Anticancer Properties of Ru and Os Half-Sandwich Complexes of N,S Bidentate Schiff Base Ligands Derived from Phenylthiocarbamide.

The versatile coordinating nature of N,S bidentate ligands is of great importance in medicinal chemistry imparting stability and enhancing biological properties of the metal complexes. Phenylthiocarbamide-based N,S donor Schiff bases converted into RuII /OsII (cymene) complexes and characterized by spectroscopic techniques and elemental analysis. The hydrolytic stability of metal complexes to undergo metal-halide ligand exchange reaction was confirmed both by the DFT and NMR experimentation. The ONIOM (QM/MM) study confirmed the histone protein targeting nature of aqua/hydroxido complex 2 aH with an excellent binding energy of -103.19 kcal/mol. The antiproliferative activity against a panel of cancer cells A549, MCF-7, PC-3, and HepG2 revealed that ruthenium complexes 1 a-3 a were more cytotoxic than osmium complexes and their respective ligands 1-3 as well. Among these ruthenium cymene complex bearing sulfonamide moiety 2 a proved a strong cytotoxic agent and showed excellent correlation of cellular accumulation, lipophilicity, and drug-likeness to the anticancer activity. Moreover, the favorable physiochemical properties such as bioavailability and gastrointestinal absorption of ligand 2 also supported the development of Ru complex 2 a as an orally active anticancer metallodrug.

A salt-baking 'recipe' of commercial nickel-molybdenum alloy foam for oxygen evolution catalysis in water splitting.

Ni-based metal foam holds promise as an electrochemical water-splitting catalyst, due to its low cost, acceptable catalytic activity and superior stability. However, its catalytic activity must be improved before it can be used as an energy-saving catalyst. Here, a traditional Chinese recipe, salt-baking, was employed to surface engineering of nickel-molybdenum alloy (NiMo) foam. During salt-baking, a thin layer of FeOOH nano-flowers was assembled on the NiMo foam surface then the resultant NiMo-Fe catalytic material was evaluated for its ability to support oxygen evolution reaction (OER) activity. The NiMo-Fe foam catalyst generated an electric current density of 100 mA cm-2 that required an overpotential of only 280 mV, thus demonstrating that its performance far exceeded that of the benchmark catalyst RuO2 (375 mV). When employed as both the anode and cathode for use in alkaline water electrolysis, the NiMo-Fe foam generated a current density (j) output that was 3.5 times greater than that of NiMo. Thus, our proposed salt-baking method is a promising simple and environmentally friendly approach for surface engineering of metal foam for designing catalysts.

Axonal Regeneration: Underlying Molecular Mechanisms and Potential Therapeutic Targets.

Axons in the peripheral nervous system have the ability to repair themselves after damage, whereas axons in the central nervous system are unable to do so. A common and important characteristic of damage to the spinal cord, brain, and peripheral nerves is the disruption of axonal regrowth. Interestingly, intrinsic growth factors play a significant role in the axonal regeneration of injured nerves. Various factors such as proteomic profile, microtubule stability, ribosomal location, and signalling pathways mark a line between the central and peripheral axons' capacity for self-renewal. Unfortunately, glial scar development, myelin-associated inhibitor molecules, lack of neurotrophic factors, and inflammatory reactions are among the factors that restrict axonal regeneration. Molecular pathways such as cAMP, MAPK, JAK/STAT, ATF3/CREB, BMP/SMAD, AKT/mTORC1/p70S6K, PI3K/AKT, GSK-3ß/CLASP, BDNF/Trk, Ras/ERK, integrin/FAK, RhoA/ROCK/LIMK, and POSTN/integrin are activated after nerve injury and are considered significant players in axonal regeneration. In addition to the aforementioned pathways, growth factors, microRNAs, and astrocytes are also commendable participants in regeneration. In this review, we discuss the detailed mechanism of each pathway along with key players that can be potentially valuable targets to help achieve quick axonal healing. We also identify the prospective targets that could help close knowledge gaps in the molecular pathways underlying regeneration and shed light on the creation of more powerful strategies to encourage axonal regeneration after nervous system injury.

Palliative Care Utilization Among Hospitalized Patients With Common Chronic Conditions in the United States.

