Third Xiangya Hospital

Tumor immune escape is an important strategy of tumor survival. There are many mechanisms of tumor immune escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of tumor cells, thereby achieving tumor immune escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the tumor microenvironment and their roles in mediating tumor escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.

Tumorigenesis is a complex and dynamic process, consisting of three stages: initiation, progression, and metastasis. Tumors are encircled by extracellular matrix (ECM) and stromal cells, and the physiological state of the tumor microenvironment (TME) is closely connected to every step of tumorigenesis. Evidence suggests that the vital components of the TME are fibroblasts and myofibroblasts, neuroendocrine cells, adipose cells, immune and inflammatory cells, the blood and lymphatic vascular networks, and ECM. This manuscript, based on the current studies of the TME, offers a more comprehensive overview of the primary functions of each component of the TME in cancer initiation, progression, and invasion. The manuscript also includes primary therapeutic targeting markers for each player, which may be helpful in treating tumors.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide and is strongly associated with the presence of oxidative stress. Disturbances in lipid metabolism lead to hepatic lipid accumulation, which affects different reactive oxygen species (ROS) generators, including mitochondria, endoplasmic reticulum, and NADPH oxidase. Mitochondrial function adapts to NAFLD mainly through the downregulation of the electron transport chain (ETC) and the preserved or enhanced capacity of mitochondrial fatty acid oxidation, which stimulates ROS overproduction within different ETC components upstream of cytochrome c oxidase. However, non-ETC sources of ROS, in particular, fatty acid β-oxidation, appear to produce more ROS in hepatic metabolic diseases. Endoplasmic reticulum stress and NADPH oxidase alterations are also associated with NAFLD, but the degree of their contribution to oxidative stress in NAFLD remains unclear. Increased ROS generation induces changes in insulin sensitivity and in the expression and activity of key enzymes involved in lipid metabolism. Moreover, the interaction between redox signaling and innate immune signaling forms a complex network that regulates inflammatory responses. Based on the mechanistic view described above, this review summarizes the mechanisms that may account for the excessive production of ROS, the potential mechanistic roles of ROS that drive NAFLD progression, and therapeutic interventions that are related to oxidative stress.

Rationale: Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with hypertension. Objective: To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19. Methods and Results: This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 [interquartile range, 55–68] years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 [interquartile range 57–69]; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 [95% CI, 0.19–0.92]; P =0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 [95% CI, 0.15–0.89]; P =0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 [95% CI, 0.12–0.70]; P =0.01) in patients with COVID-19 and coexisting hypertension. Conclusions: Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.

Circular RNAs (circRNAs) are connected at the 3' and 5' ends by exon or intron cyclization, forming a complete ring structure. circRNA is more stable and conservative than linear RNA and abounds in various organisms. In recent years, increasing numbers of reports have found that circRNA plays a major role in the biological functions of a network of competing endogenous RNA (ceRNA). circRNAs can compete together with microRNAs (miRNAs) to influence the stability of target RNAs or their translation, thus, regulating gene expression at the transcriptional level. circRNAs are involved in biological processes such as tumor cell proliferation, apoptosis, invasion, and migration as ceRNAs. circRNAs, therefore, represent promising candidates for clinical diagnosis and treatment. Here, we review the progress in studying the role of circRNAs as ceRNAs in tumors and highlight the participation of circRNAs in signal transduction pathways to regulate cellular functions.

Exosomes are nanoscale extracellular vesicles that play an important role in many biological processes, including intercellular communications, antigen presentation, and the transport of proteins, RNA, and other molecules. Recently there has been significant interest in exosome-related fundamental research, seeking new exosome-based biomarkers for health monitoring and disease diagnoses. Here, we report a separation method based on acoustofluidics (i.e., the integration of acoustics and microfluidics) to isolate exosomes directly from whole blood in a label-free and contact-free manner. This acoustofluidic platform consists of two modules: a microscale cell-removal module that first removes larger blood components, followed by extracellular vesicle subgroup separation in the exosome-isolation module. In the cell-removal module, we demonstrate the isolation of 110-nm particles from a mixture of micro- and nanosized particles with a yield greater than 99%. In the exosome-isolation module, we isolate exosomes from an extracellular vesicle mixture with a purity of 98.4%. Integrating the two acoustofluidic modules onto a single chip, we isolated exosomes from whole blood with a blood cell removal rate of over 99.999%. With its ability to perform rapid, biocompatible, label-free, contact-free, and continuous-flow exosome isolation, the integrated acoustofluidic device offers a unique approach to investigate the role of exosomes in the onset and progression of human diseases with potential applications in health monitoring, medical diagnosis, targeted drug delivery, and personalized medicine.

