Identification of Gene Signatures Associated with COVID-19 across Children, Adolescents, and Adults in the Nasopharynx and Peripheral Blood by Using a Machine Learning Approach.

BACKGROUND: Significant variations in immune profiles across different age groups manifest distinct clinical symptoms and prognoses in Coronavirus Disease 2019 (COVID-19) patients. Predominantly, severe COVID-19 cases that require hospitalization occur in the elderly, with the risk of severe illness escalating with age among young adults, children, and adolescents. OBJECTIVE: This study aimed to delineate the unique immune characteristics of COVID-19 across various age groups and evaluate the feasibility of detecting COVID-19-induced immune alterations through peripheral blood analysis. METHODS: By employing a machine learning approach, we analyzed gene expression data from nasopharyngeal and peripheral blood samples of COVID-19 patients across different age brackets. Nasopharyngeal data reflected the immune response to COVID-19 in the upper respiratory tract, while peripheral blood samples provided insights into the overall immune system status. Both datasets encompassed COVID-19 patients and healthy controls, with patients divided into children, adolescents, and adult age groups. The analysis included the expression levels of 62,703 genes per patient. Then, 9 feature-sequencing methods (least absolute shrinkage and selection operator, light gradient boosting machine, Monte Carlo feature selection, random forest, ridge regression, adaptive boosting, categorical boosting, extremely randomized trees, and extreme gradient boosting) were employed to evaluate the association of the genes with COVID-19. Key genes were then utilized to develop efficient classification models. RESULTS: The findings identified specific markers: insulin-like growth factor binding protein 3 (downregulated in the peripheral blood of COVID-19 patients), interferon alpha-inducible protein 27 (upregulated), and SERPING1 (upregulated in nasopharyngeal tissues). In addition, fibulin-2 was downregulated in adolescent patients, but upregulated in the other groups, while epoxide hydrolase 3 was upregulated in healthy controls, but downregulated in children and adolescents. CONCLUSION: This study offers valuable insights into the local and systemic immune responses of COVID-19 patients across age groups, aiding in identifying potential therapeutic targets and formulating personalized treatment strategies.

Solubility and bioavailability enhancement study of lopinavir solid dispersion matrixed with a polymeric surfactant - Soluplus.

As a biopharmaceutical classification system Class IV drug, lopinavir (LPV) shows relatively poor water solubility and permeation in vivo. In the study, we developed novel solid dispersions (SD) of LPV to improve its bioavailability and to describe their overall behaviors. By employing solvent evaporation for a preliminary formulation screening, the SDs of LPV-polymer-sorbitan monolaurate (SBM, as the wetting agent) at 1:4:0.4 (w/w) dramatically enhanced the LPV dissolution in a non-sink medium, and then hot-melt extrusion (HME) was applied to improve the dissolution further. A hydrophilic polymer - Kollidon VA 64 (VA64) and a polymeric surfactant Soluplus were employed as matrix respectively in the optimized formulations. The dissolution profiles of extrudates were significantly higher than those of SDs prepared with solvent-evaporation method. It was attributed to the stronger intermolecular interactions between LPV and the polymers in the HME process, which was also supported by the stability analysis after 6 months storage under 25 °C/60% RH. The differential scanning calorimetry, fourier transform infrared spectroscopy and equilibrium studies showed VA64 only created hydrogen bonding (H-bond) with LPV, but Soluplus generated both H-bond and micelle thanks to its amphiphilic structure. In addition, the bioavailability of LPV in Soluplus matrixed extrudate was 1.70-fold of VA64 matrixed extrudate and 3.70-fold of LPV crystal. In situ permeability and Caco-2 cell transport studies revealed that Soluplus significantly enhanced the permeability of LPV through rat intestine and Caco-2 cell monolayers by P-glycoprotein (P-gp) inhibition. Herein, Soluplus matrixed extrudate improved the LPV bioavailability through three mechanisms: H-bond with LPV, micelle formation in water and P-gp inhibition in vivo. These unique advantages of Soluplus suggested it is a promising carrier for poorly water soluble drugs, especially the substrates of P-gp.

