Arterial Hyperoxemia During Cardiopulmonary Bypass Was Not Associated With Worse Postoperative Pulmonary Function: A Retrospective Cohort Study.

BACKGROUND: Arterial hyperoxemia may cause end-organ damage secondary to the increased formation of free oxygen radicals. The clinical evidence on postoperative lung toxicity from arterial hyperoxemia during cardiopulmonary bypass (CPB) is scarce, and the effect of arterial partial pressure of oxygen (Pa o2 ) during cardiac surgery on lung injury has been underinvestigated. Thus, we aimed to examine the relationship between Pa o2 during CPB and postoperative lung injury. Secondarily, we examined the relationship between Pa o2 and global (lactate), and regional tissue malperfusion (acute kidney injury). We further explored the association with regional tissue malperfusion by examining markers of cardiac (troponin) and liver injury (bilirubin). METHODS: This was a retrospective cohort study including patients who underwent elective cardiac surgeries (coronary artery bypass, valve, aortic, or combined) requiring CPB between April 2015 and December 2021 at a large quaternary medical center. The primary outcome was postoperative lung function defined as the ratio of Pa o2 to fractional inspired oxygen concentration (F io2 ); P/F ratio 6 hours following surgery or before extubation. The association between CPB in-line sample monitor Pa o2 and primary, secondary, and exploratory outcomes was evaluated using linear or logistic regression models adjusting for available baseline confounders. RESULTS: A total of 9141 patients met inclusion and exclusion criteria, and 8429 (92.2%) patients had complete baseline variables available and were included in the analysis. The mean age of the sample was 64 (SD = 13), and 68% were men (n = 6208). The time-weighted average (TWA) of in-line sample monitor Pa o2 during CPB was weakly positively associated with the postoperative P/F ratio. With a 100-unit increase in Pa o2 , the estimated increase in postoperative P/F ratio was 4.61 (95% CI, 0.71-8.50; P = .02). Our secondary analysis showed no significant association between Pa o2 with peak lactate 6 hours post CPB (geometric mean ratio [GMR], 1.01; 98.3% CI, 0.98-1.03; P = .55), average lactate 6 hours post CPB (GMR, 1.00; 98.3% CI, 0.97-1.03; P = .93), or acute kidney injury by Kidney Disease Improving Global Outcomes (KDIGO) criteria (odds ratio, 0.91; 98.3% CI, 0.75-1.10; P = .23). CONCLUSIONS: Our investigation found no clinically significant association between Pa o2 during CPB and postoperative lung function. Similarly, there was no association between Pa o2 during CPB and lactate levels, postoperative renal function, or other exploratory outcomes.

Deep statistical modelling of nanopore sequencing translocation times reveals latent non-B DNA structures.

MOTIVATION: Non-canonical (or non-B) DNA are genomic regions whose three-dimensional conformation deviates from the canonical double helix. Non-B DNA play an important role in basic cellular processes and are associated with genomic instability, gene regulation, and oncogenesis. Experimental methods are low-throughput and can detect only a limited set of non-B DNA structures, while computational methods rely on non-B DNA base motifs, which are necessary but not sufficient indicators of non-B structures. Oxford Nanopore sequencing is an efficient and low-cost platform, but it is currently unknown whether nanopore reads can be used for identifying non-B structures. RESULTS: We build the first computational pipeline to predict non-B DNA structures from nanopore sequencing. We formalize non-B detection as a novelty detection problem and develop the GoFAE-DND, an autoencoder that uses goodness-of-fit (GoF) tests as a regularizer. A discriminative loss encourages non-B DNA to be poorly reconstructed and optimizing Gaussian GoF tests allows for the computation of P-values that indicate non-B structures. Based on whole genome nanopore sequencing of NA12878, we show that there exist significant differences between the timing of DNA translocation for non-B DNA bases compared with B-DNA. We demonstrate the efficacy of our approach through comparisons with novelty detection methods using experimental data and data synthesized from a new translocation time simulator. Experimental validations suggest that reliable detection of non-B DNA from nanopore sequencing is achievable. AVAILABILITY AND IMPLEMENTATION: Source code is available at https://github.com/bayesomicslab/ONT-nonb-GoFAE-DND.