BACKGROUND: Obesity represents an urgent problem that needs to be properly addressed, especially among children. Public and global health policy- and decision-makers need timely, reliable quantitative information to develop effective interventions aimed at counteracting the burden generated by high body mass index (BMI). Few studies have assessed the high-BMI-related burden on a global scale. METHODS AND FINDINGS: Following the methodology framework and analytical strategies used in the Global Burden of Disease Study (GBD) 2017, the global deaths and disability-adjusted life years (DALYs) attributable to high BMI were analyzed by age, sex, year, and geographical location and by Socio-demographic Index (SDI). All causes of death and DALYs estimated in GBD 2017 were organized into 4 hierarchical levels: level 1 contained 3 broad cause groupings, level 2 included more specific categories within the level 1 groupings, level 3 comprised more detailed causes within the level 2 categories, and level 4 included sub-causes of some level 3 causes. From 1990 to 2017, the global deaths and DALYs attributable to high BMI have more than doubled for both females and males. However, during the study period, the age-standardized rate of high-BMI-related deaths remained stable for females and only increased by 14.5% for males, and the age-standardized rate of high-BMI-related DALYs only increased by 12.7% for females and 26.8% for males. In 2017, the 6 leading GBD level 3 causes of high-BMI-related DALYs were ischemic heart disease, stroke, diabetes mellitus, chronic kidney disease, hypertensive heart disease, and low back pain. For most GBD level 3 causes of high-BMI-related DALYs, high-income North America had the highest attributable proportions of age-standardized DALYs due to high BMI among the 21 GBD regions in both sexes, whereas the lowest attributable proportions were observed in high-income Asia Pacific for females and in eastern sub-Saharan Africa for males. The association between SDI and high-BMI-related DALYs suggested that the lowest age-standardized DALY rates were found in countries in the low-SDI quintile and high-SDI quintile in 2017, and from 1990 to 2017, the age-standardized DALY rates tended to increase in regions with the lowest SDI, but declined in regions with the highest SDI, with the exception of high-income North America. The study's main limitations included the use of information collected from some self-reported data, the employment of cutoff values that may not be adequate for all populations and groups at risk, and the use of a metric that cannot distinguish between lean and fat mass. CONCLUSIONS: In this study, we observed that the number of global deaths and DALYs attributable to high BMI has substantially increased between 1990 and 2017. Successful population-wide initiatives targeting high BMI may mitigate the burden of a wide range of diseases. Given the large variations in high-BMI-related burden of disease by SDI, future strategies to prevent and reduce the burden should be developed and implemented based on country-specific development status.

Tumor angiogenesis is necessary for the continued survival and development of tumor cells, and plays an important role in their growth, invasion, and metastasis. The tumor microenvironment-composed of tumor cells, surrounding cells, and secreted cytokines-provides a conducive environment for the growth and survival of tumors. Different components of the tumor microenvironment can regulate tumor development. In this review, we have discussed the regulatory role of the microenvironment in tumor angiogenesis. High expression of angiogenic factors and inflammatory cytokines in the tumor microenvironment, as well as hypoxia, are presumed to be the reasons for poor therapeutic efficacy of current anti-angiogenic drugs. A combination of anti-angiogenic drugs and antitumor inflammatory drugs or hypoxia inhibitors might improve the therapeutic outcome.

