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Abstract Earth’s obliquity and eccentricity cycles are strongly imprinted on Earth’s climate and widely used to measure geological time. However, the record of these imprints on the oxygen isotope record in deep-sea benthic foraminifera (δ18Ob) shows contradictory signals that violate isotopic principles and cause controversy over climate-ice sheet interactions. Here, we present a δ18Ob record of high fidelity from International Ocean Drilling Program (IODP) Site U1406 in the northwest Atlantic Ocean. We compare our record to other records for the time interval between 28 and 20 million years ago, when Earth was warmer than today, and only Antarctic ice sheets existed. The imprint of eccentricity on δ18Ob is remarkably consistent globally whereas the obliquity signal is inconsistent between sites, indicating that eccentricity was the primary pacemaker of land ice volume. The larger eccentricity-paced early Antarctic ice ages were vulnerable to rapid termination. These findings imply that the self-stabilizing hysteresis effects of large land-based early Antarctic ice sheets were strong enough to maintain ice growth despite consecutive insolation-induced polar warming episodes. However, rapid ice age terminations indicate that resistance to melting was weaker than simulated by numerical models and regularly overpowered, sometimes abruptly.

Abstract Denosumab is a monoclonal anti-RANKL antibody that inhibits bone resorption, increases bone mass, and reduces fracture risk. Denosumab discontinuation causes an extensive wave of rebound resorption, but the cellular mechanisms remain poorly characterized. We utilized in situ hybridization (ISH) as a direct approach to identify the cells that activate osteoclastogenesis through the RANKL/OPG pathway. ISH was performed across species, skeletal sites, and following recombinant OPG (OPG:Fc) and parathyroid hormone 1–34 (PTH) treatment of mice. OPG:Fc treatment in mice induced an increased expression of RANKL mRNA mainly in trabecular, but not endocortical bone surface cells. Additionally, a decreased expression of OPG mRNA was detected in bone surface cells and osteocytes of both compartments. A similar but more pronounced effect on RANKL and OPG expression was seen one hour after PTH treatment. These findings suggest that bone surface cells and osteocytes conjointly regulate the activation of osteoclastogenesis, and that OPG:Fc treatment induces a local accumulation of osteoclastogenic activation sites, ready to recruit and activate osteoclasts upon treatment discontinuation. Analysis of publicly available single-cell RNA sequencing (scRNAseq) data from murine bone marrow stromal cells revealed that Tnfsf11 + cells expressed high levels of Mmp13, Limch1, and Wif1, confirming their osteoprogenitor status. ISH confirmed co-expression of Mmp13 and Tnfsf11 in bone surface cells of both vehicle- and OPG:Fc-treated mice. Under physiological conditions of human/mouse bone, RANKL is expressed mainly by osteoprogenitors proximate to the osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts.

Purpose/objective: Our purpose was to examine congestive heart failure (CHF) readmissions from the veterans' perspective. The use of health care provider interventions, such as standardized education materials, home telehealth, and a CHF clinic, was able to reduce readmissions rates from 35% to 23%. Our objective was to use input from the veterans to fine-tune our efforts and achieve readmission rates for patients with CHF below the national average of 21%. We wanted to identify factors that result in CHF readmissions, including disease education, self-care management, and barriers to self-care. This study was directed toward answering two questions: 1. What is the veteran’s explanation for readmission? 2. According to the veteran, what are the barriers to following their treatment regimen?, Primary Practice Setting: It was a rural 84-bed Veterans Health Administration hospital in the Western United States., Findings: Before this study, our efforts to reduce CHF readmissions were one-sided, all from the health care professionals' viewpoint. We wanted to hear what the veteran had to say; so, we interviewed 25 veterans. Four veterans were excluded due to issues with their consents. Ninety percent (n = 19/21) responded that they knew their CHF was worse by a change in their breathing (shortness of breath). They identified 48 signs/symptoms that indicated worsening CHF. Weight gain was noted as an indication of worsening CHF symptoms (n = 6/48) in 12.5% of the responses. Twenty-five percent (n = 12/48) of the veterans stated they recognized the early symptoms of worsening CHF. Thirty-eight percent (n = 8/21) of the veterans stated they had early symptoms of worsening CHF, but only two of them contacted their doctor. It is interesting to note that only 29% (n = 6/21) of the veterans recognized weight gain as a sign of worsening CHF and all of these veterans listed other symptoms (such as shortness of breath) along with weight gain. Weighing on a daily basis was practiced by only 30% of the group (n = 7/21); all but two of the veterans had no problems with weighing themselves. More than 71% of the veterans responded that they had no problems following their diet or taking their medications. More than half of the veterans did not need help with meals, transportation, or daily grooming/dressing/toileting., Conclusions: We were concerned about the evident delays in seeking medical care for worsening CHF. All veterans who did need help with the activities of daily living, medications, or diet had their needs met through their support systems. They did not perceive any barriers to seeking care. However, there remain many unanswered questions. Does the patient understand their discharge education and know how to use this information from daily weights or recognition of early symptoms, to indicate their need for urgent and emergency medical interventions? Or is it a problem that the education is not sufficient? Is it a question of the burden of care from multiple comorbid conditions or of taking too many medications? Do social issues drive readmissions? These questions are further explored in a second study, which is in the data analysis stage., Implications for Case Management Practice: There are three key findings from our study. 1. Veterans think in terms of symptoms that increase the impact of CHF on their life. 2. The relationship between daily weight and controlling CHF is not clear to veterans. 3. Hospital discharge instructions should clearly associate symptoms that are associated with worsening CHF.