING, AND PARTICIPANTS: This study used deidentified aggregated data including 13 812 location-years of vital registration data to generate estimates of levels and rates of death by age-sex-year-location. The proportion of suicides in which a firearm was the lethal means was combined with an estimate of per capita gun ownership in a revised proxy measure used to evaluate the relationship between availability or access to firearms and firearm injury deaths.
EXPOSURES: Firearm ownership and access.
MAIN OUTCOMES AND MEASURES: Cause-specific deaths by age, sex, location, and year.
RESULTS: Worldwide, it was estimated that 251 000 (95% uncertainty interval [UI], 195 000-276 000) people died from firearm injuries in 2016, with 6 countries (Brazil, United States, Mexico, Colombia, Venezuela, and Guatemala) accounting for 50.5% (95% UI, 42.2%-54.8%) of those deaths. In 1990, there were an estimated 209 000 (95% UI, 172 000 to 235 000) deaths from firearm injuries. Globally, the majority of firearm injury deaths in 2016 were homicides (64.0% [95% UI, 54.2%-68.0%]; absolute value, 161 000 deaths [95% UI, 107 000-182 000]); additionally, 27% were firearm suicide deaths (67 500 [95% UI, 55 400-84 100]) and 9% were unintentional firearm deaths (23 000 [95% UI, 18 200-24 800]). From 1990 to 2016, there was no significant decrease in the estimated global age-standardized firearm homicide rate (-0.2% [95% UI, -0.8% to 0.2%]). Firearm suicide rates decreased globally at an annualized rate of 1.6% (95% UI, 1.1-2.0), but in 124 of 195 countries and territories included in this study, these levels were either constant or significant increases were estimated. There was an annualized decrease of 0.9% (95% UI, 0.5%-1.3%) in the global rate of age-standardized firearm deaths from 1990 to 2016. Aggregate firearm injury deaths in 2016 were highest among persons aged 20 to 24 years (for men, an estimated 34 700 deaths [95% UI, 24 900-39 700] and for women, an estimated 3580 deaths [95% UI, 2810-4210]). Estimates of the number of firearms by country were associated with higher rates of firearm suicide (P globally in 2016, the majority of which were firearm homicides. Despite an overall decrease in rates of firearm injury death since 1990, there was variation among countries and across demographic subgroups.
METHODS: We assessed use of antiplatelet, cholesterol, and blood-pressure-lowering drugs in 8492 individuals with self-reported cardiovascular disease from 21 countries enrolled in the Prospective Urban Rural Epidemiology (PURE) study. Defining one or more drugs as a minimal level of secondary prevention, wealth-related inequality was measured using the Wagstaff concentration index, scaled from -1 (pro-poor) to 1 (pro-rich), standardised by age and sex. Correlations between inequalities and national health-related indicators were estimated.
FINDINGS: The proportion of patients with cardiovascular disease on three medications ranged from 0% in South Africa (95% CI 0-1·7), Tanzania (0-3·6), and Zimbabwe (0-5·1), to 49·3% in Canada (44·4-54·3). Proportions receiving at least one drug varied from 2·0% (95% CI 0·5-6·9) in Tanzania to 91·4% (86·6-94·6) in Sweden. There was significant (p<0·05) pro-rich inequality in Saudi Arabia, China, Colombia, India, Pakistan, and Zimbabwe. Pro-poor distributions were observed in Sweden, Brazil, Chile, Poland, and the occupied Palestinian territory. The strongest predictors of inequality were public expenditure on health and overall use of secondary prevention medicines.
INTERPRETATION: Use of medication for secondary prevention of cardiovascular disease is alarmingly low. In many countries with the lowest use, pro-rich inequality is greatest. Policies associated with an equal or pro-poor distribution include free medications and community health programmes to support adherence to medications.
FUNDING: Full funding sources listed at the end of the paper (see Acknowledgments).
METHODS: Prior to the current effort, the burden of PAH was included in GBD as a non-specific contributor to "other cardiovascular and circulatory disease" burden. In this study, PAH was distinguished as its own cause of death and disability in GBD, producing comparable and consistent estimates of PAH burden. We used epidemiological and vital registry data to estimate the non-fatal and fatal burden of PAH in 204 countries and territories from 1990 to 2021 using standard GBD modelling approaches. We specifically focused on PAH (group 1 pulmonary hypertension), and did not include pulmonary hypertension groups 2-5.