Genetic instability of tumor cells often leads to the occurrence of a large number of mutations, and expression of non-synonymous mutations can produce tumor-specific antigens called neoantigens. Neoantigens are highly immunogenic as they are not expressed in normal tissues. They can activate CD4+ and CD8+ T cells to generate immune response and have the potential to become new targets of tumor immunotherapy. The development of bioinformatics technology has accelerated the identification of neoantigens. The combination of different algorithms to identify and predict the affinity of neoantigens to major histocompatibility complexes (MHCs) or the immunogenicity of neoantigens is mainly based on the whole-exome sequencing technology. Tumor vaccines targeting neoantigens mainly include nucleic acid, dendritic cell (DC)-based, tumor cell, and synthetic long peptide (SLP) vaccines. The combination with immune checkpoint inhibition therapy or radiotherapy and chemotherapy might achieve better therapeutic effects. Currently, several clinical trials have demonstrated the safety and efficacy of these vaccines. Further development of sequencing technologies and bioinformatics algorithms, as well as an improvement in our understanding of the mechanisms underlying tumor development, will expand the application of neoantigen vaccines in the future.

With dramatic changes in lifestyles over the last 20 years, nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disorder in China but has not received sufficient attention. NAFLD-related advanced liver disease and its mortality along with its overall disease burden are expected to increase substantially. There is thus an imperative need to clarify the epidemiological features of NAFLD to guide a holistic approach to management. We summarize eight epidemiological features of NAFLD in China over the past two decades using systematic review and meta-analysis methodology. Our data reveal a rapid growth in the NAFLD population, especially among younger individuals. Importantly, there is a strong ethnic difference in body mass index (BMI) and genetic risk of NAFLD compared with the US population. The etiology of advanced liver disease and its complications (e.g., hepatocellular carcinoma) has been altered because of a Westernized lifestyle and the implementation of effective vaccination strategies against viral hepatitis. Regional epidemiological patterns of NAFLD indicate that economics, environment, and lifestyle are critical factors in disease progression. The analysis also indicates that a large number of patients remain undiagnosed and untreated because of the inadequacy of diagnostic tools and the absence of effective pharmacologic therapies. Given the burden of NAFLD, future policy and research efforts need to address knowledge gaps to mitigate the risk burden.

OBJECTIVES: Studies reported associations of inflammatory markers with the severity of COVID-19, but conclusions were inconsistent. We aimed to provide an overview of the association of inflammatory markers with the severity of COVID-19. METHODS: We searched PubMed, Embase, Cochrane Library, Wanfang and China National Knowledge Infrastructure (CNKI) database until March 20, 2020. Weighted mean difference (WMD) and 95% confidence intervals (CIs) were pooled using random or fixed-effects models. RESULTS: A total of 16 studies comprising 3962 patients with COVID-19 were included in our analysis. Random-effect results demonstrated that patients with COVID-19 in the nonsevere group had lower levels for CRP (WMD = -41.78 mg/l, 95% CI = [-52.43, -31.13], P < 0.001), PCT (WMD = -0.13 ng/ml, 95% CI = [-0.20, -0.05], P < 0.001), IL-6 (WMD = -21.32 ng/l, 95% CI = [-28.34, -14.31], P < 0.001), ESR (WMD = -8 mm/h, 95% CI = [-14, -2], P = 0.005), SAA (WMD = -43.35 μg/ml, 95% CI = [-80.85, -5.85], P = 0.020) and serum ferritin (WMD = -398.80 mg/l, 95% CI = [-625.89, -171.71], P < 0.001), compared with those in the severe group. Moreover, survivors had a lower level of IL-6 than non-survivors (WMD = -4.80 ng/ml, 95% CI = [-5.87, -3.73], P < 0.001). These results were consistent through sensitivity analysis and publication bias assessment. CONCLUSIONS: The meta-analysis highlights the association of inflammatory markers with the severity of COVID-19. Measurement of inflammatory markers might assist clinicians to monitor and evaluate the severity and prognosis of COVID-19.

Ulcerative colitis (UC) is an inflammatory disease that mainly affects the colon and rectum. It is believed that genetic factors, host immune system disorders, intestinal microbiota dysbiosis, and environmental factors contribute to the pathogenesis of UC. However, studies on the role of intestinal microbiota in the pathogenesis of UC have been inconclusive. Studies have shown that probiotics improve intestinal mucosa barrier function and immune system function and promote secretion of anti-inflammatory factors, thereby inhibiting the growth of harmful bacteria in the intestine. Fecal microbiota transplantation (FMT) can reduce bowel permeability and thus the severity of disease by increasing the production of short-chain fatty acids, especially butyrate, which help maintain the integrity of the epithelial barrier. FMT can also restore immune dysbiosis by inhibiting Th1 differentiation, activity of T cells, leukocyte adhesion, and production of inflammatory factors. Probiotics and FMT are being increasingly used to treat UC, but their use is controversial because of uncertain efficacy. Here, we briefly review the role of intestinal microbiota in the pathogenesis and treatment of UC.

