The mortality burden related to COVID-19 in 2020 and 2021 - years of life lost and excess mortality in 13 countries and sub-national regions in Southern and Eastern Europe, and Central Asia.

Introduction: Between 2021 and 2023, a project was funded in order to explore the mortality burden (YLL-Years of Life Lost, excess mortality) of COVID-19 in Southern and Eastern Europe, and Central Asia. Methods: For each national or sub-national region, data on COVID-19 deaths and population data were collected for the period March 2020 to December 2021. Unstandardized and age-standardised YLL rates were calculated according to standard burden of disease methodology. In addition, all-cause mortality data for the period 2015-2019 were collected and used as a baseline to estimate excess mortality in each national or sub-national region in the years 2020 and 2021. Results: On average, 15-30 years of life were lost per death in the various countries and regions. Generally, YLL rates per 100,000 were higher in countries and regions in Southern and Eastern Europe compared to Central Asia. However, there were differences in how countries and regions defined and counted COVID-19 deaths. In most countries and sub-national regions, YLL rates per 100,000 (both age-standardised and unstandardized) were higher in 2021 compared to 2020, and higher amongst men compared to women. Some countries showed high excess mortality rates, suggesting under-diagnosis or under-reporting of COVID-19 deaths, and/or relatively large numbers of deaths due to indirect effects of the pandemic. Conclusion: Our results suggest that the COVID-19 mortality burden was greater in many countries and regions in Southern and Eastern Europe compared to Central Asia. However, heterogeneity in the data (differences in the definitions and counting of COVID-19 deaths) may have influenced our results. Understanding possible reasons for the differences was difficult, as many factors are likely to play a role (e.g., differences in the extent of public health and social measures to control the spread of COVID-19, differences in testing strategies and/or vaccination rates). Future cross-country analyses should try to develop structured approaches in an attempt to understand the relative importance of such factors. Furthermore, in order to improve the robustness and comparability of burden of disease indicators, efforts should be made to harmonise case definitions and reporting for COVID-19 deaths across countries.

Dynamic changes in O-GlcNAcylation regulate osteoclast differentiation and bone loss via nucleoporin 153.

Bone mass is maintained by the balance between osteoclast-induced bone resorption and osteoblast-triggered bone formation. In inflammatory arthritis such as rheumatoid arthritis (RA), however, increased osteoclast differentiation and activity skew this balance resulting in progressive bone loss. O-GlcNAcylation is a posttranslational modification with attachment of a single O-linked ß-D-N-acetylglucosamine (O-GlcNAc) residue to serine or threonine residues of target proteins. Although O-GlcNAcylation is one of the most common protein modifications, its role in bone homeostasis has not been systematically investigated. We demonstrate that dynamic changes in O-GlcNAcylation are required for osteoclastogenesis. Increased O-GlcNAcylation promotes osteoclast differentiation during the early stages, whereas its downregulation is required for osteoclast maturation. At the molecular level, O-GlcNAcylation affects several pathways including oxidative phosphorylation and cell-cell fusion. TNFα fosters the dynamic regulation of O-GlcNAcylation to promote osteoclastogenesis in inflammatory arthritis. Targeted pharmaceutical or genetic inhibition of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) arrests osteoclast differentiation during early stages of differentiation and during later maturation, respectively, and ameliorates bone loss in experimental arthritis. Knockdown of NUP153, an O-GlcNAcylation target, has similar effects as OGT inhibition and inhibits osteoclastogenesis. These findings highlight an important role of O-GlcNAcylation in osteoclastogenesis and may offer the potential to therapeutically interfere with pathologic bone resorption.