FINDINGS: In 2021, there were an estimated 192 000 (95% uncertainty interval [UI] 155 000-236 000) prevalent cases of PAH globally. Of these, 119 000 (95 900-146 000) were in females (62%) and 73 100 (58 900-89 600) in males (38%). The age-standardised prevalence was 2·28 cases per 100 000 population (95% UI 1·85-2·80). Prevalence increased with age such that the highest prevalence was among individuals aged 75-79 years. In 2021, there were 22 000 deaths (18 200-25 400) attributed to PAH globally, with an age-standardised mortality rate of 0·27 deaths from PAH per 100 000 population (0·23-0·32). The burden of disease appears to be improving over time (38·2% improvement in age-standardised years of life lost [YLLs] in 2021 relative to 1990). YLLs attributed to PAH were similar to estimates for conditions such as chronic myeloid leukaemia, multiple sclerosis, and Crohn's disease.
INTERPRETATION: PAH is a rare but fatal disease that accounts for a considerable health-associated burden worldwide. PAH is disproportionally diagnosed among females and older adults.
FUNDING: Cardiovascular Medical Research and Education Fund and the Bill & Melinda Gates Foundation.
DESIGN: Cross-sectional survey.
SETTING: Community, 22 countries including all World Health Organization regions.
PARTICIPANTS: Persons (N=12,591) with traumatic or nontraumatic SCI aged 18 years or older.
INTERVENTIONS: Not applicable.
MAIN OUTCOME MEASURES: We estimated the prevalence of problems in 53 areas of functioning from the Brief International Classification of Functioning, Disability and Health (ICF) core set for SCI, long-term context, or ICF rehabilitation set covering 4 domains: impairments in body functions, impairments in mental functions, independence in performing activities, and restrictions in participation. Associations between areas of functioning were identified and visualized using conditional independence graphs.
RESULTS: Participants had a median age of 52 years, 73% were male, and 63% had paraplegia. Feeling tired, bowel dysfunction, sexual functions, spasticity, pain, carrying out daily routine, doing housework, getting up off the floor from lying on the back, pushing open a heavy door, and standing unsupported had the highest prevalence of problems (>70%). Clustering of associations within the 4 functioning domains was found, with the highest numbers of associations within impairments in mental functions. For the whole International Spinal Cord Injury sample, areas with the highest numbers of associations were circulatory problems, transferring bed-wheelchair, and toileting, while for the World Health Organization European and Western Pacific regions, these were dressing upper body, transferring bed-wheelchair, handling stress, feeling downhearted and depressed, and feeling happy.
CONCLUSIONS: In each domain of functioning, high prevalence of problems and high connectivity of areas of functioning were identified. The understanding of problems and the identification of potential targets for intervention can inform decision makers at all levels of the health system aiming to improve the situation of people living with SCI.
METHODS: In this international, community-based cohort study, we prospectively enrolled adults aged 35-70 years who had no intention of moving residences for 4 years from rural and urban communities across 17 countries. A portable spirometer was used to assess FEV1. FEV1 values were standardised within countries for height, age, and sex, and expressed as a percentage of the country-specific predicted FEV1 value (FEV1%). FEV1% was categorised as no impairment (FEV1% ≥0 SD from country-specific mean), mild impairment (FEV1% <0 SD to -1 SD), moderate impairment (FEV1% data available, during a median 7·8 years (IQR 5·6-9·5) of follow-up, 5488 (4·3%) deaths, 5734 (4·5%) cardiovascular disease events, and 1948 (1·5%) respiratory hospitalisation events occurred. Relative to the no impairment group, mild to severe FEV1% impairments were associated with graded increases in mortality (HR 1·27 [95% CI 1·18-1·36] for mild, 1·74 [1·60-1·90] for moderate, and 2·54 [2·26-2·86] for severe impairment), cardiovascular disease (1·18 [1·10-1·26], 1·39 [1·28-1·51], 2·02 [1·75-2·32]), and respiratory hospitalisation (1·39 [1·24-1·56], 2·02 [1·75-2·32], 2·97 [2·45-3·60]), and this pattern persisted in subgroup analyses considering country income level and various baseline risk factors. Population-attributable risk for mortality (adjusted for age, sex, and country income) from mildly to moderately reduced FEV1% (24·7% [22·2-27·2]) was larger than that from severely reduced FEV1% (3·7% [2·1-5·2]) and from tobacco use (19·7% [17·2-22·3]), previous cardiovascular disease (5·5% [4·5-6·5]), and hypertension (17·1% [14·6-19·6]). Population-attributable risk for cardiovascular disease from mildly to moderately reduced FEV1 was 17·3% (14·8-19·7), second only to the contribution of hypertension (30·1% [27·6-32·5]).
INTERPRETATION: FEV1 is an independent and generalisable predictor of mortality, cardiovascular disease, and respiratory hospitalisation, even across the clinically normal range (mild to moderate impairment).
FUNDING: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Ontario Ministry of Health and Long-Term Care, AstraZeneca, Sanofi-Aventis, Boehringer Ingelheim, Servier, and GlaxoSmithKline, Novartis, and King Pharma. Additional funders are listed in the appendix.