Safety and efficacy of biocompatible perfusion strategy in a contemporary series of patients undergoing coronary artery bypass grafting - a two-center study.

OBJECTIVE: The profile of patients referred for coronary artery bypass grafting (CABG) is continuously changing to include older patients with multiple comorbidities. We assessed the safety and efficacy of a biocompatible perfusion strategy (BPS) in a contemporary series of patients undergoing isolated CABG. METHODS: BPS consisted of a membrane oxygenator, tip-to-tip closed-system heparin-bonded cardiopulmonary bypass circuits without a cardiotomy reservoir, low systemic anticoagulation (target ACT - 250-300 sec) using heparin titration curves, low prime volume, avoidance of systemic cooling, and routine use of cell saver and anti-fibrinolytics. Data were prospectively collected using the American Society of Thoracic Surgeons National Adult Cardiac Surgery Database definitions. RESULTS: 964 consecutive patients (mean age 66 ± 11 years, 83% male) undergoing CABG between 2008 and 2012 were enrolled. 30-day mortality was 1.4%. Rates of postoperative stroke, myocardial infarction, sternal infection and reoperation for bleeding were 0.9%, 1.3%, 1.9% and 4.2%, respectively. Average 24-hour chest tube drainage was 440 ± 280 ml. Blood products were used in 34% of patients (total donor exposure of 1.7 ± 4.7 units/patient). Predictors of hospital mortality in multivariable analysis were left main disease and preoperative treatment with anti-arrhythmic or immunosuppressive medications. Predictors of allogeneic blood transfusions included older age, small body surface area, female gender, increased serum creatinine, lower preoperative LVEF and hematocrit. Priority of surgery, dual antiplatelet therapy and cardiopulmonary bypass time were not predictors of adverse outcomes or blood transfusions. CONCLUSIONS: In a contemporary cohort of patients undergoing CABG, the use of BPS is safe and effective. It is associated with excellent clinical outcomes and reduced allogeneic blood transfusions.

International participation in the Society of Thoracic Surgeons National Database.

In 2011 The Society of Thoracic Surgeons (STS) Workforce on National Databases established the International Database Task Force devoted to expanding participation in the STS National Database internationally. The vision for this initiative was to assist in the globalization of outcomes data and share knowledge, facilitating a worldwide quality collaborative in cardiac surgery. The Department of Cardiothoracic Surgery at Hadassah Medical Center, Jerusalem, Israel, was among the first of several international sites to join the collaborative. This report outlines the rationale behind clinical databases outside of North America submitting data to the STS National Database and reviews the unique challenges and practical steps of integration through experiences by Hadassah Medical Center. Our hope is that this procedural learning will serve as a template to assist future international program integration.

Nesiritide enhances myocardial protection during the revascularization of acutely ischemic myocardium.

BACKGROUND: Nesiritide, a recombinant human B-type natriuretic peptide, has been used in conjunction with inotropic agents in the management of low cardiac output and pulmonary hypertension following cardiac surgery. However, its independent effects on intraoperative myocardial protection are unknown. This study was, therefore, undertaken to determine whether nesiritide alone could enhance myocardial protection when given intraoperatively in a porcine model simulating urgent coronary artery bypass graft surgery. METHODS AND RESULTS: Twenty pigs underwent occlusion of the second and third diagonal coronary arteries using snares for 90 minutes followed by 45 minutes of antegrade, cold blood cardioplegic arrest and 180 minutes of reperfusion on cardiopulmonary bypass during which the snares were released. Ten animals received an IV bolus of Nesiritide (2 microg per kg) at the initiation of coronary occlusion followed by a 0.01-microg/kg per min IV infusion during coronary occlusion, cardioplegic arrest, and reperfusion. Ten other animals underwent the same protocol without Nesiritide (placebo). Infarct size was assessed by the area of necrosis/area of risk using histochemical staining, endothelial function by the % change in coronary vasodilation using ring chamber methodology, and lung edema using % change in wet/dry weights. Nesiritide-treated animals had significantly decreased infarct size (23.44% 3.13 SD% vs. 37.95%+/- 1.05%; p < 0.003), better preservation of endothelial function (70.1%+/- 12.3% vs. 38.9%+/- 10.3%; p < 0.001), and less lung edema (3.39%+/- 2.13% vs. 4.72 +/- 1.14%; p = 0.23). CONCLUSIONS: In a porcine model of acute coronary occlusion simulating urgent CABG surgery, the intraoperative infusion of nesiritide limits myocardial injury.

