Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation.

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs' intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics.

Lung Transplantation for Primary Ciliary Dyskinesia and Kartagener Syndrome: A Multicenter Study.

Primary ciliary dyskinesia, with or without situs abnormalities, is a rare lung disease that can lead to an irreversible lung damage that may progress to respiratory failure. Lung transplant can be considered in end-stage disease. This study describes the outcomes of the largest lung transplant population for PCD and for PCD with situs abnormalities, also identified as Kartagener's syndrome. Retrospectively collected data of 36 patients who underwent lung transplantation for PCD from 1995 to 2020 with or without SA as part of the European Society of Thoracic Surgeons Lung Transplantation Working Group on rare diseases. Primary outcomes of interest included survival and freedom from chronic lung allograft dysfunction. Secondary outcomes included primary graft dysfunction within 72 h and the rate of rejection ≥A2 within the first year. Among PCD recipients with and without SA, the mean overall and CLAD-free survival were 5.9 and 5.2 years with no significant differences between groups in terms of time to CLAD (HR: 0.92, 95% CI: 0.27-3.14, p = 0.894) or mortality (HR: 0.45, 95% CI: 0.14-1.43, p = 0.178). Postoperative rates of PGD were comparable between groups; rejection grades ≥A2 on first biopsy or within the first year was more common in patients with SA. This study provides a valuable insight on international practices of lung transplantation in patients with PCD. Lung transplantation is an acceptable treatment option in this population.

Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial metabolic reprogramming.

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infections an urgent need. We have previously shown that manipulating the lungs' intrinsic host defenses by therapeutic delivery of a unique dyad of pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODNs) with mitochondrial voltage-dependent anion channel 1 (VDAC1) without dependence on Toll-like receptor 9 (TLR9). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), enhances mitochondrial membrane potential (Δ Ψm ), and differentially modulates ETC complex activities. These combined effects promote leak of electrons from ETC complex III, resulting in superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy that has the potential to broadly protect patients against pneumonia during periods of peak vulnerability without reliance on currently available antibiotics. Author Summary: Pneumonia is a major cause of death worldwide. Increasing antibiotic resistance and expanding immunocompromised populations continue to enhance the clinical urgency to find new strategies to prevent and treat pneumonia. We have identified a novel inhaled therapeutic that stimulates lung epithelial defenses to protect mice against pneumonia in a manner that depends on production of reactive oxygen species (ROS). Here, we report that the induction of protective ROS from lung epithelial mitochondria occurs following the interaction of one component of the treatment, an oligodeoxynucleotide, with the mitochondrial voltage-dependent anion channel 1. This interaction alters energy transfer between the mitochondria and the cytosol, resulting in metabolic reprogramming that drives more electrons into the electron transport chain, then causes electrons to leak from the electron transport chain to form protective ROS. While antioxidant therapies are endorsed in many other disease states, we present here an example of therapeutic induction of ROS that is associated with broad protection against pneumonia without reliance on administration of antibiotics.

Outcomes of Heller Myotomy for Esophageal Achalasia: Lessons From a 48-Year Prospective Experience With 4 Different Techniques.