With rapid lifestyle transitions, the increasing burden of nonalcoholic fatty liver disease (NAFLD) in China has emerged as a major public health issue. To obtain a comprehensive overview of the status of NAFLD over the past decade, we evaluated the epidemiology, risk factors, complications, and management of NAFLD in China through a systematic review and meta-analysis. Five English literature databases and three Chinese databases were searched for relevant topics from 2008 to 2018. A total of 392 studies with a population of 2,054,554 were included. National prevalence of NAFLD was 29.2%, with a heavier disease burden among the middle-aged, males, those in northwest China and Taiwan, regions with a gross domestic product per capita greater than 100,000 yuan, and Uygur and Hui ethnic groups. Currently, original studies on natural history and complications of NAFLD in China are scarce. Several studies revealed that NAFLD is positively correlated with the incidence of extrahepatic tumors, diabetes, cardiovascular disease and metabolic syndrome. The Chinese population may have a higher hereditary risk of NAFLD due to more frequent nonsynonymous mutations in genes regulating lipid metabolism. Ultrasonography is the primary imaging tool in the detection of NAFLD in China. Serum tests and risk stratification algorithms for staging NAFLD remain under investigation. Specific pharmaceutical treatments for NAFLD are still undergoing clinical trials. It is noteworthy that the Chinese are underrepresented compared with their proportion of the NAFLD population in such trials. Conclusion: China experienced an unexpected rapid increase in the burden of NAFLD over a short period. Rising awareness and urgent actions need to be taken in order to control the NAFLD pandemic in China.

In the mammalian skeletal system, osteogenesis and angiogenesis are intimately linked during bone growth and regeneration in bone modeling and during bone homeostasis in bone remodeling. Recent studies have expanded our knowledge about the molecular and cellular mechanisms responsible for coupling angiogenesis and bone formation. Type H vessels, termed such because of high expression of Endomucin (Emcn) and CD31, have recently been identified and have the ability to induce bone formation. Factors including platelet-derived growth factor type BB (PDGF-BB), slit guidance ligand 3 (SLIT3), hypoxia-inducible factor 1-alpha (HIF-1α), Notch, and vascular endothelial growth factor (VEGF) are involved in the coupling of angiogenesis and osteogenesis. This review summarizes the current understanding of signaling pathways that regulate type H vessels and how type H vessels modulate osteogenesis. Further studies dissecting the regulation and function of type H vessels will provide new insights into the role of bone vasculature in the metabolism of the skeleton. We also discuss considerations for therapeutic approaches targeting type H vessels to promote fracture healing, prevent pathological bone loss, osteonecrosis, osteoarthritis, and bone metastases.

Non-coding RNAs do not encode proteins and regulate various oncological processes. They are also important potential cancer diagnostic and prognostic biomarkers. Bioinformatics and translation omics have begun to elucidate the roles and modes of action of the functional peptides encoded by ncRNA. Here, recent advances in long non-coding RNA (lncRNA) and circular RNA (circRNA)-encoded small peptides are compiled and synthesized. We introduce both the computational and analytical methods used to forecast prospective ncRNAs encoding oncologically functional oligopeptides. We also present numerous specific lncRNA and circRNA-encoded proteins and their cancer-promoting or cancer-inhibiting molecular mechanisms. This information may expedite the discovery, development, and optimization of novel and efficacious cancer diagnostic, therapeutic, and prognostic protein-based tools derived from non-coding RNAs. The role of ncRNA-encoding functional peptides has promising application perspectives and potential challenges in cancer research. The aim of this review is to provide a theoretical basis and relevant references, which may promote the discovery of more functional peptides encoded by ncRNAs, and further develop novel anticancer therapeutic targets, as well as diagnostic and prognostic cancer markers.

