An integrated cell atlas of the lung in health and disease.

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas

An integrated cell atlas of the lung in health and disease

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1 + profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas. </p

An integrated cell atlas of the lung in health and disease

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP

An integrated cell atlas of the lung in health and disease

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas

Temporal patterns of cancer burden in Asia, 1990–2019: a systematic examination for the Global Burden of Disease 2019 study

BackgroundCancers represent a challenging public health threat in Asia. This study examines the temporal patterns of incidence, mortality, disability and risk factors of 29 cancers in Asia in the last three decades. MethodsThe age, sex and year-wise estimates of incidence, mortality, and disability-adjusted life years (DALYs) of 29 cancers for 49 Asian countries from 1990 through 2019 were generated as a part of the Global Burden of Disease, Injuries and Risk Factors 2019 study. Besides incidence, mortality and DALYs, we also examined the cancer burden measured in terms of DALYs and deaths attributable to risk factors, which had evidence of causation with different cancers. The development status of countries was measured using the socio-demographic index. Decomposition analysis was performed to gauge the change in cancer incidence between 1990 and 2019 due to population growth, aging and age-specific incidence rates. FindingsAll cancers combined claimed an estimated 5.6 million [95% uncertainty interval, 5.1–6.0 million] lives in Asia with 9.4 million [8.6–10.2 million] incident cases and 144.7 million [132.7–156.5 million] DALYs in 2019. The age-standardized incidence rate (ASIR) of all cancers combined in Asia was 197.6/100,000 [181.0–214.4] in 2019, varying from 99.2/100,000 [76.1–126.0] in Bangladesh to 330.5/100,000 [298.5–365.8] in Cyprus. The age-standardized mortality rate (ASMR) was 120.6/100,000 [110.1–130.7] in 2019, varying 4-folds across countries from 71.0/100,000 [59.9–83.5] in Kuwait to 284.2/100,000 [229.2–352.3] in Mongolia. The age-standardized DALYs rate was 2970.5/100,000 [2722.6–3206.5] in 2019, varying from 1578.0/100,000 [1341.2–1847.0] in Kuwait to 6574.4/100,000 [5141.7–8333.0] in Mongolia. Between 1990 and 2019, deaths due to 17 of the 29 cancers either doubled or more, and 20 of the 29 cancers underwent an increase of 150% or more in terms of new cases. Tracheal, bronchus, and lung cancer (both sexes), breast cancer (among females), colon and rectum cancer (both sexes), stomach cancer (both sexes) and prostate cancer (among males) were among top-5 cancers in most Asian countries in terms of ASIR and ASMR in 2019 and cancers of liver, stomach, hodgkin lymphoma and esophageal cancer posted the most significant decreases in age-standardized rates between 1990 and 2019. Among the modifiable risk factors, smoking, alcohol use, ambient particulate matter (PM) pollution and unsafe sex remained the dominant risk factors between 1990 and 2019. Cancer DALYs due to ambient PM pollution, high body mass index and fasting plasma glucose has increased most notably between 1990 and 2019. InterpretationWith growing incidence, cancer has become more significant public health threat in Asia, demanding urgent policy attention and guidance. Its heightened risk calls for increased cancer awareness, preventive measures, affordable early-stage detection, and cost-effective therapeutics in Asia. The current study can serve as a useful resource for policymakers and researchers in Asia for devising interventions for cancer management and control. FundingThe GBD study is funded by the Bill and Melinda Gates Foundation.This work is supported by: - University Grants Commission - Chandigarh University - National Science and Technology Council - grant no. [112-2410-H-003-031] - Bill and Melinda Gates Foundation - grant no. [OPP1152504] - Fundamental Research Funds for the Central Universities - grant no. [30923011101] - Social Science Foundation of Jiangsu Province - grant no. [21GLD008] - National Natural Science Foundation of China - grant no. [72204112

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Efficacy and Safety of Novel Oral Anticoagulants in Patients with Cervical Artery Dissections

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; American and European guidelines support antiplatelet agents and anticoagulants as reasonable treatments of cervical artery dissection (CAD), though randomized clinical trials are lacking. The utility of novel oral anticoagulants (NOAC), effective in reducing embolic stroke risk in non-valvular atrial fibrillation (NVAF), has not been reported in patients with CAD. We report on the use, safety, and efficacy of NOACs in the treatment of CAD. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We retrospectively identified patients diagnosed with CAD at a single academic center between January 2010 and August 2013. Patients were categorized by their antithrombotic treatment at hospital discharge with a NOAC (dabigatran, rivaroxaban, or apixaban), traditional anticoagulant (AC: warfarin or treatment dose low-molecular weight heparin), or antiplatelet agent (AP: aspirin, clopidogrel, or aspirin/extended-release dypyridamole). Using appropriate tests, we compared the baseline medical history, presenting clinical symptoms and initial radiographic characteristics among patients in the 3 treatment groups. We then evaluated for the following outcomes: recurrent stroke, vessel recanalization, and bleeding complications. p values &lt;0.05 were considered significant. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Of the 149 included patients (mean age 43.4 years; 63.1% female; 70.5% vertebral artery CAD), 39 (26.2%), 70 (47.0%), and 40 (26.8%) were treated with a NOAC, AC, and AP, respectively. More patients with severe stenosis or occlusion were treated with NOAC than with AC or AP (61.8 vs. 60.0 vs. 22.5%, p = 0.002). Other baseline clinical and radiographic findings, including the presence of acute infarction and hematoma, did not differ between the 3 treatment groups. One hundred and thirty-five (90.6%) patients had clinical follow-up (median time 7.5 months) and 125 (83.9%) had radiographic follow-up (median time 5 months) information. There were 2 recurrent strokes in the NOAC group and 1 in each of the AC and AP groups (p = 0.822). There were more major hemorrhagic events in the AC group (11.4%) compared to the NOAC (0.0%) and AP (2.5%) groups (p = 0.034). Three patients treated with NOAC and none treated with AC or AP had a worsened degree of stenosis on follow-up imaging (8.6 vs. 0.0 vs. 0.0%, p = 0.019). &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Compared to traditional anticoagulants for CAD, treatment with NOACs is associated with similar rates of recurrent stroke, fewer hemorrhagic complications, but greater rates of radiographic worsening. These data suggest that NOACs may be a reasonable alternative in the management of CAD. Prospective validation of these findings is needed.</jats:p