Derivation and validation of pragmatic clinical models to predict hospital length of stay after cardiac surgery in Ontario, Canada: a population-based cohort study.

BACKGROUND: Cardiac surgery is resource intensive and often requires multidisciplinary involvement to facilitate discharge. To facilitate evidence-based resource planning, we derived and validated clinical models to predict postoperative hospital length of stay (LOS). METHODS: We used linked, population-level databases with information on all Ontario residents and included patients aged 18 years or older who underwent coronary artery bypass grafting, valvular or thoracic aorta surgeries between October 2008 and September 2019. The primary outcome was hospital LOS. The models were derived by using patients who had surgery before Sept. 30, 2016, and validated after that date. To address the rightward skew in LOS data and to identify top-tier resource users, we used logistic regression to derive a model to predict the likelihood of LOS being more than the 98th percentile (> 30 d), and γ regression in the remainder to predict continuous LOS in days. We used backward stepwise variable selection for both models. RESULTS: Among 105 193 patients, 2422 (2.3%) had an LOS of more than 30 days. Factors predicting prolonged LOS included age, female sex, procedure type and urgency, comorbidities including frailty, high-risk acute coronary syndrome, heart failure, reduced left ventricular ejection fraction and psychiatric and pulmonary circulatory disease. The C statistic was 0.92 for the prolonged LOS model and the mean absolute error was 2.4 days for the continuous LOS model. INTERPRETATION: We derived and validated clinical models to identify top-tier resource users and predict continuous LOS with excellent accuracy. Our models could be used to benchmark clinical performance based on expected LOS, rationally allocate resources and support patient-centred operative decision-making.

Association of frailty with days alive at home after cardiac surgery: a population-based cohort study.

BACKGROUND: Frailty is a geriatric syndrome that leaves people vulnerable to adverse outcomes. In cardiac surgery, minimal data describe associations between frailty and patient-centred outcomes. Our objective was to estimate the association between frailty and days alive at home after cardiac surgery. METHODS: We conducted a population-based cohort study using linked health administrative data in the Canadian province of Ontario. All individuals >65 yr at the time of cardiac surgery were assigned a frailty score using a validated frailty index. Days alive and at home in the 30 and 365 days after surgery were calculated. The unadjusted and adjusted associations between frailty and days alive at home were calculated. RESULTS: We identified 61 389 patients from 2009 to 2015. Frailty was associated with reduced days at home within 30 days (adjusted ratio of means for every 10% increase in frailty=0.79; 95% confidence interval [CI], 0.78-0.81; P<0.0001) and 365 days (adjusted ratio of means for every 10% increase in frailty=0.92; 95% CI, 0.91-0.93; P<0.0001) of surgery. Results were consistent in sensitivity analyses (5.0 fewer days alive at home [95% CI, 4.8-5.2] within 30 days and 9.0 fewer days alive at home [95% CI, 8.7-9.2] within 365 days after surgery). CONCLUSION: Frailty is associated with a reduction in days alive at home after major cardiac surgery. This information should be considered in prognostic discussions before surgery and in care planning for vulnerable older patient groups. Days alive at home may be a useful outcome for routine measurement in quality, reporting, and studies using routinely collected data.

In vitro inhibition of metabolism but not transport of gliclazide and repaglinide by Cree medicinal plant extracts.

ETHNOPHARMACOLOGICAL RELEVANCE: Interactions between conventional drug and traditional medicine therapies may potentially affect drug efficacy and increase the potential for adverse reactions. Cree traditional healing is holistic and patients may use medicinal plants simultaneously with the conventional drugs. However, there is limited information that these medicinal plants may interact with drugs and additional mechanistic information is required. In this study, extracts from traditionally used Cree botanicals were assessed for their potential interaction that could alter the disposition of two blood glucose lowering drugs, gliclazide (Diamicron) and repaglinide (Gluconorm) though inhibition of either metabolism or transport across cell membranes. MATERIALS AND METHODS: The effect of 17 extracts on metabolism was examined in a human liver microsome assay by HPLC and individual cytochrome P450s 2C9, 2C19, 2C8 and 3A4 in a microplate fluorometric assay. Gliclazide, rhaponticin and its aglycone derivative, rhapontigenin were also examined in the fluorometric assay. The effect on transport was examined with 11 extracts using the intestinal epithelial Caco-2 differentiated cell monolayer model at times up to 180 min. RESULTS: Both blood glucose lowering medications, gliclazide and repaglinide traversed the Caco-2 monolayer in a time-dependent manner that was not affected by the Cree plant extracts. Incubation of the Cree plant extracts inhibited CYP2C9, 2C19, 2C8 and 3A4-mediated metabolism, and the formation of four repaglinide metabolites: M4, m/z 451-A, m/z 451-B and the glucuronide of repaglinide in the human liver microsome assay. Gliclazide caused no significant inhibition. Likewise, rhaponticin had little effect on the enzymes causing changes of less than 10% with an exception of 17% inhibition of CYP2C19. By contrast, the aglycone rhapontigenin showed the greatest effects on all CYP-mediated metabolism. Its inhibition ranged from a mean of 58% CYP3A4 inhibition to 89% inhibition of CYP2C9. While rhaponticin and the aglycone did not show significant effects on repaglinide metabolism, they demonstrated inhibition of gliclazide metabolism. The aglycone significantly affected levels of gliclazide and its metabolites. CONCLUSION: These studies demonstrate that the Cree plant extracts examined have the potential in vitro to cause drug interactions through effects on key metabolic enzymes.

Diacylglycerol kinase ζ regulates RhoA activation via a kinase-independent scaffolding mechanism.

Rho GTPases share a common inhibitor, Rho guanine nucleotide dissociation inhibitor (RhoGDI), which regulates their expression levels, membrane localization, and activation state. The selective dissociation of individual Rho GTPases from RhoGDI ensures appropriate responses to cellular signals, but the underlying mechanisms are unclear. Diacylglycerol kinase ζ (DGKζ), which phosphorylates diacylglycerol to yield phosphatidic acid, selectively dissociates Rac1 by stimulating PAK1-mediated phosphorylation of RhoGDI on Ser-101/174. Similarly, phosphorylation of RhoGDI on Ser-34 by protein kinase Cα (PKCα) selectively releases RhoA. Here we show DGKζ is required for RhoA activation and Ser-34 phosphorylation, which were decreased in DGKζ-deficient fibroblasts and rescued by wild-type DGKζ or a catalytically inactive mutant. DGKζ bound directly to the C-terminus of RhoA and the regulatory arm of RhoGDI and was required for efficient interaction of PKCα and RhoA. DGKζ-null fibroblasts had condensed F-actin bundles and altered focal adhesion distribution, indicative of aberrant RhoA signaling. Two targets of the RhoA effector ROCK showed reduced phosphorylation in DGKζ-null cells. Collectively our findings suggest DGKζ functions as a scaffold to assemble a signaling complex that functions as a RhoA-selective, GDI dissociation factor. As a regulator of Rac1 and RhoA activity, DGKζ is a critical factor linking changes in lipid signaling to actin reorganization.