c-Met is a receptor tyrosine kinase belonging to the MET (MNNG HOS transforming gene) family, and is expressed on the surfaces of various cells. Hepatocyte growth factor (HGF) is the ligand for this receptor. The binding of HGF to c-Met initiates a series of intracellular signals that mediate embryogenesis and wound healing in normal cells. However, in cancer cells, aberrant HGF/c-Met axis activation, which is closely related to c-Met gene mutations, overexpression, and amplification, promotes tumor development and progression by stimulating the PI3K/AKT, Ras/MAPK, JAK/STAT, SRC, Wnt/β-catenin, and other signaling pathways. Thus, c-Met and its associated signaling pathways are clinically important therapeutic targets. In this review, we elaborate on the molecular structure of c-Met and HGF and the mechanism through which their interaction activates the PI3K/AKT, Ras/MAPK, and Wnt signaling pathways. We also summarize the connection between c-Met and RON and EGFR, which are also receptor tyrosine kinases. Finally, we introduce the current therapeutic drugs that target c-Met in primary tumors, and their use in clinical research.

OBJECTIVES: We aimed to provide the most updated estimates on the global burden of inflammatory bowel disease (IBD) to improve management strategies. DESIGN: We extracted data from the Global Burden of Disease (GBD) 2019 database to evaluate IBD burden with different measures in 204 countries and territories from 1990 to 2019. SETTING: Studies from the GBD 2019 database generated by population-representative data sources identified through a literature review and research collaborations were included. PARTICIPANTS: Patients with an IBD diagnosis. OUTCOMES: Total numbers, age-standardised rates of prevalence, mortality and disability-adjusted life-years (DALYs), and their estimated annual percentage changes (EAPCs) were the main outcomes. RESULTS: In 2019, there were approximately 4.9 million cases of IBD worldwide, with China and the USA having the highest number of cases (911 405 and 762 890 (66.9 and 245.3 cases per 100 000 people, respectively)). Between 1990 and 2019, the global age-standardised rates of prevalence, deaths and DALYs decreased (EAPCs=-0.66,-0.69 and -1.04, respectively). However, the age-standardised prevalence rate increased in 13 out of 21 GBD regions. A total of 147 out of 204 countries or territories experienced an increase in the age-standardised prevalence rate. From 1990 to 2019, IBD prevalent cases, deaths and DALYs were higher among females than among males. A higher Socio-demographic Index was associated with higher age-standardised prevalence rates. CONCLUSIONS: IBD will continue to be a major public health burden due to increasing numbers of prevalent cases, deaths and DALYs. The epidemiological trends and disease burden of IBD have changed dramatically at the regional and national levels, so understanding these changes would be beneficial for policy makers to tackle IBD.

CircRNAs are a novel type of RNAs. With the newly developed technology of next-generation sequencing (NGS), especially RNA-seq technology, over 30,000 circRNAs have already been found. Owing to their unique structure, they are more stable than linear RNAs. CircRNAs play important roles in the carcinogenesis of cancer. The expression of circRNAs is correlated with patients' clinical characteristics, and circRNAs play a vital role in many aspects of malignant phenotypes, including cell cycle, apoptosis, vascularization, and invasion; metastasis as a RNA sponge, binding to RBP; or translation. Therefore, it is meaningful to further study the mechanism of interactions between circRNAs and tumors. The role of circRNAs as molecular markers or potential targets will provide promising application perspectives, such as early tumor diagnosis, therapeutic evaluation, prognosis prediction, and even gene therapy for tumors.

BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. FUNDING: Gates Foundation and Bloomberg Philanthropies.

Roseburia intestinalis is an anaerobic, Gram-positive, slightly curved rod-shaped flagellated bacterium that produces butyrate in the colon. R. intestinalis has been shown to prevent intestinal inflammation and maintain energy homeostasis by producing metabolites. Evidence shows that this bacterium contributes to various diseases, such as inflammatory bowel disease, type 2 diabetes mellitus, antiphospholipid syndrome, and atherosclerosis. This review reveals the potential therapeutic role of R. intestinalis in human diseases. Patients with inflammatory bowel disease exhibit significant changes in R. intestinalis abundance, and they may benefit a lot from modulations targeting R. intestinalis . The data reviewed here demonstrate that R. intestinalis plays its role in regulating barrier homeostasis, immune cells, and cytokine release through its metabolite butyrate, flagellin and other. Recent advancements in the application of primary culture technology, culture omics, single-cell sequencing, and metabonomics technology have improved research on Roseburia and revealed the benefits of this bacterium in human health and disease treatment.