OBJECTIVE: To provide information on long-term outcomes of Heller myotomy for esophageal achalasia with or without an antireflux fundoplication. BACKGROUND: Since the adoption of the Heller myotomy, surgeons have modified the original technique in order to balance the cure of dysphagia and the consequent cardial incontinence. METHODS: Totally, 470 patients underwent primary Heller myotomy between 1955 and 2020. A long abdominal myotomy (AM) was performed in 83 patients, the Ellis limited transthoracic myotomy (TM) in 30, the laparotomic Heller-Dor (L-HD) in 202, the videolaparoscopic Heller-Dor (VL-HD) in 155. The HD was performed under intraoperative manometric assessment. Starting on 1973 these patients underwent a prospective follow-up program of timed lifelong clinical, radiological, endoscopic evaluations. RESULTS: Median follow-up time was 23.06 years [interquantile range (IQR): 15.04-32.06] for AM, 29.22 years (IQR: 13.46-40.17) for TM, 14.85 years (IQR: 11.05-21.56) for L-HD and 7.51 years (IQR: 3.25-9.60) for VL-HD. In AM, relapse of dysphagia occurred in 25/71 (35.21%), in TM in 11/30 (36.66%), in LH-D in 10/201 (4.97%), in VL-HD in 3/155 (1.93%). Erosive-ulcerative esophagitis was diagnosed for AM in 28.16%, for TM in 30%, for L-HD in 8.45%, for VL-HD in 2.58%. Overall, the outcome was satisfactory in 52.11% for AM, 41.9% for TM, 89.05% for L-HD, 96.12% for VL-HD. CONCLUSIONS: The Dor fundoplication drastically reduces postmyotomy gastroesophageal reflux. The Heller-Dor operation is a competitive option for the cure of esophageal achalasia if this operation is performed according to the rules of surgical physiology learned by means of intraoperative manometry.

Reconsidered surgical aortic valve replacement after declined transcatheter valve implantation.

BACKGROUND: Outcomes for high surgical risk patients who declined transcatheter aortic valve implantation (TAVI) and then reconsidered for conventional aortic valve replacement (rSAVR) for severe calcific aortic stenosis are not well known. METHODS: This single-centre, case-control study (rSAVR vs Conservative group) retrospectively analysed patients for rSAVR (2009-2019). Multivariable logistic regression was used to identify independent predictors of composite of neurological sequelae/renal failure/deep sternal wound infection/re-exploration and death. Survival was compared using Kaplan-Meier curves and log-rank test. A Cox proportional hazards model was used to determine predictors of survival. RESULTS: TAVI was denied in 519/1095 patients, 114(10.4%) had rSAVR (cases) and 405 (37%) were managed conservatively (controls). Mean age for rSAVR was 80 years (IQR: 73.5-85 years). The commonest reason for declining TAVI was prohibitive high risk due to multiple comorbidities. Among rSAVR, hospital mortality was 2.2% and stroke was 4.4%. Median follow-up was conservative; 14.4 months versus rSAVR; 34.8 months. Five-year survival was conservative; 12.6% versus rSAVR; and 59.5% (overall conservative; 38.0% vs. rSAVR; 60.5%, p < 0.001). rSAVR was protective (hazard ratio [HR]: 0.37, 95% confidence interval [CI]: 0.26, 0.51, p < 0.001) and high comorbidities had high hazard (HR: 1.57, 95% CI: 1.19, 2.07, p = 0.001). rSAVR had fewer hospital readmission episodes (Conservative; 13.6/patient-year vs. rSAVR; 6.9/patient-year, p = 0.002). CONCLUSIONS: rSAVR may be considered in high surgical risk elderly patients who have been declined TAVI in centres with low operative mortality. rSAVR may be superior to conservative management in carefully selected patients.

Risk Factors and Outcomes for Gastroparesis After Lung Transplantation.