Objective: Limited data exist around the receipt of palliative care (PC) in patients hospitalized with common chronic conditions. We studied the independent predictors, temporal trends in rates of PC utilization in patients hospitalized with acute exacerbation of common chronic diseases. Methods: Population-based cohort study of all hospitalizations with an acute exacerbation of heart disease (HD), cerebrovascular accident (CVA), cancer (CA), and chronic lower respiratory disease (CLRD). Patients aged ≥18 years or older between January 1, 2004, and December 31, 2017, referred for inpatient PC were extracted from the National Inpatient Sample. Poisson regression analyses were used to estimate temporal trends. Results: Between 2004 and 2017, of 91,877,531 hospitalizations, 55.2%, 13.9%, 17.2%, and 13.8% hospitalizations were related to HD, CVA, CA, and CLRD, respectively. There was a temporal increase in the uptake of PC across all disease groups. Age-adjusted estimated rates of PC per 100,000 hospitalizations/year were highest for CA (2308 (95% CI 2249-2366) to 10,794 (95% CI 10,652-10,936)), whereas the CLRD cohort had the lowest rates of PC referrals (255 (95% CI 231-278) to 1882 (95% CI 1821-1943)) between 2004 and 2017, respectively. In the subgroup analysis of patients who died during hospitalization, the CVA group had the highest uptake of PC per 100,000 hospitalizations/year (4979 (95% CI 4918-5040)) followed by CA (4241 (95% CI 4189-4292)), HD (3250 (95% CI 3211-3289)) and CLRD (3248 (95% CI 3162-3405)). Conclusion: PC service utilization is increasing but remains disparate, particularly in patients that die during hospital admission from common chronic conditions. These findings highlight the need to develop a multidisciplinary, patient-centered approach to improve access to PC services in these patients.

Metallic nanoparticles for catalytic reduction of toxic hexavalent chromium from aqueous medium: A state-of-the-art review.

The ever increasing concentration of toxic and carcinogenic hexavalent chromium (Cr (VI)) in various environmental mediums including water-bodies due to anthropogenic activities with rapid civilization and industrialization have become the major issue throughout the globe during last few decades. Therefore, developing new strategies for the treatment of Cr(VI) contaminated wastewaters are in great demand and have become a topical issue in academia and industry. To date, various techniques have been used for the remediation of Cr(VI) contaminated wastewaters including solvent extraction, adsorption, catalytic reduction, membrane filtration, biological treatment, coagulation, ion exchange and photo-catalytic reduction. Among these methods, the transformation of highly toxic Cr(VI) to benign Cr(III) catalyzed by metallic nanoparticles (M-NPs) with reductant has gained increasing attention in the past few years, and is considered to be an effective approach due to the superior catalytic performance of M-NPs. Thus, it is a timely topic to review this emerging technique for Cr(VI) reduction. Herein, recent development in synthesis of M-NPs based non-supported, supported, mono-, bi- and ternary M-NPs catalysts, their characterization and performance for the reduction of Cr(VI) to Cr(III) are reviewed. The role of supporting host to stabilize the M-NPs and leading to enhance the reduction of Cr(VI) are discussed. The Cr(VI) reduction mechanism, kinetics, and factors affecting the kinetics are overviewed to collect the wealthy kinetics data. Finally, the challenges and perspective in Cr(VI) reduction catalyzed by M-NPs are proposed. We believe that this review will assist the researchers who are working to develop novel M-NPs catalysts for the reduction of Cr(VI).

Synthesis, anticancer evaluation and molecular docking studies of methotrexate's novel Schiff base derivatives against malignant glioma cell lines.

Recent years have witnessed advancement in cancer research that has led to the development of improved cytotoxic therapies with reduced side effects. Methotrexate (MTX) is a commonly used anticancer drug having robust activity, but with serious side effects. Several derivatives of MTX have been reported by modification at different sites to reduce its side effects and enhance efficacy. The current work describes the development of active MTX Schiff base derivatives by treating MTX with several aldehydes viz 2-chlorobenzaldehyde, 3-nitrobenzaldehyde, 5-chloro-2-hydroxybenz-aldehyde, 2-hydroxy-5-nitrobenzaldehyde, 2-thiocarboxyaldehyde, trans-2-pentenal and glutaraldehyde. Newly synthesized derivatives were evaluated for their anticancer potential against human malignant glioma U87 (MG-U87) cell lines at different concentrations of 200 µM, 100 µM, 50 µM, 25 µM, 12.5 µm, 6.25 µm and 0 µM. MTX derivatives with 2-Chlorobenzaldehyde (IC50 ∼100 µM), 2-Thiocarboxyaldehyde (IC50 <200 µM) and 2- Pentenal (IC50 ∼250 µM) showed much better activity at 100 µM compared to 400 µM concentration of MTX. Molecular docking studies were performed that showed a good correlation with the results obtained from in vitro experiments. The excellent agreement between molecular modeling and growth inhibition assay shows that the binding mode hypothesis is justly close to the experimentally biological values, therefore, may prove helpful for further lead optimization and clinical trials.Communicated by Ramaswamy H. Sarma.

