Highlights d Statin treatment among 13,981 patients with COVID-19 was retrospectively studied d Statin use in this cohort was associated with a lower risk of all-cause mortality d Adding an ACE inhibitor or an ARB did not affect statinassociated outcome in the cohort d The benefit of statins among this cohort may be due to immunomodulatory benefits

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dHOX cluster genes are activated sequentially in their positional order along the chromosome during vertebrate development. This phenomenon, known as temporal colinearity, depends on transcriptional silencing of 5= HOX genes. Chromatin looping was recently identified as a conserved feature of silent HOX clusters, with CCCTC-binding factor (CTCF) binding sites located at the loop bases. However, the potential contribution of CTCF to HOX cluster silencing and the underlying mechanism have not been established. Here, we demonstrate that the HOXA locus is organized by CTCF into chromatin loops and that CTCF depletion causes significantly enhanced activation of HOXA3 to -A7, -A9 to -A11, and -A13 in response to retinoic acid, with the highest effect observed for HOXA9. Our subsequent analyses revealed that CTCF facilitates the stabilization of Polycomb repressive complex 2 (PRC2) and trimethylated lysine 27 of histone H3 (H3K27me3) at the human HOXA locus. Our results reveal that CTCF functions as a controller of HOXA cluster silencing and mediates PRC2-repressive higher-order chromatin structure. HOX genes are organized in clusters in vertebrate genomes and are essential for the patterning of the anterior-posterior body axis. These genes are activated in a temporal-spatial manner according to their position along the chromosome in vertebrates. This phenomenon, temporal-spatial colinearity, is pivotal for the correct patterning of animal bodies and depends on the proper silencing of 5= HOX genes (1). In a cellular model, a progressive transition from a repressed to an active chromatin state along the cluster from 3= to 5= has been proposed to mediate HOX colinearity (2-5), accompanied by nuclear reorganization (6-9) and changes in the higher-order chromatin structure of the clusters (10). A recent study revealed a transition in HOX cluster architecture from an initial single 3-dimensional (3-D) structure to a bimodal state that separates the active and inactive genes during colinear activation of HOX genes in mouse embryos (11). Whether spatial chromatin organization is the cause or a consequence of colinear activation and 5= silencing remains unknown. In addition, the factors responsible for the organization of the higher-order chromatin structure of HOX clusters remain to be identified.Recent findings have indicated that CCCTC-binding factor (CTCF) acts as a "master weaver" of the genome (12). Approximately 20,000 CTCF-binding sites (CBSs) have been identified in the human genome (13-15). These sites are frequently associated with cohesin complexes, which mediate sister chromatid cohesion during mitosis and gene regulation in postmitotic cells (16)(17)(18)(19). Multiple highly conserved CBSs have been identified in the human HOXA cluster. Bioinformatics analyses have suggested that CTCF mediates 3-D structure and thereby regulates gene expression in HOX clusters (10). CTCF-binding site 5 in the HOXA cluster (CBS5) has been reported to function as a developmental stage-specific insulator that regulates the expressio...