BACKGROUND: Gastroparesis is common after lung transplantation and is associated with worse transplant outcomes, including the development of chronic lung allograft dysfunction (CLAD). This study sought to identify the prevalence, risk factors, and outcomes associated with a new diagnosis of gastroparesis after lung transplantation. METHODS: This was a single-center retrospective study of patients who underwent lung transplantation in 2008-2018. The primary outcome was a new diagnosis of gastroparesis within 3 years of transplant. Secondary outcomes included a new diagnosis of gastroesophageal reflux and the association between gastroparesis and both post-transplant survival and CLAD-free survival. Multivariable logistic regression was used to compare diagnosis of gastroparesis and gastroesophageal reflux, while multivariable Cox proportional hazards models were used to analyze gastroparesis and post-transplant outcomes. RESULTS: Of 616 patients with no prior history of gastroparesis, 107 (17.4%) were diagnosed with delayed gastric emptying within 3 years of transplant. On multivariable logistic regression, black race (OR 2.16, 95% CI 1.18-3.98, p = 0.013) was significantly associated with a new diagnosis of gastroparesis. Age, sex, history of diabetes, connective tissue disease, type of transplant, diagnosis group, renal function, and body mass index were not predictive of gastroparesis post-transplant. Gastroparesis was significantly associated with CLAD (HR 1.76, 95% CI 1.20-2.59, p = 0.004), but not with overall mortality (HR 1.16, p = 0.43). CONCLUSION: While gastroparesis is common after lung transplantation, it remains difficult to predict which patients will develop these complications post-transplant. Black patients were more likely to be diagnosed with gastroparesis after adjusting for relevant confounders. Gastroparesis is associated with increased risk of CLAD, and further studies are needed to assess whether early detection and treatment can reduce the incidence of CLAD.

Identification of Lung Transplant Recipients With a Survival Benefit After Fundoplication.

BACKGROUND: Gastroesophageal reflux disease (GERD) and aspiration of enteric contents are associated with worse outcomes after lung transplantation. The purpose of this study was to elucidate populations of patients who benefit the most from fundoplication after lung transplantation. METHODS: Lung transplantations from 2001 to 2019 (n = 971) were retrospectively reviewed and stratified by fundoplication before (n = 128) or after (n = 24) chronic lung allograft dysfunction (CLAD) development vs patients who did not undergo fundoplication. Patients with a fundoplication before CLAD were propensity matched to patients without a fundoplication. The primary outcome of interest was posttransplant survival. Time-to-event rates were calculated using a multivariable Cox proportional hazards model and Kaplan-Meier functions. RESULTS: Fundoplication before CLAD improved posttransplant survival before and after propensity matching, and it remained a significant predictor after adjusting for baseline characteristics (hazard ratio [HR],0.57; 95 % confidence interval [CI], 0.4 to 0.8; P = .001). Transplant recipients with a restrictive disorder (HR, 0.46; 95 % CI, 0.3 to 0.73; P = .001), age younger than 65 years (HR, 0.48; 95 % CI, 0.32 to 0.71; P < ;0.001), and with both single (HR, 0.47; 95 % CI, 0.28 to 0.79; P = .005) and double (HR, 0.55; 95 % CI, 0.32 to 0.93; P = .027) lung transplants had a significant decrease in mortality after fundoplication. The effect was present after excluding early deaths and CLAD diagnoses. Gastroesophageal reflux disease diagnosed by pH, impedance, or esophagogastroduodenoscopy was not associated with worse outcomes. Among patients with CLAD, a fundoplication was an independent predictor of post-CLAD survival (HR, 0.27; 95 % CI; 0.12 to 0.61; P = .002). CONCLUSIONS: Fundoplication before or after CLAD development is an independent predictor of survival. Younger patients with restrictive disease, independent of the type of transplant, have a survival benefit. Gastroesophageal reflux disease diagnosed by conventional methods was not associated with worse survival.

Is It Safe to Let Trainees Operate on High Risk Cardiac Surgery Cases?