Clinical outcomes of percutaneous coronary intervention for chronic total occlusion in prior coronary artery bypass grafting patients.

OBJECTIVE: To compare the clinical characteristics and outcomes in patients with stable angina who have undergone chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in native arteries with or without prior coronary artery bypass grafting (CABG) surgery in a national cohort. BACKGROUND: There are limited data on outcomes of patients presenting with stable angina undergoing CTO PCI with previous CABG. METHODS: We identified 20,081 patients with stable angina who underwent CTO PCI between 2007-2014 in the British Cardiovascular Intervention Society database. Clinical, demographical, procedural and outcome data were analyzed in two groups; group 1-CTO PCI in native arteries without prior CABG (n = 16,848), group 2-CTO PCI in native arteries with prior CABG (n = 3,233). RESULTS: Patients in group 2 were older, had more comorbidities and higher prevalence of severe left ventricular systolic dysfunction. Following multivariable analysis, no significant difference in mortality was observed during index hospital admission (OR:1.33, CI 0.64-2.78, p = .44), at 30-days (OR: 1.28, CI 0.79-2.06, p = .31) and 1 year (OR:1.02, CI 0.87-1.29, p = .87). Odds of in-hospital major adverse cardiovascular events (MACE) (OR:1.01, CI 0.69-1.49, p = .95) and procedural complications (OR:1.02, CI 0.88-1.18, p = .81) were similar between two groups but procedural success rate was lower in group 2 (OR: 0.34, CI 0.31-0.39, p < .001). The adjusted risk of target vessel revascularization (TVR) remained similar between the two groups at 30-days (OR:0.68, CI 0.40-1.16, P-0.16) and at 1 year (OR:1.01, CI 0.83-1.22, P-0.95). CONCLUSION: Patients with prior CABG presenting with stable angina and treated with CTO PCI in native arteries had more co-morbid illnesses but once these differences were adjusted for, prior CABG did not independently confer additional risk of mortality, MACE or TVR.

Ethnic disparities in care and outcomes of non-ST-segment elevation myocardial infarction: a nationwide cohort study.

AIMS: Little is known about ethnic disparities in care and clinical outcomes of patients admitted with non-ST-segment elevation myocardial infarction (NSTEMI) in national cohorts from universal healthcare systems derived from Europe. METHODS AND RESULTS: We identified 280 588 admissions with NSTEMI in the UK Myocardial Infarction National Audit Project (MINAP), 2010-2017, including White patients (n = 258 364) and Black, Asian, and Minority Ethnic (BAME) patients (n = 22 194). BAME patients were younger (66 years vs. 73 years, P < 0.001) and more frequently had hypertension (66% vs. 54%, P < 0.001), hypercholesterolaemia (49% vs. 34%, P < 0.001), and diabetes (48% vs. 24%, P < 0.001). BAME patients more frequently received invasive coronary angiography (80% vs. 68%, P < 0.001), percutaneous coronary intervention (PCI) (52% vs. 43%, P < 0.001), and coronary artery bypass graft surgery (9% vs. 7%, P < 0.001). Following propensity score matching, BAME compared with White patients had similar in-hospital all-cause mortality [odds ratio (OR) 0.91, confidence interval (CI) 0.76-1.06; P = 0.23], major bleeding (OR 0.99, CI 0.75-1.25; P = 0.95), re-infarction (OR 1.15, CI 0.84-1.46; P = 0.34), and major adverse cardiovascular events (MACE) (OR 0.94, CI 0.80-1.07; P = 0.35). CONCLUSION: BAME patients with NSTEMI had higher cardiometabolic risk profiles and were more likely to undergo invasive angiography and revascularization, with similar clinical outcomes as those of their White counterparts. Among the quality indicators assessed, there is no evidence of care disparities among BAME patients presenting with NSTEMI.

