Ssm1 is responsible for the mouse strain-specific DNA methylation of the transgene HRD. In adult mice of the C57BL/6 (B6) strain, the transgene is methylated at essentially all CpGs. However, when the transgene is bred into the DBA/2 (D2) strain, it is almost completely unmethylated. Strain-specific methylation arises during differentiation of embryonic stem (ES) cells. Here we show that Ssm1 causes striking chromatin changes during the development of the early embryo in both strains. In undifferentiated ES cells of both strains, the transgene is in a chromatin state between active and inactive. These states are still observed 1 week after beginning ES cell differentiation. However, 4 weeks after initiating differentiation, in B6, the transgene has become heterochromatic, and in D2, the transgene has become euchromatic. HRD is always expressed in D2, but in B6, it is expressed only in early embryos. The transgene is already more methylated in B6 ES cells than in D2 ES cells and becomes increasingly methylated during development in B6, until essentially all CpGs in the critical guanosine phosphoribosyl transferase core are methylated. Clearly, DNA methylation of HRD precedes chromatin compaction and loss of expression, suggesting that the B6 form of Ssm1 interacts with DNA to cause strain-specific methylation that ultimately results in inactive chromatin.

Objectives To compare postoperative outcomes in patients prescribed long-acting opioids vs opioid-naïve patients who underwent elective noncardiac surgeries. Design Retrospective cohort study. Setting Single urban academic institution. Methods and Subjects We retrospectively compared postoperative outcomes in long-acting opioid users vs opioid-naïve patients who underwent elective noncardiac surgeries. Inpatient and ambulatory surgery cohorts were separately analyzed. Preoperative medication lists were queried for the presence of long-acting opioids or absence of opioids. Multivariable logistic regression was performed to analyze the impact of long-acting opioid use on readmission rate, respiratory failure, and adverse cardiac events. Multivariable zero-truncated negative binomial regression was used to examine length of stay. Results After exclusions, there were 93,644 adult patients in the study population, 23,605 of whom underwent inpatient surgeries and 70,039 of whom underwent ambulatory surgeries. After adjusting for potential confounders and inpatient surgeries, preoperative long-acting opioid use was associated with increased risk of prolonged length of stay (incidence rate ratio = 1.1, 99% confidence interval [CI] = 1.0–1.2, P < 0.01) but not readmission. For ambulatory surgeries, preoperative long-acting opioid use was associated with increased risk of all-cause as well as pain-related readmission (odds ratio [OR] = 2.1, 99% CI = 1.5–2.9, P < 0.001; OR = 2.0, 99% CI = 0.85–4.2, P = 0.02, respectively). There were no significant differences for respiratory failure or adverse cardiac events. Conclusions The use of preoperative long-acting opioids was associated with prolonged length of stay for inpatient surgeries and increased risk of all-cause and pain-related readmission for ambulatory surgeries. Timely interventions for patients on preoperative long-acting opioids may be needed to improve these outcomes.

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To examine the association of preoperative opioids and/or benzodiazepines on postoperative outcomes in total knee and hip arthroplasty, we retrospectively compared postoperative outcomes in those prescribed preoperative opioids and/or benzodiazepines versus those who were not who underwent elective total knee and hip arthroplasty at a single urban academic institution. Multivariable logistic regression was performed for readmission rate, respiratory failure, infection, and adverse cardiac events. Multivariable zero-truncated negative binomial regression was used for length of stay. After exclusions, there were 4307 adult patients in the study population, 2009 of whom underwent total knee arthroplasty and 2298 of whom underwent total hip arthroplasty. After adjusting for potential confounders, preoperative benzodiazepine use was associated with increased odds of readmission (p < 0.01). Preoperative benzodiazepines were not associated with increased odds of respiratory failure nor increased length of stay. Preoperative opioids were not associated with increased odds of the examined outcomes. There were insufficient numbers of infection and cardiac events for analysis. In this study population, preoperative benzodiazepines were associated with increased odds of readmission. Preoperative opioids were not associated with increased odds of the examined outcomes. Studies are needed to further examine risks associated with preoperative benzodiazepine use.