Novel adhesive skin closures improve wound healing following saphenous vein harvesting.

BACKGROUND AND AIMS: New techniques for skin closure that minimize tissue inflammation and avoid foreign material may decrease morbidity following saphenous vein harvesting. The 3M Steri-Strip S surgical skin closure system is a new, noninvasive method of wound closure, which consists of polymeric components coated with a pressure-sensitive skin adhesive. This prospective, randomized study was undertaken to compare the results of the noninvasive skin closure method to the traditional subcuticular skin closure technique on saphenous vein harvest sites. METHODS: Twenty-six patients undergoing coronary artery bypass surgery with saphenous vein harvesting were prospectively randomized to skin closure using 3M Steri-Strip S Surgical Skin Closure System or subcuticular suture closure with a skin sealant. Wounds were evaluated on postoperative days 7 and 2l for erythema, edema, pain, cosmesis, and the time taken to close the incision. RESULTS: Skin closure with 3M Steri-Strip S was significantly faster, resulted in significantly less erythema, edema, and significantly improved cosmesis. CONCLUSIONS: 3M Steri-Strip S Skin Closure improves wound healing of saphenous vein sites, compared to traditional subcuticular skin closure techniques.

Endoscopic versus conventional radial artery harvest--is smaller better?

BACKGROUND: We sought to assess our initial experience with the recently introduced technique of endoscopic radial artery harvest (ERH) for coronary artery bypass grafting (CABG). METHODS: Data were prospectively collected on 108 consecutive patients undergoing isolated CABG with ERH, and compared to 120 patients having conventional harvest (CH). Follow-up was achieved in 227 patients (99%). At the time of follow-up the severity of motor and sensory symptoms, as well as cosmetic result in the harvest forearm, were subjectively graded using a 5-point scale. Grade 1-- high intensity deficits, poor cosmetic result. Grade 5 -- no deficits, excellent cosmetic result. RESULTS: Hospital mortality, myocardial infarction, and stroke rates were similar between the groups. Follow-up mortality, reintervention rate, and average angina class were also similar. Harvest time was longer in the ERH group (61 +/- 24 min vs. 45 +/- 11 min, p < 0.001). Three patients in the ERH group were converted to CH and one radial artery was discarded. There were no vascular complications of the hand in either group. Average score of motor (ERH 4.4 +/- 0.9, CH 4.2 +/- 1.0) or sensory symptoms (ERH 3.7 +/- 1.1, CH 3.8 +/- 1.2) were similar. In the CH group sensory deficits were observed in the distribution of both the lateral antebrachial cutaneous and the superficial radial nerves (SRN). In contrast, sensory deficits in the ERH group were limited to the distribution of the SRN. Cosmetic result score was higher in the ERH group (ERH 4.2 +/- 1.0, CH 3.1 +/- 1.4, p < 0.0001). CONCLUSIONS: ERH is safe. It is technically demanding with a significant learning curve. Motor and sensory symptoms are not completely eliminated by using a smaller incision, but cosmetic results are clearly superior.

Coronary artery bypass grafting in patients with severe left ventricular dysfunction--early and mid-term outcomes.