Clinical Characteristics, Management Strategies, and Outcomes of Non-ST-Segment-Elevation Myocardial Infarction Patients With and Without Prior Coronary Artery Bypass Grafting.

Background There are limited data on the management strategies, temporal trends and clinical outcomes of patients who present with non-ST-segment-elevation myocardial infarction and have a prior history of CABG. Methods and Results We identified 287 658 patients with non-ST-segment-elevation myocardial infarction between 2010 and 2017 in the United Kingdom Myocardial Infarction National Audit Project database. Clinical and outcome data were analyzed by dividing into 2 groups by prior history of coronary artery bypass grafting (CABG): group 1, no prior CABG (n=262 362); and group 2, prior CABG (n=25 296). Patients in group 2 were older, had higher GRACE (Global Registry of Acute Coronary Events) risk scores and burden of comorbid illnesses. More patients underwent coronary angiography (69% versus 63%) and revascularization (53% versus 40%) in group 1 compared with group 2. Adjusted odds of receiving inpatient coronary angiogram (odds ratio [OR], 0.91; 95% CI, 0.88-0.95; P<0.001) and revascularization (OR, 0.73; 95% CI, 0.70-0.76; P<0.001) were lower in group 2 compared with group 1. Following multivariable logistic regression analyses, the OR of in-hospital major adverse cardiovascular events (composite of inpatient death and reinfarction; OR, 0.97; 95% CI, 0.90-1.04; P=0.44), all-cause mortality (OR, 0.96; 95% CI, 0.88-1.04; P=0.31), reinfarction (OR, 1.02; 95% CI, 0.89-1.17; P=0.78), and major bleeding (OR, 1.01; 95% CI, 0.90-1.11; P=0.98) were similar across groups. Lower adjusted risk of inpatient mortality (OR, 0.67; 95% CI, 0.46-0.98; P=0.04) but similar risk of bleeding (OR,1.07; CI, 0.79-1.44; P=0.68) and reinfarction (OR, 1.13; 95% CI, 0.81-1.57; P=0.47) were observed in group 2 patients who underwent percutaneous coronary intervention compared with those managed medically. Conclusions In this national cohort, patients with non-ST-segment-elevation myocardial infarction with prior CABG had a higher risk profile, but similar risk-adjusted in-hospital adverse outcomes compared with patients without prior CABG. Patients with prior CABG who received percutaneous coronary intervention had lower in-hospital mortality compared with those who received medical management.

Preoperative Atrial Fibrillation is associated with long-term morTality in patients undergoing suRgical AortiC valvE Replacement.

INTRODUCTION: Atrial fibrillation (AF) is frequent after any cardiac surgery, but evidence suggests it may have no significant impact on survival if sinus rhythm (SR) is effectively restored early after the onset of the arrhythmia. In contrast, management of preoperative AF is often overlooked during or after cardiac surgery despite several proposed protocols. This study sought to evaluate the impact of preoperative AF on mortality in patients undergoing isolated surgical aortic valve replacement (AVR). METHODS: We performed a retrospective, single-center study involving 2628 consecutive patients undergoing elective, primary isolated surgical AVR from 2008 to 2018. A total of 268/2628 patients (10.1%) exhibited AF before surgery. The effect of preoperative AF on mortality was evaluated with univariate and multivariate analyses. RESULTS: Short-term mortality was 0.8% and was not different between preoperative AF and SR cohorts. Preoperative AF was highly predictive of long-term mortality (median follow-up of 4 years [Q1-Q3 2-7]; hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.79-2.79, p < .001), and remained strongly and independently predictive after adjustment for other risk factors (HR: 1.54, 95% CI: 1.21-1.96, p < .001) compared with preoperative SR. In propensity score-matched analysis, the adjusted mortality risk was higher in the AF cohort (OR: 1.47, 95% CI: 1.04-1.99, p = .03) compared with the SR cohort. CONCLUSIONS: Preoperative AF was independently predictive of long-term mortality in patients undergoing isolated surgical AVR. It remains to be seen whether concomitant surgery or other preoperative measures to correct AF may impact long-term survival.

Sex-Specific Regulation of Interferon-γ Cytotoxicity in Mouse Liver by Autophagy.