Association of Conventional Ultrafiltration on Postoperative Pulmonary Complications.

BACKGROUND: Postoperative pulmonary complications increase mortality after cardiac surgery. Conventional ultrafiltration may reduce pulmonary complications by removing mediators of bypass-induced inflammation and countering hemodilution. We tested the primary hypothesis that conventional ultrafiltration reduces postoperative pulmonary complications, and secondarily, improves early pulmonary function assessed by the ratio of PaO2 to fractional inspired oxygen concentration. METHODS: This retrospective analysis compared the incidence of postoperative pulmonary complications in adult patients who underwent cardiac surgery, with and without the use of conventional ultrafiltration, by using logistic regression with adjustment for confounding variables. The primary outcome was a composite of reintubation, prolonged ventilation, pneumonia, or pleural effusion. Secondarily, we examined early postoperative lung function using a quantile regression model. We also explored whether red blood cell transfusion differed between groups. RESULTS: Of 8026 patients, 1043 (13%) received conventional ultrafiltration. After adjustment for confounding variables, the incidence of the composite primary outcome was higher in the conventional ultrafiltration group (12.1% vs 9.9%; P = .03), with an estimated odds ratio of 1.25 (95% CI, 1.02-1.53; P = .03). The median (quantiles) PaO2-to-fractional inspired oxygen concentration ratio was 373 (303-433) vs 368 (303-428), with the estimated adjusted difference in medians of 5 (95% CI, -5.9 to 16; P = .37). The estimated odds ratio of intraoperative transfusion was 1.38 (95% CI, 1.19-1.60; P < .0001) and for postoperative transfusion was 1.30 (95% CI, 1.14-1.49; P = .0001). CONCLUSIONS: Use of conventional ultrafiltration was not associated with a reduction in the composite of postoperative pulmonary complications or improved early pulmonary function. We found no evidence of benefit from use of conventional ultrafiltration during cardiac surgery.

Sequential hypothermic and normothermic perfusion preservation and transplantation of expanded criteria donor livers.

BACKGROUND: The purpose of this study was to assess the safety and feasibility of sequential hypothermic oxygenated perfusion and normothermic machine perfusion and the potential benefits of graft viability preservation and assessment before liver transplantation. METHODS: With the Food and Drug Administration and institutional review board approval, 17 expanded criteria donor livers underwent sequential hypothermic oxygenated perfusion and normothermic machine perfusion using our institutionally developed perfusion device. RESULTS: Expanded criteria donor livers were from older donors, donors after cardiac death, with steatosis, hypertransaminasemia, or calcified arteries. Perfusion duration ranged between 1 and 2 hours for the hypothermic oxygenated perfusion phase and between 4 and 9 hours for the normothermic machine perfusion phase. Three livers were judged to be untransplantable during normothermic machine perfusion based on perfusate lactate, bile production, and macro-appearance. One liver was not transplanted because of recipient issue after anesthesia induction and failed reallocation. Thirteen livers were transplanted, including 9 donors after cardiac death livers (donor warm ischemia time 16-25 minutes) and 4 from donors after brain death. All livers had the standardized lactate clearance >60% (perfusate lactate cleared to <4.0 mmol/L) within 3 hours of normothermic machine perfusion. Bile production rate was 0.2 to 10.7 mL/h for donors after brain death livers and 0.3 to 6.1 mL/h for donors after cardiac death livers. After transplantation, 5 cases had early allograft dysfunction (3 donors after cardiac death and 2 donors after brain death livers). No graft failure or patient death has occurred during follow-up time of 6 to 13 months. Two livers developed ischemic cholangiopathy. Compared with our previous normothermic machine perfusion study, the bile duct had fewer inflammatory cells in histology, but the post-transplant outcomes had no difference. CONCLUSION: Sequential hypothermic oxygenated perfusion and normothermic machine perfusion preservation is safe and feasible and has the potential benefits of preserving and evaluating expanded criteria donor livers.

