Preoperative Diastolic Dysfunction and Postoperative Outcomes after Noncardiac Surgery.

OBJECTIVE: To determine if diastolic dysfunction is independently associated with increased mortality, acute kidney injury, and hospital length of stay after noncardiac surgery. DESIGN: Retrospective observational cohort. SETTING: Academic referral center. PARTICIPANTS: All patients undergoing noncardiac and nonliver-transplant surgeries at University of California - Los Angeles between April 2013 and October 2017, who also had transthoracic echocardiograms performed within 6 months preceding their procedures. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients' demographic, comorbidity, echocardiographic, and perioperative data were queried from the electronic health record. Diastolic dysfunction was graded by automated application of 2016 American Society of Echocardiography guidelines to queried echocardiographic measurements. During the study period, 12,871 eligible records were identified, of which 7,312 represented unique procedures with complete information. Twenty-three percent of patients had echocardiographic evidence of diastolic dysfunction (7.0% grade 1, 8.1% grade 2, 0.6% grade 3, and 7.5% nonspecific). Patients with diastolic dysfunction tended to be older and have higher American Society of Anesthesiologists scores with more comorbidities. Overall, 166 patients (2.3%) experienced an in-hospital death. After adjustment for potentially confounding variables, diastolic dysfunction was not significantly associated with increased in-hospital mortality, acute kidney injury, or hospital length of stay. CONCLUSIONS: Diastolic dysfunction does not appear to be associated with increased in-hospital mortality, acute kidney injury, or hospital length of stay in a cohort of noncardiac surgical patients at an academic medical center. These results highlight uncertainties in perioperative risk determination.

Characterization of enhancers and the role of the transcription factor KLF7 in regulating corneal epithelial differentiation.

During tissue development, transcription factors bind regulatory DNA regions called enhancers, often located at great distances from the genes they regulate, to control gene expression. The enhancer landscape during embryonic stem cell differentiation has been well characterized. By contrast, little is known about the shared and unique enhancer regulatory mechanisms in different ectodermally derived epithelial cells. Here we use ChIP sequencing (ChIP-seq) to identify domains enriched for the histone marks histone H3 lysine 4 trimethylation, histone H3 lysine 4 monomethylation, and histone H3 lysine 27 acetylation (H3K4me3, H3K4me1, and H3K27ac) and define, for the first time, the super enhancers and typical enhancers active in primary human corneal epithelial cells. We show that regulatory regions are often shared between cell types of the ectodermal lineage and that corneal epithelial super enhancers are already marked as potential regulatory domains in embryonic stem cells. Kruppel-like factor (KLF) motifs were enriched in corneal epithelial enhancers, consistent with the important roles of KLF4 and KLF5 in promoting corneal epithelial differentiation. We now show that the Kruppel family member KLF7 promotes the corneal progenitor cell state; on many genes, KLF7 antagonized the corneal differentiation-promoting KLF4. Furthermore, we found that two SNPs linked previously to corneal diseases, astigmatism, and Stevens-Johnson syndrome fall within corneal epithelial enhancers and alter their activity by disrupting transcription factor motifs that overlap these SNPs. Taken together, our work defines regulatory enhancers in corneal epithelial cells, highlights global gene-regulatory relationships shared among different epithelial cells, identifies a role for KLF7 as a KLF4 antagonist in corneal epithelial cell differentiation, and explains how two SNPs may contribute to corneal diseases.

The Association Between Rheumatoid Arthritis and Adverse Postoperative Outcomes: A Retrospective Analysis.

BACKGROUND: Patients with rheumatoid arthritis have a high overall incidence of mortality, primarily because of cardiovascular complications. Thus, we tested the primary hypothesis that rheumatoid arthritis is independently associated with increased postoperative cardiovascular complications. Second, we determined whether rheumatoid arthritis is associated with increased thromboembolic complications, microcirculatory complications, and mortality. METHODS: We obtained censuses of 2009 to 2010 inpatient hospital discharge data across 7 states (Arizona, California, Florida, Iowa, Maryland, Michigan, and New Jersey). Rheumatoid arthritis was identified using the present-on-admission diagnosis code 714.0. Each rheumatoid arthritis discharge that had surgery was propensity matched to a control discharge. Multivariable logistic regression was used to compare matched rheumatoid arthritis and control patients on risk of in-hospital cardiovascular complications. RESULTS: Among 5.5 million qualifying discharges, the matching procedure yielded successful 66,886 matched pairs. One thousand ninety-five (1.64%) of the matched rheumatoid arthritis discharges and 1006 (1.50%) of the matched controls had in-hospital cardiovascular complications. The adjusted odds ratio (99% confidence interval) was estimated at 1.08 (0.96-1.21; P = 0.08). There were no significant differences in the odds of in-hospital thromboembolic complications (1.03 [0.93-1.15]; P = 0.42), in-hospital microcirculatory complications (0.94 [0.86-1.01]; P = 0.03), or in-hospital mortality (1.11 [0.98-1.25]; P = 0.04). CONCLUSIONS: Rheumatoid arthritis was not associated with an increased risk for postoperative cardiovascular complications.

A molecular characterization of spontaneous frameshift mutagenesis within the trpA gene of Escherichia coli.

Spontaneous frameshift mutations are an important source of genetic variation in all species and cause a large number of genetic disorders in humans. To enhance our understanding of the molecular mechanisms of frameshift mutagenesis, 583 spontaneous Trp+ revertants of two trpA frameshift alleles in Escherichia coli were isolated and DNA sequenced. In order to measure the contribution of methyl-directed mismatch repair to frameshift production, mutational spectra were constructed for both mismatch repair-proficient and repair-defective strains. The molecular origins of practically all of the frameshifts analyzed could be explained by one of six simple models based upon misalignment of the template or nascent DNA strands with or without misincorporation of primer nucleotides during DNA replication. Most frameshifts occurred within mononucleotide runs as has been shown often in previous studies but the location of the 76 frameshift sites was usually outside of runs. Mismatch repair generally was most effective in preventing the occurrence of frameshifts within runs but there was much variation from site to site. Most frameshift sites outside of runs appear to be refractory to mismatch repair although the small number of occurrences at most of these sites make firm conclusions impossible. There was a dense pattern of reversion sites within the trpA DNA region where reversion events could occur, suggesting that, in general, most DNA sequences are capable of undergoing spontaneous mutational events during replication that can lead to small deletions and insertions. Many of these errors are likely to occur at low frequencies and be tolerated as events too costly to prevent or repair. These studies also revealed an unpredicted flexibility in the primary amino acid sequence of the trpA product, the alpha subunit of tryptophan synthase.