BACKGROUND AND AIMS: Interferon-γ (IFNγ) is a central activator of immune responses in the liver and other organs. IFNγ triggers tissue injury and inflammation in immune diseases, which occur predominantly in females for unknown reasons. Recent findings that autophagy regulates hepatotoxicity from proinflammatory cytokines led to an examination of whether defective hepatocyte autophagy underlies sex-specific liver injury and inflammation induced by IFNγ. APPROACH AND RESULTS: A lentiviral autophagy-related 5 (Atg5) knockdown was performed to decrease autophagy-sensitized alpha mouse liver (AML 12) hepatocytes to death from IFNγ in combination with IL-1ß or TNF. Death was necrosis attributable to impaired energy homeostasis and adenosine triphosphate depletion. Male mice with decreased autophagy from a tamoxifen-inducible, hepatocyte-specific Atg5 knockout were resistant to IFNγ hepatotoxicity whereas female knockout mice developed liver injury and inflammation. Female mice had increased IFNγ-induced signal transducer and activator of transcription 1 (STAT1) levels compared to males. Blocking STAT1, but not interferon regulatory factor 1, signaling prevented IFNγ-induced hepatocyte death in autophagy-deficient AML12 cells and female mice. The mechanism of death is STAT1-induced overexpression of nitric oxide synthase 2 (NOS2) as in vitro hepatocyte death and in vivo liver injury were blocked by NOS2 inhibition. CONCLUSIONS: Decreased hepatocyte autophagy sensitizes mice to IFNγ-induced liver injury and inflammation through overactivation of STAT1 signaling that causes NOS2 overexpression. Hepatotoxicity is restricted to female mice, suggesting that sex-specific effects of defective autophagy may underlie the increased susceptibility of females to IFNγ-mediated immune diseases.

Effect of primary percutaneous coronary intervention on in-hospital outcomes among active cancer patients presenting with ST-elevation myocardial infarction: a propensity score matching analysis.

AIMS: Primary percutaneous coronary intervention (pPCI) is the gold standard, guideline-recommended revascularization strategy in patients presenting with ST-elevation myocardial infarction (STEMI). However, there are limited data on its use and effectiveness among patients with active cancer presenting with STEMI. METHODS AND RESULTS: All STEMI hospitalizations between 2004 and 2015 from the National Inpatient Sample were retrospectively analysed, stratified by cancer type. Propensity score matching was performed to estimate the average treatment effect of pPCI in each cancer on in-hospital adverse events, including major adverse cardiovascular and cerebrovascular events (MACCE) and its individual components, and compare treatment effect between cancer and non-cancer patients. Out of 1 870 815 patients with STEMI, 38 932 (2.1%) had a current cancer diagnosis [haematological: 11 251 (28.9% of all cancers); breast: 4675 (12.0%); lung: 9538 (24.5%); colon: 3749 (9.6%); prostate: 9719 (25.0%)]. Patients with cancer received pPCI less commonly than those without cancer (from 54.2% for lung cancer to 70.6% for haematological vs. 82.3% in no cancer). Performance of pPCI was strongly associated with lower adjusted probabilities of MACCE and all-cause mortality in the cancer groups compared with the no cancer group. There was no significant difference in estimated average pPCI treatment effect between the cancer groups and non-cancer group. CONCLUSION: Primary percutaneous coronary intervention is underutilized in STEMI patients with current cancer despite its significantly lower associated rates of in-hospital all-cause mortality and MACCE that is comparable to patients without cancer. Further work is required to assess the long-term benefit and safety of pPCI in this high-risk group.

Clinical Characteristics, Management Strategies and Outcomes of Acute Myocardial Infarction Patients With Prior Coronary Artery Bypass Grafting.