Hemodynamic evaluation of a new pulsatile blood pump during low flow cardiopulmonary bypass support.

BACKGROUND: The VentriFlo® True Pulse Pump (VentriFlo, Inc, Pelham, NH, USA) is a new pulsatile blood pump intended for use during short-term circulatory support. The purpose of this study was to evaluate the feasibility of the VentriFlo and compare it to a conventional centrifugal pump (ROTAFLOW, Getinge, Gothenberg, Sweden) in acute pig experiments. METHODS: Pigs (40-45 kg) were supported by cardiopulmonary bypass (CPB) with the VentriFlo (n = 9) or ROTAFLOW (n = 5) for 6 h. Both VentriFlo and ROTAFLOW circuits utilized standard CPB components. We evaluated hemodynamics, blood chemistry, gas analysis, plasma hemoglobin, and microcirculation at the groin skin with computer-assisted video microscopy (Optilia, Sollentuna, Sweden). RESULTS: Pigs were successfully supported by CPB for 6 h without any pump-related complications in either group. The VentriFlo delivered an average stroke volume of 29.2 ± 4.8 ml. VentriFlo delivered significantly higher pulse pressure (29.1 ± 7.2 mm Hg vs. 4.4 ± 7.0 mm Hg, p < 0.01) as measured in the carotid artery, with mean aortic pressure and pump flow comparable with those in ROTAFLOW. In blood gas analysis, arterial pH was significantly lower after five hours support in the VentriFlo group (7.30 ± 0.07 vs. 7.43 ± 0.03, p = 0.001). There was no significant difference in plasma hemoglobin level in both groups after six hours of CPB support. In microcirculatory assessment, VentriFlo tended to keep normal capillary flow, but it was not statistically significant. CONCLUSIONS: VentriFlo-supported pigs showed comparable hemodynamic parameters with significantly higher pulse pressure compared to ROTAFLOW without hemolysis.

Sperm Cyst "Looping": A Developmental Novelty Enabling Extreme Male Ornament Evolution.

Postcopulatory sexual selection is credited as a principal force behind the rapid evolution of reproductive characters, often generating a pattern of correlated evolution between interacting, sex-specific traits. Because the female reproductive tract is the selective environment for sperm, one taxonomically widespread example of this pattern is the co-diversification of sperm length and female sperm-storage organ dimension. In Drosophila, having testes that are longer than the sperm they manufacture was believed to be a universal physiological constraint. Further, the energetic and time costs of developing long testes have been credited with underlying the steep evolutionary allometry of sperm length and constraining sperm length evolution in Drosophila. Here, we report on the discovery of a novel spermatogenic mechanism-sperm cyst looping-that enables males to produce relatively long sperm in short testis. This phenomenon (restricted to members of the saltans and willistoni species groups) begins early during spermatogenesis and is potentially attributable to heterochronic evolution, resulting in growth asynchrony between spermatid tails and the surrounding spermatid and somatic cyst cell membranes. By removing the allometric constraint on sperm length, this evolutionary innovation appears to have enabled males to evolve extremely long sperm for their body mass while evading delays in reproductive maturation time. On the other hand, sperm cyst looping was found to exact a cost by requiring greater total energetic investment in testes and a pronounced reduction in male lifespan. We speculate on the ecological selection pressures underlying the evolutionary origin and maintenance of this unique adaptation.

Microplegia vs 4:1 Blood Cardioplegia: Effectiveness and Cost Savings in Complex Cardiac Operations.