BACKGROUND: The prevalence of patients with severe left ventricular dysfunction (LVD) referred for coronary artery bypass grafting (CABG) is increasing. The aim of the present study was to assess the outcomes of patients with severe LVD undergoing CABG. METHODS: Outcomes of 115 consecutive patients with severe LVD (left ventricular ejection fraction [LVEF]30% (HEF). To further evaluate the LVD patients, they were divided into three subgroups base on LVEF: 0% to 10%, 11% to 20%, and 21% to 30%. Data were collected prospectively and entered into the departmental database of the Society of Thoracic Surgeons. RESULTS: Patients in the LVD group had increased incidence of diabetes, chronic obstructive pulmonary disease (COPD), peripheral vascular disease, prior myocardial infarction (MI), congestive heart failure, and less elective procedures compared to the HEF group. Despite this greater risk profile, operative mortality (LVD 2.6% vs. HEF 1.2%, p = 0.19), the incidence of stroke (2.6% vs. 1.0%, p = 0.13), and perioperative MI (0.9% vs. 0.7%) were not statistically different between the groups. The incidence of respiratory (14.8% vs. 1.9%, p < 0.001), renal (5.2% vs. 1.0%, p < 0.001), and vascular (5.2% vs. 0.5%, p < 0.001) complications was significantly higher in the LVD group, resulting in a longer hospital length of stay (8 +/- 8 vs. 6 +/- 4 days, p < 0.0001). In a multivariate analysis, advanced age was as an independent predictor of hospital mortality. Average follow-up in 108 (94%) LVD patients was 36 +/- 22 months (range 2 to 78 months). Twenty-one patients expired during the follow-up, for nine the causes were cardiac-related. Three- and 5-year survival rates were 91 +/- 3% and 76 +/- 6%, respectively. Independent predictors of mid-term mortality in the LVD group by a multivariate analysis included female gender, renal failure, respiratory complications, and grade I/II mitral regurgitation (MR). At the time of follow-up, 72% of LVD patients were in functional class I/II. There were no statistically significant differences in short- and mid-term outcomes among the LVD subgroups. CONCLUSION: CABG in patients with severe LVD can be performed with a low mortality, albeit with higher morbidity and longer length of hospital stay, than patients with LVEF >30%. Low ejection fraction per se was not a predictor of hospital mortality. CABG should be considered a safe and effective therapy for low ejection fraction patients with ischemic heart disease. Mitral valve repair/replacement in the presence of moderate degree of MR should be considered at the time of the initial operation.

Aprotinin decreases ischemic damage during coronary revascularization.

BACKGROUND AND AIM: This study sought to determine whether the favorable anti-inflammatory effects of aprotinin might limit ischemic damage during the revascularization of ischemic myocardium. METHODS: Twenty pigs underwent 90 minutes of coronary occlusion followed by 45 minutes of blood cardioplegic arrest and 180 minutes of reperfusion. Ten animals received a loading dose of aprotinin (40,000 kallikrein inhibiting units/kg) during the start of coronary occlusion followed by an infusion of 20,000 kallikrein inhibiting units/kg/hour. Ten other animals received no aprotinin. Summary statistics are expressed as the mean +/- standard error. RESULTS: The aprotinin-treated animals required less cardioversions for ventricular arrhythmias (1.0 +/- 0.7 vs. 3.6 +/- 0.6; p < 0.001), accumulated less lung water (1.0 +/- 0.2% change vs. 6.2 +/- 0.9% change; p = 0.038), had more complete coronary relaxation to bradykinin (34.1 +/- 5.9% change vs. 9.2 +/- 3.5% change; p = 0.01), and had reduced infarct size (area necrosis/area risk = 20 +/- 1.1% vs. 39 +/- 1.2%; p = 0.003). CONCLUSIONS: Aprotinin limits ischemic injury during acute coronary revascularization by decreasing ventricular arrhythmias and lung edema, preserving endothelial function, and minimizing myocardial necrosis.

Does off-pump revascularization reduce coronary endothelial dysfunction?