OBJECTIVE: To investigate the management strategies, temporal trends, and clinical outcomes of patients with a history of coronary artery bypass graft (CABG) surgery and presenting with acute myocardial infarction (MI). PATIENTS AND METHODS: We undertook a retrospective cohort study using the National Inpatient Sample database from the United States (January 2004-September 2015), identified all inpatient MI admissions (7,250,768 records) and stratified according to history of CABG (group 1, CABG-naive [94%]; group 2, prior CABG [6%]). RESULTS: Patients in group 2 were older, less likely to be female, had more comorbidities, and were more likely to present with non-ST-elevation myocardial infarction compared with group 1. More patients underwent coronary angiography (68% vs 48%) and percutaneous coronary intervention (PCI) (44% vs 26%) in group 1 compared with group 2. Following multivariable logistic regression analyses, the adjusted odd ratio (OR) of in-hospital major adverse cardiovascular and cerebrovascular events (OR, 0.98; 95% CI, 0.95 to 1.005; P=.11), all-cause mortality (OR, 1; 95% CI, 0.98 to 1.04; P=.6) and major bleeding (OR, 0.99; 95% CI, 0.94 to 1.03; P=.54) were similar to group 1. Lower adjusted odds of in-hospital major adverse cardiovascular and cerebrovascular events (OR, 0.64; 95% CI, 0.57 to 0.72; P<.001), all-cause mortality (OR, 0.45; 95% CI, 0.38 to 0.53; P<.001), and acute ischemic stroke (OR, 0.71; 95% CI, 0.59 to 0.86; P<.001) were observed in group 2 patients who underwent PCI compared with those managed medically without any increased risk of major bleeding (OR, 1.08; 95% CI, 0.94 to 1.23; P=.26). CONCLUSIONS: In this national cohort, MI patients with prior-CABG had a higher risk profile, but similar in-hospital adverse outcomes compared with CABG-naive patients. Prior-CABG patients who received PCI had better in-hospital clinical outcomes compared to those who received medical management.

Prosthesis-Patient Mismatch Increases Early and Late Mortality in Low Risk Aortic Valve Replacement.

The concept of prosthesis-patient mismatch (PPM) has gained much attention since first described 40 years ago. Previous studies have shown conflicting evidence regarding increased early and late morbidity and mortality with PPM after aortic valve replacement (AVR). The aim of this study was to evaluate the effects of PPM on short- and long-term mortality in low-risk patients after isolated AVR. A retrospective, single-center study involving 1707 consecutive patients ≤80 years of age with preserved left ventricular systolic function who underwent elective, primary isolated AVR operations from 2008 to 2018. Patients were stratified into 2 groups according to the presence of PPM (n = 96), defined as effective orifice area index <0.85 cm2/m2 body surface area, and no-PPM (n = 1611). The effect of PPM on mortality was evaluated with univariate and multivariate analyses. 30-day mortality was 0.8% (4.2% in PPM group vs 0.6 in no-PPM group; P = 0.005). PPM occurred more in female gender, obese and older patients. PPM was highly associated with long-term all-cause mortality (median 4 years [Q1-Q3 2-7]; HR: 1.79, 95% CI: 1.27-2.55, P = 0.002), and remained strongly and independently associated after adjustment for other risk factors (HR: 1.60, 95% CI: 1.10-2.34, P = 0.014). In propensity score-matched analysis, the adjusted mortality risk was higher in PPM group (HR: 2.03, 95% CI: 1.22-3.39, P = 0.006) compared to no-PPM group. In a single-centre observational study, PPM increased early mortality and was independently associated with long-term all-cause mortality after low-risk, primary isolated AVR operations. Strategies to avoid PPM should be explored and implemented.

Trends of repeat revascularization choice in patients with prior coronary artery bypass surgery.

OBJECTIVE: To examine rates and predictors repeat revascularization strategies (percutaneous coronary intervention [PCI] and coronary artery bypass grafting [CABG]) in patients with prior CABG. METHODS: Using the National Inpatient Sample, patients with a history of CABG hospitalized for revascularization by PCI or CABG from January 2004 to September 2015 were included. Regression analyses were performed to examine predictors of receipt of either revascularization strategy as well as in-hospital outcomes. RESULTS: The rate of redo CABG doubled between 2004 (5.3%) and 2015 (10.3%). Patients who underwent redo CABG were more comorbid and experienced significantly worse major adverse cardiovascular and cerebrovascular events (odds ratio [OR]: 5.36 95% CI 5.11-5.61), mortality (OR 2.84 95% CI 2.60,-3.11), bleeding (OR 5.97 95% CI 5.44-6.55) and stroke (OR 2.15 95% CI 1.92-2.41), but there was no difference in cardiac complications between groups. Thoracic complications were high in patients undergoing redo CABG (8%), especially in females. Factors favoring receipt of redo CABG compared to PCI included male sex, age < 80 years, and absence of diabetes and renal failure. CONCLUSION: Reoperation in patients with prior CABG has doubled in the United States over a 12-year period. Patients undergoing redo CABG are more complex and associated with worse clinical outcomes than those receiving PCI.