Increasing complexity in cardiac operations has raised the discussion on trainee autonomy and the number of cases required to achieve competency. This study compares outcomes among cases done by trainees vs consultants for high risk patients. 696 (trainee=158 vs consultant=438) major high risk cardiac operations (Euroscore >10) were reviewed at a single center. Observations were propensity matched to consultant or trainee based on several baseline characteristics. Euroscore was: Trainee; 12.3 ± 1.6 versus Consultant; 12.8 ± 2.2, p=.036. Multivariable analysis did not identify trainee as a risk factor for worse in-hospital mortality (OR; 0.95, CI; 0.4-2.2, p=.914) or composite outcome of length of stay >30 days, deep sternal infection, new hemodialysis, new stroke or transient ischemic attack, in-hospital death or reoperation (OR; 0.64, CI; 0.39-1.03, p=.069). NYHA class, diabetes and emergency/salvage surgery were predictors of worse composite outcome. After propensity matching (130 pairs), there was no difference in reoperation rates (3.1% versus 4.6%, p=.727), inhospital death (5.4% versus 7.7%, p=.607) or composite outcome (20.8% versus 29.2%, p=.152). There was no statistical difference in cross clamp times (Trainee; 74.0 ± 32.7 min vs Consultant; 82.6 ± 51.1, p=.229) and bypass times (Trainee; 116.3 ± 52.8 min versus Consultant 135.3 ± 72.6 min, p=.055). The length of stay was similar (18.2 ± 13.2 days versus 19.9 ± 15.6 days, p=.302). It is possible for trainees to perform high risk cardiac surgery without compromising the quality of patient care.

Aspiration of conjugated bile acids predicts adverse lung transplant outcomes and correlates with airway lipid and cytokine dysregulation.

INTRODUCTION: Duodeno-gastroesophageal reflux aspiration is associated with chronic lung allograft dysfunction (CLAD). Reflux aspirate can contain bile acids (BA), functional molecules in the gastro-intestinal tract with emulsifying properties. We sought to determine and quantify the various BA species in airways of the lung transplant recipients to better understand the various effects of aspirated BA that contribute to post-transplantation outcomes. METHODS: Bronchial washings (BW) were prospectively collected from lung transplant recipients and subsequently assayed by liquid chromatography-mass spectrometry for 13 BA and 25 lipid families. Patients were monitored for CLAD, rejection, inflammation and airway infections. RESULTS: Detectable BA were present in 45/50 patients (90%) at 3 months after transplant. Elevated BA and predominance of conjugated species were independent predictors of CLAD (hazard ratio 7.9; 95% confidence interval 2.7-23.6; p < 0.001 and 7.3; 2.4-22; p < 0.001, respectively) and mortality (hazard ratio 4.4; 1.5-12.7; p = 0.007 and 4.8; 1.4-15.8; p = 0.01, respectively). High BA associated with increased positive bacterial cultures (60% vs 25%, p = 0.02). Primary conjugated species independently correlated with the rate of bacterial cultures during the first-year post-transplant (Beta coefficient: 0.77; 0.28-1.26; p = 0.003) and changes in airway lipidome and cytokines. CONCLUSIONS: Higher BA levels and predominance of conjugated BA are independent predictors of chronic lung allograft dysfunction, mortality and bacterial infections. Primary conjugated BA are related to distinct changes in airway lipidome and inflammatory cytokines. This elucidates novel evidence into the mechanism following BA aspiration and proposes novel markers for prediction of adverse post-transplant outcomes.

Survival benefit from a second arterial conduit to the circumflex circulation persists in elderly after coronary artery bypass surgery.

BACKGROUND: This retrospective propensity matched study investigated the impact of age on the survival benefit from a second arterial conduit to the left-sided circulation. METHODS: Data for isolated coronary artery bypass surgery were collected from October 2004 to March 2014. All patients with an internal mammary artery graft to left anterior descending artery and additional arterial or venous graft to the circumflex circulation were included. Propensity matching was used to balance co-variates and generate odds of death for each observation. Odds ratios (venous vs. arterial) were charted against age. RESULTS: The in-hospital mortality rate was 1.12% (arterial) vs. 1.24% (venous) (p = 0.77). The overall 10-year survival was 74.6% (venous) vs. 82.6% (arterial) (p = 0.001). A total of 1226 patients were successfully matched to the venous or arterial (second conduit to circumflex territory after left internal mammary artery to left anterior descending artery) cohorts. Odds ratio for death (venous to arterial) showed a linear decremental overall survival benefit for the second arterial graft to circumflex circulation with increasing age. CONCLUSIONS: The survival benefit of a second arterial graft persists through all age groups with a gradual decline with increasing age over the decades. Elderly patients should not be denied a second arterial graft to the circumflex circulation based on age criterion alone.

