Blood Pressure Trajectories in the 20 Years Before Death.

Importance: There is mixed evidence that blood pressure (BP) stabilizes or decreases in later life. It is also unclear whether BP trajectories reflect advancing age, proximity to end of life, or selective survival of persons free from hypertension. Objective: To estimate individual patient BP for each of the 20 years before death and identify potential mechanisms that may explain trajectories. Design, Study, and Participants: We analyzed population-based Clinical Practice Research Datalink primary care and linked hospitalization electronic medical records from the United Kingdom, using retrospective cohort approaches with generalized linear mixed-effects modeling. Participants were all available individuals with BP measures over 20 years, yielding 46 634 participants dying aged at least 60 years, from 2010 to 2014. We also compared BP slopes from 10 to 3 years before death for 20 207 participants who died, plus 20 207 birth-year and sex-matched participants surviving longer than 9 years. Main Outcomes and Measures: Clinically recorded individual patient repeated systolic BP (SBP) and diastolic BP (DBP). Results: In 46 634 participants (51.7% female; mean [SD] age at death, 82.4 [9.0] years), SBPs and DBPs peaked 18 to 14 years before death and then decreased progressively. Mean changes in SBP from peak values ranged from -8.5 mm Hg (95% CI, -9.4 to -7.7) for those dying aged 60 to 69 years to -22.0 mm Hg (95% CI, -22.6 to -21.4) for those dying at 90 years or older; overall, 64.0% of individuals had SBP changes of greater than -10 mm Hg. Decreases in BP appeared linear from 10 to 3 years before death, with steeper decreases in the last 2 years of life. Decreases in SBP from 10 to 3 years before death were present in individuals not treated with antihypertensive medications, but mean yearly changes were steepest in patients with hypertension (-1.58; 95% CI, -1.56 to -1.60 mm Hg vs -0.70; 95% CI, -0.65 to -0.76 mm Hg), dementia (-1.81; 95% CI, -1.77 to -1.87 mm Hg vs -1.41; 95% CI, -1.38 to -1.43 mm Hg), heart failure (-1.66; 95% CI, -1.62 to -1.69 mm Hg vs -1.37; 95% CI, -1.34 to -1.39 mm Hg), and late-life weight loss. Conclusions and Relevance: Mean SBP and DBP decreased for more than a decade before death in patients dying at 60 years and older. These BP decreases are not simply attributable to age, treatment of hypertension, or better survival without hypertension. Late-life BP decreases may have implications for risk estimation, treatment monitoring, and trial design.

A genome-wide map of CTCF multivalency redefines the CTCF code.

The "CTCF code" hypothesis posits that CTCF pleiotropic functions are driven by recognition of diverse sequences through combinatorial use of its 11 zinc fingers (ZFs). This model, however, is supported by in vitro binding studies of a limited number of sequences. To study CTCF multivalency in vivo, we define ZF binding requirements at ∼50,000 genomic sites in primary lymphocytes. We find that CTCF reads sequence diversity through ZF clustering. ZFs 4-7 anchor CTCF to ∼80% of targets containing the core motif. Nonconserved flanking sequences are recognized by ZFs 1-2 and ZFs 8-11 clusters, which also stabilize CTCF broadly. Alternatively, ZFs 9-11 associate with a second phylogenetically conserved upstream motif at ∼15% of its sites. Individually, ZFs increase overall binding and chromatin residence time. Unexpectedly, we also uncovered a conserved downstream DNA motif that destabilizes CTCF occupancy. Thus, CTCF associates with a wide array of DNA modules via combinatorial clustering of its 11 ZFs.