Clinical Outcomes of Percutaneous Coronary Intervention for Chronic Total Occlusion in Native Coronary Arteries vs Saphenous Vein Grafts.

BACKGROUND: There are limited data comparing outcomes of patients with previous coronary artery bypass grafting (CABG) presenting with stable angina who undergo percutaneous coronary intervention (PCI) to either a saphenous vein grafts (SVG) or a chronic total occlusion (CTO) in the native coronary arteries. We compared clinical characteristics and outcomes of these two groups in a national cohort. METHODS AND RESULTS: We formed a longitudinal cohort (2007-2014; n = 11,132) of patients who underwent SVG-PCI (group 1; n = 8619) or CTO-PCI in native arteries (group 2; n = 2513) in the British Cardiovascular Intervention Society (BCIS) database. Median age was 68 years in both groups, but patients in group 2 were less likely to be female, had a higher prevalence of diabetes mellitus, hypertension, hypercholesterolemia, and previous myocardial infarction, as well as worsened angina and breathlessness, but history of prior stroke, renal diseases, and the presence of left ventricular systolic dysfunction were similar to group 1. Following multivariable analysis, no significant difference in mortality was observed during index hospital admission (odds ratio [OR], 1.70; 95% confidence interval [CI], 0.63-4.58; P=.29), at 30 days (OR, 1.81; 95% CI, 0.99-3.3; P=.05), and 1 year (OR, 1.11; 95% CI, 0.85-1.44; P=.43), nor was a significant difference found in in-hospital MACE rates (OR, 1.36; 95% CI, 0.85-2.19; P=.19). However, CTO-PCI was associated with more procedural complications (OR, 2.88; 95% CI, 2.38-3.47; P<.01) and vessel perforation (OR, 4.82; 95% CI, 2.80-8.28; P<.01) as compared with the SVG-PCI group. Risk of target-vessel revascularization at 1 year was similar (SVG-PCI 5.6% vs CTO-PCI 6.9%; P=.08). CONCLUSION: In this national cohort, CTO-PCI was performed in higher-risk patients, and was associated with more procedural complications but similar short-term or long-term mortality and in-hospital MACE.

Decreased Hepatocyte Autophagy Leads to Synergistic IL-1ß and TNF Mouse Liver Injury and Inflammation.

BACKGROUND AND AIMS: The proinflammatory cytokine IL-1ß has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL-1ß promotes liver injury in these diseases is unclear, as no IL-1ß receptor-linked death pathway has been identified. Autophagy functions in hepatocyte resistance to injury and death, and findings of decreased hepatic autophagy in many liver diseases suggest a role for impaired autophagy in disease pathogenesis. Recent findings that autophagy blocks mouse liver injury from lipopolysaccharide led to an examination of autophagy's function in hepatotoxicity from proinflammatory cytokines. APPROACH AND RESULTS: AML12 cells with decreased autophagy from a lentiviral autophagy-related 5 (Atg5) knockdown were resistant to toxicity from TNF, but sensitized to death from IL-1ß, which was markedly amplified by TNF co-treatment. IL-1ß/TNF death was necrosis by trypan blue and propidium iodide positivity, absence of mitochondrial death pathway and caspase activation, and failure of a caspase inhibitor or necrostatin-1s to prevent death. IL-1ß/TNF depleted autophagy-deficient cells of ATP, and ATP depletion and cell death were prevented by supplementation with the energy substrate pyruvate or oleate. Pharmacological inhibitors and genetic knockdown studies demonstrated that IL-1ß/TNF-induced necrosis resulted from lysosomal permeabilization and release of cathepsins B and L in autophagy-deficient cells. Mice with a tamoxifen-inducible, hepatocyte-specific Atg5 knockout were similarly sensitized to cathepsin-dependent hepatocellular injury and death from IL-1ß/TNF in combination, but neither IL-1ß nor TNF alone. Knockout mice had increased hepatic inflammation, and IL-1ß/TNF-treated, autophagy-deficient AML12 cells secreted exosomes with proinflammatory damage-associated molecular patterns. CONCLUSIONS: The findings delineate mechanisms by which decreased hepatocyte autophagy promotes IL-1ß/TNF-induced necrosis from impaired energy homeostasis and lysosomal permeabilization and inflammation through the secretion of exosomal damage-associated molecular patterns.

Outcomes Following Percutaneous Coronary Intervention in Saphenous Vein Grafts With and Without Embolic Protection Devices.