Fundoplication after lung transplantation in patients with systemic sclerosis-related end-stage lung disease.

Introduction: Gastroesophageal reflux and aspiration are risk factors for chronic lung allograft dysfunction in lung transplant recipients. Patients with systemic sclerosis are at an increased risk of aspiration due to esophageal dysmotility and an ineffective lower esophageal sphincter. The aim of this study is to understand the effect of fundoplication on outcomes in systemic sclerosis recipients. Methods: Between 2001 and 2019, 168 systemic sclerosis patients were referred for lung transplantation-51 (30.3%) were listed and 36 (21.4%) were transplanted. Recipients were stratified whether they underwent a fundoplication (n = 10, 27.8%) or not (n = 26, 72.2%). Freedom from chronic lung allograft dysfunction and survival were analyzed using log-rank test. Multivariable analysis for known risk factors was performed using a Cox-proportional hazards model. Results: Median time to fundoplication after transplantation was 16.4 months (interquartile range: 9.6-25.1) and all were laparoscopic (Dor 50%, Nissen 40%, Toupet 10%). There were no differences in acute rejection ⩾ A1 (26.9% vs 30%), or primary graft dysfunction grades 2-3 at 72 h (42.3% vs 40%) between groups. Recipients with fundoplication had an increased freedom from chronic lung allograft dysfunction (p = 0.035) and overall survival (p = 0.01). Fundoplication was associated with a reduced risk of mortality adjusting for other comorbidities (hazard ratio = 0.13; 95% confidence interval = 0.02-0.65; p = 0.014). Double and single lung transplant did not have different post-transplant survival. Conclusion: Fundoplication in systemic sclerosis lung transplant recipients is associated with greater freedom from chronic lung allograft dysfunction and overall survival. Screening for reflux and aspiration followed by early fundoplication may delay graft deterioration in this population.

Surgical vs transfemoral aortic valve replacement in low-risk patients: An updated meta-analysis of trial and registry data.

BACKGROUND: Transfemoral aortic valve replacement (TAVR) has been studied extensively in patients with improving safety and efficacy in high to intermediate-risk patients with aortic stenosis. TAVR has been now approved for patients with low surgical risk. OBJECTIVE: The purpose of this study is to integrate the evidence from randomized controlled trials (RCT) and large registry data comparing TAVR to surgical aortic valve repair (SAVR). METHODS: Seven studies (three RCTs, one post hoc study of a RCT, and three registries) were included. Incidence rate ratios (IRR) of outcomes of interest (overall mortality, 30-day mortality, cardiovascular death, stroke, pacemaker implantation [PPMI], myocardial infarction, moderate-severe paravalvular leak [PVL], and re-intervention) were compared using a random-effects model. RESULTS: The pooled analysis included 24 819 patients (TAVR, 8227 and SAVR, 16 592). 2,952 (11.9%) patients were from RCTs and 21 867 (88.1%) were registry patients. Thirty-day mortality was lower in TAVR (logIRR, -0.43; 95% CI. -0.61 to -0.25; P < .001), whereas the rate of moderate-severe PVL (logIRR, 1.44; 95% CI, 0.58-2.3; P < .001) and PPMI (logIRR, 1.13; 95% CI, 1.02-1.24; P < .001) were higher. There were no significant differences in the rates of overall mortality, reintervention, cardiovascular death, myocardial infarction, or stroke between SAVR and TAVR. CONCLUSIONS: Early mortality is higher in SAVR while rates of PVL and PPMI are substantially higher in TAVR. There is no significant advantage with TAVR for overall survival, cardiovascular death, stroke, MI, and re-intervention rates.