BACKGROUND: Microplegia has been studied during isolated coronary artery bypass grafting and valve surgery but not in more complex operations. Objectives of this study were to demonstrate safety and effectiveness of microplegia relative to Buckberg cardioplegia during these operations. METHODS: From January 2012 to January 2017, 242 patients underwent multicomponent operations with simplified microplegia delivered via syringe pump and 10,512 with modified Buckberg cardioplegia. Operations included aortic root, arch, or ascending aorta replacement in 424 (94%) patients, aortic valve surgery in 324 (72%) patients, and concomitant coronary artery bypass grafting in 47 (10%) patients. Outcomes were compared in 226 propensity-matched pairs. RESULTS: There was no difference in median postoperative troponin T between groups after adjusting for aortic clamp time. Microplegia patients received significantly less crystalloid with their cardioplegia (mean 27 ± 8.0 mL/operation vs 735 ± 357 mL/operation; P < .001) and had lower peak intraoperative glucose (196 ± 40 mg/dL vs 248 ± 69 mg/dL; P < .001). Microplegia and Buckberg groups had similar in-hospital mortality (2.7% [n = 6] vs 2.2% [n = 5]; P = .8), stroke (2.2% [n = 5] vs 3.6% [n = 8]; P = .4), renal failure (8% [n = 18] vs 5.8% [n = 13]; P = .4), prolonged ventilation (23% [n = 51] vs 24% [n = 54]; P = .7), median postoperative length of stay (both 8.1 days; P > .9), and median red cell units administered to patients requiring transfusion (4 units vs 3 units; P = .14). The mean cost of cardioplegia per case with microplegia was 1/26th that of Buckberg cardioplegia. CONCLUSIONS: Our simplified microplegia technique offers several advantages over Buckberg cardioplegia without compromising myocardial protection or safety in complex, multicomponent operations with extended aortic clamp times.

Ex Situ Liver Machine Perfusion: The Impact of Fresh Frozen Plasma.

The primary aim of this single-center, phase 1 exploratory study was to investigate the safety, feasibility, and impact on intrahepatic hemodynamics of a fresh frozen plasma (FFP)-based perfusate in ex situ liver normothermic machine perfusion (NMP) preservation. Using an institutionally developed perfusion device, 21 livers (13 donations after brain death and 8 donations after circulatory death) were perfused for 3 hours 21 minutes to 7 hours 52 minutes and successfully transplanted. Outcomes were compared in a 1:4 ratio to historical control patients matched according to donor and recipient characteristics and preservation time. Perfused livers presented a very low resistance state with high flow during ex situ perfusion (arterial and portal flows 340 ± 150 and 890 ± 70 mL/minute/kg liver, respectively). This hemodynamic state was maintained even after reperfusion as demonstrated by higher arterial flow observed in the NMP group compared with control patients (220 ± 120 versus 160 ± 80 mL/minute/kg liver, P = 0.03). The early allograft dysfunction (EAD) rate, peak alanine aminotransferase (ALT), and peak aspartate aminotransferase (AST) levels within 7 days after transplantation were lower in the NMP group compared with the control patients (EAD 19% versus 46%, P = 0.02; peak ALT 363 ± 318 versus 1021 ± 999 U/L, P = 0.001; peak AST 1357 ± 1492 versus 2615 ± 2541 U/L, P = 0.001 of the NMP and control groups, respectively). No patient developed ischemic type biliary stricture. One patient died, and all other patients are alive and well at a follow-up of 12-35 months. No device-related adverse events were recorded. In conclusion, with this study, we showed that ex situ NMP of human livers can be performed safely and effectively using a noncommercial device and an FFP-based preservation solution. Future studies should further investigate the impact of an FFP-based perfusion solution on liver hemodynamics during ex situ normothermic machine preservation.

New Cardioscope-Based Platform for Minimally Invasive and Percutaneous Beating Heart Interventions.