OBJECTIVES: The aim of this study was to describe the early (inpatient and 30-day) and late (1-year) outcomes of percutaneous coronary intervention (PCI) in saphenous vein grafts (SVGs), with and without the use of embolic protection devices (EPD), in a large, contemporary, unselected national cohort from the database of the British Cardiovascular Intervention Society. BACKGROUND: There are limited, and discrepant, data on the clinical benefits of the adjunctive use of EPDs during PCI to SVGs in the contemporary era. METHODS: A longitudinal cohort of patients (2007 to 2014, n = 20,642) who underwent PCI to SVGs in the British Cardiovascular Intervention Society database was formed. Clinical, demographic, procedural, and outcome data were analyzed by dividing into 2 groups: no EPD (PCI to SVGs without EPDs, n = 17,730) and EPD (PCI to SVGs with EPDs, n = 2,912). RESULTS: Patients in the EPD group were older, had more comorbidities, and had a higher prevalence of moderate to severe left ventricular systolic dysfunction. Mortality was lower in the EPD group during hospital admission (0.70% vs. 1.29%; p = 0.008) and at 30 days (1.44% vs. 2.01%; p = 0.04) but similar at 1 year (6.22% vs. 6.01%; p = 0.67). Following multivariate analyses, no significant difference in mortality was observed during index admission (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.42 to 1.19; p = 0.19), at 30 days (OR: 0.87; 95% CI: 0.60 to 1.25; p = 0.45), and at 1 year (OR: 0.92; 95% CI: 0.77 to 1.11; p = 0.41), along with similar rates of in-hospital major adverse cardiovascular events (OR: 1.16; 95% CI: 0.83 to 1.62; p = 0.39) and stroke (OR: 0.68; 95% CI: 0.20 to 2.35; p = 0.54). In propensity score-matched analyses, lower inpatient mortality was observed in the EPD group (OR: 0.46; 95% CI: 0.13 to 0.80; p = 0.002), although the adjusted risk for the periprocedural no-reflow or slow-flow phenomenon was higher in patients in whom EPDs were used (OR: 2.16; 95% CI: 1.71 to 2.73; p < 0.001). CONCLUSIONS: In this contemporary cohort, EPDs were used more commonly in higher risk patients but were associated with similar clinical outcomes in multivariate analyses. Lower inpatient mortality was observed in the EPD group in univariate and propensity score-matched analyses.

Outcomes Following Percutaneous Coronary Intervention in Non-ST-Segment-Elevation Myocardial Infarction Patients With Coronary Artery Bypass Grafts.

Background There are limited data on outcomes of patients with previous coronary artery bypass graft (CABG) presenting with non-ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). We compare clinical characteristics and outcomes in non-ST-segment-elevation myocardial infarction patients undergoing PCI with or without prior CABG surgery in a national cohort. Methods and Results We identified 205 039 patients with non-ST-segment-elevation myocardial infarction who underwent PCI between 2007 and 2014 in the British Cardiovascular Intervention Society database. Clinical, demographic, procedural, and outcome data were analyzed by dividing into 3 groups: group 1, PCI in native coronary arteries and no prior CABG (n=186 670); group 2, PCI in native arteries with prior CABG (n=8825); group 3, PCI in grafts (n=9544). Patients in group 2 and 3 were older and had more comorbidities and higher mortality at 30 days (group 2, 2.6% and group 3, 1.9%) and 1 year (group 2, 8.29% and group 3, 7.08%) as compared with group 1 (1.7% and 4.87%). After multivariable analysis, no significant difference in outcomes was observed in 30-days mortality (odds ratio; group 2=0.87 [CI, 0.69-1.80; P=0.20], group 3=0.91 [CI, 0.71-1.17; P=0.46]), in-hospital major adverse cardiovascular event (odds ratio: group 2=1.08 [CI, 0.88-1.34; P=0.45], group 3=0.97 [CI=0.77-1.23; P=0.82]), and in-hospital stroke (odds ratio: group 2=1.37 [CI, 0.71-2.69; P=0.35], group 3=1.13 [CI, 0.55-2.34; P=0.73]; group 1=reference). Conclusions Patients with prior CABG are presenting with non-ST-segment-elevation myocardial infarction and treated with PCI had more comorbid illnesses, but once these differences were adjusted for, prior CABG did not independently confer additional risk of mortality and major adverse cardiovascular event.