Extended post-ex vivo lung perfusion cold preservation predicts primary graft dysfunction and mortality: Results from a multicentric study.

BACKGROUND: Ex vivo lung perfusion (EVLP) allows for a reassessment of lung grafts initially deemed unsuitable for transplantation, increasing the available donor pool; however, this requires a pre- and post-EVLP period of cold ischemic time (CIT). Paucity of data exists on how the sequence of cold normothermic-cold preservations affect outcomes. METHODS: A total of 110 patients were retrospectively analyzed. Duration of 3 preservation phases was measured: cold pre-EVLP, EVLP, and cold post-EVLP. The donor and recipient clinical data were collected. Primary graft dysfunction (PGD) and survival were monitored. Risk of mortality or PGD was calculated using Cox proportional hazards and logistic regression models to adjust for baseline characteristics. RESULTS: Using the highest quartile, patients were stratified into extended vs non-extended pre-EVLP (<264 vs ≥264 minutes) and post-EVLP (<287 vs ≥287 minutes) CIT. The rates of 1-year mortality (8.4% vs 29.6%, p = 0.013), PGD 2-3 (20.5% vs 52%, p = 0.002), and PGD 3 (8.4% vs 29.6%, p = 0.005) at 72 hours were increased in the extended post-EVLP CIT group. After adjusting for baseline risk factors, the extended group remained an independent predictor of PGD ≥2 (odd ratio: 6.18, 95% CI: 1.88-20.3, p = 0.003) and PGD 3 (odd ratio: 20.4, 95% CI: 2.56-161.9, p = 0.004) at 72 hours and 1-year mortality (hazard ratio: 17.9, 95% CI: 3.36-95.3, p = 0.001). Cold pre-EVLP was not a significant predictor of primary outcomes. CONCLUSIONS: Extended cold post-EVLP preservation is associated with a risk for PGD and 1-year mortality. Pre-EVLP CIT does not increase mortality or high-grade PGD. These findings from a multicenter trial should caution on the implementation of extended cold preservation after EVLP.

Is Resident Training Safe in Cardiac Surgery?

BACKGROUND: There exists a knowledge gap regarding the safety of training in cardiac surgery. The purpose of this analysis was to establish the safety of resident training in cardiac surgery and compare the results of the trainee cases to those performed by consultants. METHODS: In all, 5894 (trainee, 3343; consultant, 2551) major cardiac operations (European System for Cardiac Operative Risk Evaluation less than 10) from 2013 to 2018 were reviewed. Multivariate analysis was performed for inhospital mortality and composite outcome of length of stay longer than 30 days, deep sternal infection, new hemodialysis, new stroke or transient ischemic attack, inhospital death, or reoperation. Observations were propensity matched to consultant or trainee with the 16 covariates. RESULTS: Trainees performed 56.7% of cases. Multivariate analysis identified renal disease (odds ratio [OR] 2.93; 95% confidence interval [CI], 1.3 to 6.7; P < .02), peripheral vascular disease (OR 4.62; 95% CI, 1.82 to 11.71; P < .01), and emergency/salvage procedure (OR 7.23; 95% CI, 2.00 to 26.11; P < .01) as predictors of inhospital mortality. Emergency/salvage procedure was the only predictor of worse composite outcomes (OR 2.65; 95% CI, 1.54 to 4.55; P < .001). Trainee cases had similar inhospital mortality and composite outcomes. After propensity matching (1842 observations), bypass time and cross-clamp time were significantly longer for trainees for isolated coronary artery bypass graft surgery and aortic valve replacement. There was no difference between deep sternal infection, new hemodialysis, new stroke/transient ischemic attack, inhospital death, or reoperation. Overall composite outcome differed between groups (trainee 9% vs consultant 16.6%, P = .001) owing to difference in the length of stay longer than 30 days (trainee 4.2% vs consultant 9.9%, P = .001). CONCLUSIONS: Resident training is safe in cardiac surgery without compromising the quality of patient care.