BACKGROUND: Off-pump coronary revascularization (OPCAB) has been shown to reduce markers of acute inflammation but its effect on coronary endothelial function is unknown. This experimental study sought to determine whether OPCAB reduces endothelial dysfunction, compared to standard cardiopulmonary bypass (CPB) with and without the anticomplement agent soluble complement receptor-1 (sCR(1)). METHODS: In 10 pigs, OPCAB was simulated by snaring the left anterior descending (LAD) artery for 15 minutes followed by 3 hours of reperfusion. On-pump revascularization was simulated in 20 pigs by 15 minutes of LAD occlusion on CPB with cold blood cardioplegic arrest followed by 3 hours of reperfusion. Ten of these animals received sCR(1) (10 mg/kg) prior to CPB. Inflammatory response was monitored by percent (%) lung water increase, wall motion scores (WMS) with transthoracic echocardiography where 4 = normal to -1 = dyskinesia, and endothelial function in the distal LAD with bradykinin-induced coronary artery relaxation using organ chamber methodology. RESULTS: OPCAB had no effect on lung edema (% increase = 1.7 +/- 1.4 OPCAB vs. 3.4 +/- 0.5 CPB vs. 2.3 +/- 0.9 CPB + sCR(1)) and failed to prevent wall motion changes (WMS = 2.65 +/- 0.08 OPCAB vs. 2.70 +/- 0.04 CPB vs. 3.10 +/- 0.07* CPB + sCR(1), *p < 0.01) and coronary endothelial dysfunction (% relaxation = 41 +/- 9 OPCAB vs. 40 +/- 9 CPB vs. 78 +/- 8** CPB + sCR(1), **p < 0.001), which was best preserved with sCR(1). CONCLUSIONS: This study suggests that agents which directly inhibit complement activation such as sCR(1) are more important in preventing endothelial dysfunction during coronary revascularization than merely avoiding CPB.

Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events.

BACKGROUND: This study sought to determine whether tight glycemic control with a modified glucose-insulin-potassium (GIK) solution in diabetic coronary artery bypass graft (CABG) patients would improve perioperative outcomes. METHODS AND RESULTS: One hundred forty-one diabetic patients undergoing CABG were prospectively randomized to tight glycemic control (serum glucose, 125 to 200 mg/dL) with GIK or standard therapy (serum glucose <250 mg/dL) using intermittent subcutaneous insulin beginning before anesthesia and continuing for 12 hours after surgery. GIK patients had lower serum glucose levels (138+/-4 versus 260+/-6 mg/dL; P<0.0001), a lower incidence of atrial fibrillation (16.6% versus 42%; P=0.0017), and a shorter postoperative length of stay (6.5+/-0.1 versus 9.2+/-0.3 days; P=0.003). GIK patients also showed a survival advantage over the initial 2 years after surgery (P=0.04) and decreased episodes of recurrent ischemia (5% versus 19%; P=0.01) and developed fewer recurrent wound infections (1% versus 10%, P=0.03). CONCLUSIONS: Tight glycemic control with GIK in diabetic CABG patients improves perioperative outcomes, enhances survival, and decreases the incidence of ischemic events and wound complications.

Endoscopic radial artery harvest for coronary artery bypass grafting: initial clinical experience.

BACKGROUND: Recently, an endoscopic technique was developed to harvest the radial artery (RA) via a 3-cm wrist incision in patients undergoing coronary artery bypass graft (CABG). The aim of this study was to evaluate our initial clinical experience with this technology. METHODS: Data were prospectively collected on 75 consecutive patients undergoing CABG with endoscopic RA harvest using the Ultra-Retractor (CardioVations, Somerville, NJ, USA) and the harmonic scalpel (Ethicon Endo-Surgery, Cincinnati, OH, USA). RESULTS: There were 66 men (88%) and 9 women (12%) with a mean age of 60 years (range, 31-77 years). Forty-eight (64%) of cases had non-elective surgery. Thirty-one (41%) of patients had diabetes. Sixty seven percent of the operations were performed on pump and 33% off pump. Average RA harvest time was 66 minutes (range, 25-120 minutes) with a significant learning curve (75 minutes for the first 20 cases and 63 minutes for the last 50 cases). Two (2.6 %) radial arteries were discarded, one because of extensive calcifications and the other because of damage to the conduit. No patients suffered death, perioperative myocardial infarction, or stroke. There was one reexploration of the forearm for a tunnel hematoma. Follow-up was achieved in 100% of patients and averaged 3.6 months (range, 0.5-13 months). Two patients died during the follow-up. There were no myocardial infarctions or reinterventions, with 96% of patients in functional class I /II. There were no motor deficits. There were no sensory deficits in the distribution of the lateral antebrachial cutaneous nerve, but transient mild dorsal thenar numbness or paresthesias were observed in 86% of patients. Cosmetic results were defined as good to excellent in 82% of patients. CONCLUSIONS: Short-term results of endoscopic RA harvest are excellent. There is a significant learning curve. Longterm follow-up as well as structural and functional assessments of the conduit are indicated.

