Enhanced Recovery After Surgery Is Associated With Improved Outcomes and Reduced Racial and Ethnic Disparities After Isolated Coronary Artery Bypass Surgery: A Retrospective Analysis With Propensity-Score Matching.

OBJECTIVES: To evaluate whether enhanced recovery after surgery (ERAS) protocol implementation was associated with improved outcomes and decreased racial and ethnic outcome disparities after isolated coronary artery bypass graft (CABG) surgery. DESIGN: A retrospective analysis of an institutional CABG database with propensity-score matching. SETTING: At a single tertiary care teaching hospital. PARTICIPANTS: One thousand seven hundred thirty-five patients undergoing isolated CABG: 656 patients from 2016 to 2017 (pre-ERAS) and 1,079 patients from 2018 to 2020 (post-ERAS). Each patient cohort was divided into a White subgroup and a racial and ethnic minorities (Minorities) subgroup. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Propensity-matched post-ERAS patients (n = 584) compared to pre-ERAS patients (n = 584) demonstrated reductions in total length of stay (LOS) (median [interquartile range]): (7 [5-10] v 8 [6-11.5] days, p = .006), postoperative LOS (5 [4-7] v 5 [4-7] days, p = .001), total ventilation time (6.1 [4.8-9.5] v 6.6 [5.2-10.9] hours, p = .004), postoperative morphine milligram equivalents (mean ± standard deviation: 68.6 ± 57.5 v 100.0 ± 59.4, p < .001), and increased likelihood of early extubation (48.8% v 42.3%, p = .026); the Minorities subgroup demonstrated reductions in likelihood of intensive care unit (ICU) readmission (1.3% v 8.1%, p = .012) and postoperative morphine milligram equivalents (73.6 ± 64.0 v 107.8 ± 71.9, p < .001). Logistic regression models demonstrated that disparities in ICU readmission and postoperative LOS between White and Minorities patients were eliminated post-ERAS. CONCLUSIONS: ERAS for isolated CABG surgery was associated with reduced total and postoperative LOS, reduced total ventilation time, and increased early extubation for all patients, as well as reduced ICU readmission for the Minorities subgroup. ERAS implementation was associated with reduced disparities between White and racial and ethnic minority patients for ICU readmission and postoperative LOS.

Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.

Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model.

Trends in the Management of Patients With Left Ventricular Assist Devices Presenting for Noncardiac Surgery: A 10-Year Institutional Experience.

In our institution, the vast majority of patients presenting for noncardiac surgery (NCS) while supported by a left ventricular assist device (LVAD) are now cared for by noncardiac-trained anesthesiologists as the result of a decade of educational intervention to effect this transition. This represents a significant departure from the published experiences of other institutions. With institutional review board approval, we queried the database of our anesthesia record keeping system (CompuRecord) to determine various aspects of the perioperative management of these patients from July 1, 2003, through June 30, 2013, during which time 271 NCS procedures were performed on adult patients supported by LVADs. Over the entire study period (2003-2013), anesthetic care was provided by a cardiac anesthesiologist 47% of the time and by a noncardiac anesthesiologist 53% of the time. However, by the time period 2012-2013, 88% of the NCS procedures were staffed by a noncardiac anesthesiologist. Despite the prevalence of continuous flow devices in this series, the use of invasive blood pressure monitoring decreased dramatically by the later years of the study. Vasoactive and inotropic medications were rarely required intraoperatively. No intraoperative cardiac arrests, thromboembolic complications, or device malfunctions occurred. Our conclusion is that NCS procedures on LVAD-supported patients can be safely managed by educated noncardiac anesthesiologists.

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

Lysine auxotrophy combined with deletion of the SecA2 gene results in a safe and highly immunogenic candidate live attenuated vaccine for tuberculosis.

Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a major global health problem, despite the widespread use of the M. bovis Bacille Calmette-Guerin (BCG) vaccine and the availability of drug therapies. In recent years, the high incidence of coinfection of M. tuberculosis and HIV, as well as escalating problems associated with drug resistance, has raised ominous concerns with regard to TB control. Vaccination with BCG has not proven highly effective in controlling TB, and also has been associated with increasing concerns about the potential for the vaccine to cause disseminated mycobacterial infection in HIV infected hosts. Thus, the development of an efficacious and safe TB vaccine is generally viewed as a critical to achieving control of the ongoing global TB pandemic. In the current study, we have analyzed the vaccine efficacy of an attenuated M. tuberculosis strain that combines a mutation that enhances T cell priming (ΔsecA2) with a strongly attenuating lysine auxotrophy mutation (ΔlysA). The ΔsecA2 mutant was previously shown to be defective in the inhibition of apoptosis and markedly increased priming of antigen-specific CD8(+) T cells in vivo. Similarly, the ΔsecA2ΔlysA strain retained enhanced apoptosis and augmented CD8(+) T cell stimulatory effects, but with a noticeably improved safety profile in immunosuppressed mice. Thus, the M. tuberculosis ΔsecA2ΔlysA mutant represents a live attenuated TB vaccine strain with the potential to deliver increased protection and safety compared to standard BCG vaccination.

Caveolin-1 expression determines the route of neutrophil extravasation through skin microvasculature.

Interleukin-8 plays a key role in the acute inflammatory response by mediating recruitment of neutrophils through vessel walls into affected tissues. During this process, molecular signals guide circulating blood neutrophils to target specific vessels for extravasation and to migrate through such vessels via particular routes. Our results show that levels of endothelial caveolin-1, the protein responsible for the induction of the membrane domains known as caveolae, are critical to each of these processes. We demonstrate that, in response to the intradermal injection of interleukin-8, neutrophils are preferentially recruited to a unique subset of venules that express high levels of intercellular adhesion molecule-1 and low levels of caveolin-1. Our results show that neutrophils traverse human dermal microvascular endothelial cells using one of two pathways: a transcellular route directly through the cell or a paracellular route through cellular junctions. Caveolin-1 expression appears to favor the transcellular path while down-regulation of caveolin-1 promotes the paracellular route.

Enhanced priming of adaptive immunity by a proapoptotic mutant of Mycobacterium tuberculosis.

The inhibition of apoptosis of infected host cells is a well-known but poorly understood function of pathogenic mycobacteria. We show that inactivation of the secA2 gene in Mycobacterium tuberculosis, which encodes a component of a virulence-associated protein secretion system, enhanced the apoptosis of infected macrophages by diminishing secretion of mycobacterial superoxide dismutase. Deletion of secA2 markedly increased priming of antigen-specific CD8(+) T cells in vivo, and vaccination of mice and guinea pigs with a secA2 mutant significantly increased resistance to M. tuberculosis challenge compared with standard M. bovis bacille Calmette-Guérin vaccination. Our results define a mechanism for a key immune evasion strategy of M. tuberculosis and provide what we believe to be a novel approach for improving mycobacterial vaccines.