Prior Percutaneous Coronary Interventions May Be Associated With Increased Mortality After Coronary Bypass Grafting: A Meta-Analysis.

There is conflicting evidence for adverse outcomes after coronary artery bypass surgery (CABG) with prior percutaneous intervention (PCI). A literature search was performed from 1998 to 2017 and articles with primary or secondary outcomes of survival, major adverse cardiovascular events (MACE), and myocardial infarction in CABG patients with prior PCI were included. Forest plots were generated from odds ratios for survival, MACE, and myocardial infarction for unmatched and propensity-matched data. Heterogeneity between studies was assessed for all outcomes using I2. Funnel plots were generated for early survival, survival at 5 years, survival at >5 years, and MACE. Thirty-one studies were included over 18 years with 194,544 patients without PCI prior to CABG and 23,519 patients (12.09%) with prior PCI. Prior PCI did not adversely affect survival among the included studies (inverse rate ratio: 1.12, 95% confidence interval: 0.98-1.27, P = 0.110. MACE was significantly worse for those with prior PCI (odds ratio: 1.26, confidence interval: 1.02-1.55, P = 0.03). The relative risk of mortality associated with prior PCI has decreased significantly over the last 2 decades. Studies with higher percentage of prior PCI patients had higher relative mortalities. There was significant heterogeneity between studies for the treatment effects. PCI prior to CABG in recent times does not adversely affect survival despite adverse early and late MACE rates. However, high institutional rates of prior PCI may be associated with increasing mortality after CABG.

MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis.

The possible association between the membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1) and inflammation has been suggested, but the molecular mechanisms underlying this link, especially during atherogenesis, remain unclear. In endothelial cells (ECs) exposed to disturbed flow (d-flow), p90 ribosomal S6 kinase (p90RSK) bound to MAGI1, causing MAGI1-S741 phosphorylation and sentrin/SUMO-specific protease 2 T368 phosphorylation-mediated MAGI1-K931 deSUMOylation. MAGI1-S741 phosphorylation upregulated EC activation via activating Rap1. MAGI1-K931 deSUMOylation induced both nuclear translocation of p90RSK-MAGI1 and ATF-6-MAGI1 complexes, which accelerated EC activation and apoptosis, respectively. Microarray screening revealed key roles for MAGI1 in the endoplasmic reticulum (ER) stress response. In this context, MAGI1 associated with activating transcription factor 6 (ATF-6). MAGI1 expression was upregulated in ECs and macrophages found in atherosclerotic-prone regions of mouse aortas as well as in the colonic epithelia and ECs of patients with inflammatory bowel disease. Further, reduced MAGI1 expression in Magi1-/+ mice inhibited d-flow-induced atherogenesis. In sum, EC activation and ER stress-mediated apoptosis are regulated in concert by two different types of MAGI1 posttranslational modifications, elucidating attractive drug targets for chronic inflammatory disease, particularly atherosclerosis.

Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections.