Pretreatment with statins enhances myocardial protection during coronary revascularization.

OBJECTIVE: This experimental study was undertaken to determine whether pretreatment with statins would enhance myocardial protection and minimize ischemic injury during revascularization of acutely ischemic myocardium. METHODS: In 20 pigs the second and third diagonal arteries were occluded for 90 minutes, followed by 45 minutes of blood cardioplegic arrest and 180 minutes of reperfusion. Ten pigs received atorvastatin (40 mg orally every day) for 21 days before surgical intervention; 10 others received no statins. Ischemic damage was assessed on the basis of the need for cardioversions for ventricular arrhythmias, regional wall-motion scores (4 = normal to -1 = dyskinesia) were determined by means of 2-dimensional echocardiography, endothelial function was assessed on the basis of bradykinin-induced coronary artery relaxation, and infarct size was calculated by determining the area of necrosis to the area of risk by means of histochemical staining. Results are given as means +/- SE. RESULTS: Statin-treated animals required fewer cardioversions (0.11 +/- 0.01 vs 2.87 +/- 0.20, P =.0001), had improved wall-motion scores (2.81 +/- 0.10 vs 1.52 +/- 0.08, P =.01), had lower infarct size (21% +/- 2% vs 41% +/- 2%, P =.0001), and had more complete coronary artery relaxation (34% +/- 5% vs 8% +/- 4%, P =.01). Total serum cholesterol levels were similar between the groups (62 +/- 5 mg/dL for statin-treated animals vs 68 +/- 5 mg/dL for non-statin-treated animals, P =.30). CONCLUSIONS: Pretreatment with statins enhances myocardial protection during revascularization by means of mechanisms that are independent of their cholesterol-lowering properties.

Pretreatment with angiotensin-converting enzyme inhibitors attenuates ischemia-reperfusion injury.

BACKGROUND: The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that ischemic events are decreased in patients receiving angiotensin-converting enzyme (ACE) inhibitors. This study sought to determine whether pretreatment with ACE inhibitors would attentuate ischemic injury during surgical revascularization of ischemic myocardium. METHODS: In a porcine model, the second and third diagonal vessels were occluded for 90 minutes, followed by 45 minutes of cardioplegic arrest, and 180 minutes of reperfusion. Ten pigs received quinapril (20 mg p.o. q.d.) for 7 days prior to surgery; 10 others received no-ACE inhibitors. RESULTS: Quinapril-treated animals required less cardioversions for ventricular arrhythmias (1.58 +/- 0.40 vs 2.77 +/- 0.22; p < 0.05), had higher wall motion scores assessed by two-dimensional echocardiography (4 = normal to -1 = dyskinesia; 2.11 +/- 0.10 vs 1.50 +/- 0.07; p < 0.05), more complete coronary artery endothelial relaxation to bradykinin (45% +/- 3% vs 7% +/- 4%; p < 0.005), and lower infarct size (24.0% +/- 3.0% vs 40.0% +/- 1.7%; p < 0.0001). CONCLUSIONS: ACE inhibition prior to coronary revascularization enhances myocardial protection by decreasing ventricular irritability, improving regional wall motion, lowering infarct size, and preserving endothelial function.