With heart disease increasing worldwide, demand for new minimally invasive techniques and transcatheter technologies to treat structural heart disease is rising. Cardioscopy has long been considered desirable, as it allows direct tissue visualization and intervention to deliver therapy via a closed chest, with real-time fiber-optic imaging of intracardiac structures. Herein, the feasibility of the advanced cardioscopic platform, allowing both transapical and fully percutaneous access is reported. The latter technique, in particular, is believed to represent a milestone in the development of the cardioscope. Cardioscope prototypes were used in 7 bovine models (77.2-101.1 kg) for transapical or percutaneous insertion. Miniature custom-built, water-sealed cameras (diameters: Storz, 7 Fr; Medigus, 1.2 mm) were used. For percutaneous cardiopulmonary bypass, the pulmonary artery was occluded by a balloon catheter (Intraclude, 10.5 Fr, 100 cm) and perfused with a crystalloid solution. Cameras were inserted transapically (n = 4) through the left ventricular apex or percutaneously (n = 5) via the carotid artery. Insertion of the optimized cardioscope devices was feasible via either approach. Intracardiac structures (left ventricle, mitral valve opening/closure, chordal apparatus, aortic valve leaflets, and regurgitation) were visualized clearly and without deformation. Catheter tips were successfully bent >180° inside the left ventricle; rotation and navigation to view various intracardiac structures were feasible in all cases. This study showed the technical feasibility of direct cardioscopic visualization using transapical and percutaneous approaches. This advanced cardioscopic instrumentarium represents a promising platform for future interventions and surgery under direct visualization of the beating heart.

Using Semantic Web Technologies to Enable Cancer Genomics Discovery at Petabyte Scale.

Increased efforts in cancer genomics research and bioinformatics are producing tremendous amounts of data. These data are diverse in origin, format, and content. As the amount of available sequencing data increase, technologies that make them discoverable and usable are critically needed. In response, we have developed a Semantic Web-based Data Browser, a tool allowing users to visually build and execute ontology-driven queries. This approach simplifies access to available data and improves the process of using them in analyses on the Seven Bridges Cancer Genomics Cloud (CGC; www.cancergenomicscloud.org). The Data Browser makes large data sets easily explorable and simplifies the retrieval of specific data of interest. Although initially implemented on top of The Cancer Genome Atlas (TCGA) data set, the Data Browser's architecture allows for seamless integration of other data sets. By deploying it on the CGC, we have enabled remote researchers to access data and perform collaborative investigations.

Developing a protocol for normothermic ex-situ limb perfusion.

BACKGROUND: Ischemia time represents a significant limitation for successful extremity transplantation because of the rapid deterioration of ischemic muscle. Normothermic ex-situ preservation is an emergent method to prolong the organ viability following procurement, by replicating the physiologic conditions. The aim of this study was to develop an ex-situ normothermic limb perfusion system to preserve the viability and function of porcine limbs for 12 hours following procurement. METHODS: A total of 18 swine limbs were perfused. Thirteen limbs were used to develop the perfusion protocol. Five limbs were perfused according to the optimized protocol. These limbs were perfused at 39°C for twelve hours using an oxygenated colloid solution containing red blood cells. Glucose and electrolytes were kept within physiologic range by partial perfusate exchange. Limb specific perfusion quality was assessed by muscle contractility upon electrical nerve stimulation, compartment pressure, creatine kinase (CK) and myoglobin concentrations, tissue oxygen saturation (near infrared spectroscopy), indocyanine green angiography, and infrared radiation by thermographic imaging. RESULTS: The last five limbs reached the 12 hours' perfusion target maintaining normal compartment pressure (16.4 ± 8.20 mmHg), minimal weight increase (0.54 ± 7.35%), and mean muscle temperature of 33.6 ± 1.67°C. Myoglobin and CK concentrations were 875 ± 291.4 ng/mL, and 53344 ± 14850.34 U/L, respectively, at the end of perfusion. Muscle contraction was present in all limbs until cessation of perfusion. Differences in uniformity and quality of distal perfusion were identified with thermography and angiography imaging at 12 hours of perfusion. CONCLUSIONS: Ex-situ normothermic limb perfusion preserves swine limb physiology and function for at least 12 hours.

Moderate hypothermia technique for chronic implantation of a total artificial heart in calves.

The benefit of whole-body hypothermia in preventing ischemic injury during cardiac surgical operations is well documented. However, application of hypothermia during in vivo total artificial heart implantation has not become widespread because of limited understanding of the proper techniques and restrictions implied by constitutional and physiological characteristics specific to each animal model. Similarly, the literature on hypothermic set-up in total artificial heart implantation has also been limited. Herein we present our experience using hypothermia in bovine models implanted with the Cleveland Clinic continuous-flow total artificial heart.

Using near-infrared spectroscopy to monitor lower extremities in patients on venoarterial extracorporeal membrane oxygenation.

