Jiong‐Wei Wang

AIMS: The prediction of future trends in cardiovascular disease (CVD) mortality and their risk factors can assist policy-makers in healthcare planning. This study aims to project geospatial trends in CVDs and their underlying risk factors from 2025 to 2050. METHODS AND RESULTS: Using historical data on mortality and disability-adjusted life years (DALYs) from the Global Burden of Disease (GBD) 2019 study, encompassing the period of 1990 to 2019, Poisson regression was performed to model mortality and DALYs associated with CVD and its associated risk factors from 2025 to 2050. Subgroup analysis was based on GBD super-regions. Between 2025 and 2050, a 90.0% increase in cardiovascular prevalence, 73.4% increase in crude mortality, and 54.7% increase in crude DALYs are projected, with an expected 35.6 million cardiovascular deaths in 2050 (from 20.5 million in 2025). However, age-standardized cardiovascular prevalence will be relatively constant (-3.6%), with decreasing age-standardized mortality (-30.5%) and age-standardized DALYs (-29.6%). In 2050, ischaemic heart disease will remain the leading cause of cardiovascular deaths (20 million deaths) while high systolic blood pressure will be the main cardiovascular risk factor driving mortality (18.9 million deaths). Central Europe, Eastern Europe, and Central Asia super-region is set to incur the highest age-standardized cardiovascular mortality rate in 2050 (305 deaths per 100 000 population). CONCLUSION: In the coming decades, the relatively constant age-standardized prevalence of global CVD suggests that the net effect of summative preventative efforts will likely continue to be unchanged. The fall in age-standardized cardiovascular mortality reflects the improvement in medical care following diagnosis. However, future healthcare systems can expect a rapid rise in crude cardiovascular mortality, driven by the ageing global populace. The continued rise in CVD burden will largely be attributed to atherosclerotic diseases. REGISTRATION: Not applicable.

Rationale: Bovine milk constitutes an essential part of human diet, especially for children, due to its enrichment of various nutrients. We recently developed an effective protocol for the isolation of extracellular vesicles from milk (mEVs) and discovered that mEVs contained large amounts of immune-active proteins and modulated the gut immunity and microbiota in healthy mice. Here, we aimed to explore the therapeutic effects of mEVs on inflammatory bowel disease. Methods: MicroRNAs and protein content in mEVs were analyzed by RNA sequencing and proteomics, respectively, followed by functional annotation. Ulcerative colitis (UC) was induced by feeding mice with dextran sulfate sodium. Intestinal immune cell populations were phenotyped by flow cytometry, and the gut microbiota was analyzed via 16S rRNA sequencing. Results: We showed that abundant proteins and microRNAs in mEVs were involved in the regulation of immune and inflammatory pathways and that oral administration of mEVs prevented colon shortening, reduced intestinal epithelium disruption, inhibited infiltration of inflammatory cells and tissue fibrosis in a mouse UC model. Mechanistically, mEVs attenuated inflammatory response via inhibiting TLR4-NF-B signaling pathway and NLRP3 inflammasome activation. Furthermore, mEVs were able to correct cytokine production disorder and restore the balance between T helper type 17 (Th17) cells and interleukin-10 + Foxp3 + regulatory T (Treg) cells in the inflamed colon. The disturbed gut microbiota in UC was also partially recovered upon treatment with mEVs. The correlation between the gut microbiota and cytokines suggests that mEVs may modulate intestinal immunity via influencing the gut microbiota. Conclusions: These findings reveal that mEVs alleviate colitis by regulating intestinal immune homeostasis via inhibiting TLR4-NF-B and NLRP3 signaling pathways, restoring Treg/Th17 cell balance, and reshaping the gut microbiota.

Background: Malnutrition and obesity are interdependent pathologies along the same spectrum. We examined global trends and projections of disability-adjusted life years (DALYs) and deaths from malnutrition and obesity until 2030. Methods: . Countries were stratified into low, low-middle, middle, high-middle, and high SDI bands. Regression models were constructed to predict DALYs and mortality up to 2030. Association between age-standardised prevalence of the diseases and mortality was also assessed. Findings: In 2019, age-standardised malnutrition-related DALYs was 680 (95% UI: 507-895) per 100,000 population. DALY rates decreased from 2000 to 2019 (-2.86% annually), projected to fall 8.4% from 2020 to 2030. Africa and low SDI countries observed highest malnutrition-related DALYs. Age-standardised obesity-related DALY estimates were 1933 (95% UI: 1277-2640). Obesity-related DALYs rose 0.48% annually from 2000 to 2019, predicted to increase by 39.8% from 2020 to 2030. Highest obesity-related DALYs were in Eastern Mediterranean and middle SDI countries. Interpretation: The ever-increasing obesity burden, on the backdrop of curbing the malnutrition burden, is predicted to rise further. Funding: None.

Cell Derived Nanovesicles (CDNs) have been developed from the rapidly expanding field of exosomes, representing a class of bioinspired Drug Delivery Systems (DDS). However, translation to clinical applications is limited by the low yield and multi-step approach in isolating naturally secreted exosomes. Here, we show the first demonstration of a simple and rapid production method of CDNs using spin cups via a cell shearing approach, which offers clear advantages in terms of yield and cost-effectiveness over both traditional exosomes isolation, and also existing CDNs fabrication techniques. The CDNs obtained were of a higher protein yield and showed similarities in terms of physical characterization, protein and lipid analysis to both exosomes and CDNs previously reported in the literature. In addition, we investigated the mechanisms of cellular uptake of CDNs in vitro and their biodistribution in an in vivo mouse tumour model. Colocalization of the CDNs at the tumour site in a cancer mouse model was demonstrated, highlighting the potential for CDNs as anti-cancer strategy. Taken together, the results suggest that CDNs could provide a cost-effective alternative to exosomes as an ideal drug nanocarrier.