Viral pneumonias cause profound worldwide morbidity, necessitating novel strategies to prevent and treat these potentially lethal infections. Stimulation of intrinsic lung defenses via inhalation of synergistically acting Toll-like receptor (TLR) agonists protects mice broadly against pneumonia, including otherwise-lethal viral infections, providing a potential opportunity to mitigate infectious threats. As intact lung epithelial TLR signaling is required for the inducible resistance and as these cells are the principal targets of many respiratory viruses, the capacity of lung epithelial cells to be therapeutically manipulated to function as autonomous antiviral effectors was investigated. Our work revealed that mouse and human lung epithelial cells could be stimulated to generate robust antiviral responses that both reduce viral burden and enhance survival of isolated cells and intact animals. The antiviral protection required concurrent induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase sources, although neither type I interferon enrichment nor type I interferon signaling was required for the inducible protection. Taken together, these findings establish the sufficiency of lung epithelial cells to generate therapeutically inducible antiviral responses, reveal novel antiviral roles for ROS, provide mechanistic insights into inducible resistance, and may provide an opportunity to protect patients from viral pneumonia during periods of peak vulnerability.IMPORTANCE Viruses are the most commonly identified causes of pneumonia and inflict unacceptable morbidity, despite currently available therapies. While lung epithelial cells are principal targets of respiratory viruses, they have also been recently shown to contribute importantly to therapeutically inducible antimicrobial responses. This work finds that lung cells can be stimulated to protect themselves against viral challenges, even in the absence of leukocytes, both reducing viral burden and improving survival. Further, it was found that the protection occurs via unexpected induction of reactive oxygen species (ROS) from spatially segregated sources without reliance on type I interferon signaling. Coordinated multisource ROS generation has not previously been described against viruses, nor has ROS generation been reported for epithelial cells against any pathogen. Thus, these findings extend the potential clinical applications for the strategy of inducible resistance to protect vulnerable people against viral infections and also provide new insights into the capacity of lung cells to protect against infections via novel ROS-dependent mechanisms.

Migration of spinal pedicle screw with aerodigestive perforation and subsequent device expectoration.

INTRODUCTION: Spinal fixation is a common surgical procedure. Frequently, fixation for spinal stabilization requires use of instrumentation such as pedicle screws and fixation plates. Aerodigestive and vascular perforations from such procedures are infrequent albeit known complications from these procedures. PRESENTATION OF CASE: This case details an uncommon situation in which a patient with anterior cervical spine fixation in the distant past was found to have a migratory pedicle screw. The patient had symptoms of neck pain and dysphagia. Radiographic studies were helpful in demonstrating the problem. While undergoing a physical examination, the patient was witnessed to expectorate the screw. Further work up with panendoscopy was undertaken and the patient managed conservatively. DISCUSSION: The upper aerodigestive system rarely experiences perforation from spinal stabilization hardware. When it occurs, management should include a dedicated investigation of the involved portions of the digestive system to avoid further complication. CONCLUSION: This case presents an rare occurrence of aerodigestive perforation of a spinal pedicle screw which was self-removed.

A second arterial conduit to the circumflex circulation significantly improves survival after coronary artery bypass surgery.

OBJECTIVES: Conventional coronary artery bypass surgery involves the use of a single left internal mammary artery to the left anterior descending artery and saphenous vein grafts reserved for other sites. This retrospective propensity-matched study investigated the impact of a second arterial conduit to the left-sided circulation on early and long-term survival after coronary artery bypass surgery. METHODS: Data were retrospectively collected from 2004 to 2014 for all revascularizations with at least 1 arterial and/or 1 venous graft to the circumflex circulation, in addition to an internal mammary artery to the left anterior descending artery. Propensity-matched groups were created based on baseline characteristics. Hazard functions were estimated using Cox multivariable regression, and the Kaplan-Meier survival curves were compared between the matched cohorts. RESULTS: A total of 1226 patients with a venous conduit to the left-sided circulation were successfully matched to an equal number of patients with an arterial conduit. Regression analysis identified a second arterial conduit, logistic European System for Cardiac Operative Risk Evaluation score (EuroSCORE), pulmonary disease, left ventricular ejection fraction, New York Heart Association (NYHA) Class and previous myocardial infarction as significant predictors of survival. A second arterial graft to the left circumflex circulation was a predictor of improved survival (hazard ratio 0.64, 95% confidence interval 0.51-0.80; P < 0.001). There were significant early and late survival benefits (arterial vs venous: 98.2% vs 96.3%, P = 0.003 at 1 year; 82.4% vs 62.2%, P < 0.001 at 10 years) from a second arterial conduit to the circumflex circulation. CONCLUSIONS: There are significant early and late incremental survival benefits from a second arterial conduit to the circumflex circulation.