Patients on peripheral extracorporeal membrane oxygenation (ECMO) are at risk for lower extremity ischemia. Effective monitoring is needed to identify complications quickly and allow timely correction. Near-infrared spectroscopy has been used extensively in cerebral monitoring during cardiac surgery. We present its use in monitoring lower extremity perfusion in patients on ECMO. Five patients on ECMO had near-infrared spectroscopy monitors placed on the calf of both lower extremities. Continuous real-time tissue oxygen saturation data (stO2) was displayed and recorded. Two patients had lower extremity complications in the leg with the arterial cannula. The patients with complications had lower stO2 in the cannulated leg at the time of ECMO insertion, larger differences in stO2 between the legs at the time of insertion, lower nadir stO2s, and larger peak differences in stO2 between the legs than patients without limb complications. The use of near-infrared spectroscopy for continuous monitoring of tissue oxygenation in the lower extremities in patients on ECMO may allow early identification of patients with lower extremity complications.

Use of del Nido Cardioplegia for Adult Cardiac Surgery at the Cleveland Clinic: Perfusion Implications.

Cardiac arrest by cardioplegia provides a reproducible and safe method to induce and maintain electromechanical cardiac quiescence. Techniques of intraoperative myocardial protection are constantly evolving. For the past three decades, modified Buckberg cardioplegia solution has been used for adult cardiac surgery at the Cleveland Clinic. This formulation serves as the crystalloid component, which is delivered 4:1 with oxygenated patient's blood to crystalloid. Meanwhile, our use of the del Nido cardioplegia solution in adult patients, heretofore primarily used in pediatric cardiac surgical centers, has been increasing over the past several years. Single-dose, cold blood del Nido cardioplegia can be delivered antegrade if the duration of the operation will be limited and if there is no significant coronary artery disease or aortic insufficiency that would limit the distribution of cardioplegia. The addition of del Nido cardioplegia to our cardioplegia armamentarium allows us to customize our myocardial protection strategies for different surgical needs. This article aims to provide information on technical aspects of del Nido cardioplegia in adult cardiac surgery and its use at the Cleveland Clinic in the adult surgical population.

The genus Drosophila as a model for testing tree- and character-based methods of species identification using DNA barcoding.

DNA barcoding has recently been proposed as a promising tool for the (1) rapid assignment of unknown samples to described species by non-expert workers and (2) a potential method of new species discovery based on degree of DNA sequence divergence. Two broad methods have been used, one based on degree of DNA sequence variation, within and between species and another requiring the recovery of species as discrete clades (monophyly) on a phylogenetic tree. An alternative method relies on the identification of a set of specific diagnostic nucleotides for a given species (characters). The genus Drosophila has long served as a model system in genetics, development, ecology and evolutionary biology. As a result of this work, species boundaries within this genus are quite well delimited, with most taxa being defined by morphological characters and also conforming to a biological species concept (e.g., partial or complete reproductive isolation has used to erect and define species). In addition, some of the species in this group have also been subjected to phylogenetic analysis, yielding cases where taxa both conform and conflict with a phylogenetic species concept. Here, we analyzed 1058 COI sequences belonging to 68 species belonging to Drosophila and its allied genus Zaprionus and with more than a single representative to assess the performance of the three DNA barcoding methods. 26% of the species could not be defined using distance methods, i.e. had a barcoding gap of ≤ 0, and 23% were not monophyletic. We focused then on four groups of closely-related species whose taxonomy is well-established on non-molecular basis (e.g., morphology, geography, reproductive isolation) and to which most of the problematic species belonged. We showed that characters performed better than other approaches in the case of paraphyletic species, but all methods failed in the case of polyphyletic species. For these polyphyletic species, other sources of evidence (e.g., morphology, geography, reproductive isolation) are more relevant than COI sequences, highlighting the limitation of DNA barcoding and the needs for integrative taxonomy approaches. In conclusion, DNA barcoding of Drosophila shows no reason to alter the 250 years old tradition of character-based taxonomy, and many reasons to shy away from the alternatives.