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Background: ECMO plays a crucial role in treating severe respiratory and cardiac failure in pediatric patients. However, its impact on the regulation of erythropoietin (EPO) and erythropoiesis remains poorly understood. Factors such as improved oxygenation, inflammation, and hemodilution associated with ECMO treatment may influence EPO production and erythropoiesis. This study aimed to examine the effects of ECMO on EPO regulation and erythropoiesis in pediatric patients., Methods: This retrospective study serially quantified EPO serum levels, measured markers of erythropoiesis, and tabulated clinical outcomes of pediatric ECMO patients. Descriptive statistics and Pearson correlation coefficients were used to identify associations between biomarkers and clinical care parameters., Results: Preliminary findings suggest a disconnection between elevated EPO levels and reduced markers of erythropoiesis or iron metabolism, indicating ineffective erythropoiesis. Patients receiving more than 10 mL/kg/day of RBC transfusions had higher reticulocyte counts. Non-survivors had sustained elevations of EPO serum levels but reduced erythropoietic activity., Conclusion: In ECMO-treated pediatric patients, ineffective erythropoiesis is a significant concern and may be associated with higher mortality rates. Understanding the mechanisms behind this pathology could better inform clinical approaches and optimize management strategies. Further research is imperative to uncover the factors resulting in ineffective erythropoiesis in these patients and to develop targeted interventions., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background The medical workplace presents challenges for workplace-based learning. Structured debriefing of shared clinical experiences has been proposed as a way to take advantage of workplace-based learning in a setting that facilitates deep learning conversations. Objective To investigate faculty and learner acceptance of private, face-to-face, structured debriefing of performance of entrustable professional activities (EPAs). Methods During the 2020-2021 academic year, faculty at the University of Colorado (CU) and the University of Utah (UU) debriefed fellow performance of jointly selected EPAs in neonatal-perinatal medicine pertinent to shared 1- to 3-week clinical rotations. Private face-to-face debriefing was structured by a comprehensive EPA-specific list of behavioral anchors describing 3 levels of entrustment/accomplishment. Sessions ended with joint decisions as to level of entrustment/accomplishment and goals for improvement. We used thematic analysis of semistructured fellow interviews and faculty focus groups to identify themes illustrated with representative quotations. Results We interviewed 17 fellows and 18 faculty. CU participants debriefed after clinical rotations; UU usually debriefed during rotations. Debriefing sessions for 1 to 2 EPAs lasted 20 to 40 minutes. Themes represented in fellow interviews and faculty focus groups suggested that debriefing facilitated formative feedback along with shared understanding of clinical performance and assessment criteria. The standardized format and private conversations supported assessment of aspects of performance for which review might otherwise have been overlooked or avoided. The conversations also provided valuable opportunities for formative discussion of other matters of importance to fellows. Conclusions Structured debriefing of recently shared clinical experiences fostered formative assessment viewed positively by teachers and learners.

Stereolithography (SLA) and other photopolymerization-based additive manufacturing approaches are becoming popular for the fabrication of microfluidic devices and cell-infused platforms, but many of the resins employed in these techniques are cytotoxic to cells or do not have the appropriate mechanical properties for microfluidic components. Here, using a commercially available resin, we demonstrate that biocompatibility and a range of mechanical properties can be achieved through post-print optimization involving baking, soaking, network swelling, and UV exposure. We show that UV-vis spectrophotometry can be used to detect methacrylate monomer/oligomer, and utilizing this method, we found that baking at 120 °C for 24 hours was the optimal method for removing cytotoxic chemical species and creating nontoxic cell culture platforms, though UV exposure and soaking in 100% ethanol also can substantially reduce cytotoxicity. Furthermore, we show that the mechanical properties can be modified, including up to 50% for the Young's modulus and an order of magnitude for the flexural modulus, through the post-processing approach employed. Based on the study results, users can choose post-processing approaches to achieve needed cytotoxicity and mechanical profiles, simultaneously.

Background: Fetal Centers use imaging studies to predict congenital diaphragmatic hernia (CDH) prognosis and the need for fetal therapy. Given improving CDH survival, we hypothesized that current fetal imaging severity predictions no longer reflect true outcomes and fail to justify the risks of fetal therapy., Methods: We analyzed our single-center contemporary data in a left-sided CDH cohort (n = 58) by prognostic criteria determined by MRI observed-to-expected total fetal lung volumes: severe <25%, moderate 25-35%, and mild >35%. We compared contemporary survival to prior studies and the TOTAL trials., Results: Contemporary survival was significantly higher than past studies for all prognostic classifications (mild 100% vs 80-94%, moderate 95% vs 59-75%, severe 79% vs 13-25%; P < 0.01), and to either control or fetal therapy arms of the TOTAL trials., Conclusions: Current fetal imaging criteria are overly pessimistic and may lead to unwarranted fetal intervention. Fetal therapies remain experimental. Future studies will require updated prognostic criteria., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Coronavirus disease 2019 (COVID-19) is associated with coagulation abnormalities and increased risk for venous and arterial thrombi. This study aimed to evaluate D-dimer levels and lupus anticoagulant (LAC) positivity in pregnant individuals with and without Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection., Study Design: This was a prospective cohort study of pregnant individuals delivering at a single academic institution from April 2020 to March 2022. Individuals with a positive SARS-CoV-2 result during pregnancy were compared with a convenience sample of those without a positive SARS-CoV-2 result. For individuals with SARS-CoV-2 infection, severity was assessed based on the National Institutes of Health classification system. The primary outcome was D-dimer level measured during delivery admission. The secondary outcomes were LAC positivity and thromboembolic events. Outcomes were compared between individuals with and without a positive SARS-CoV-2 result, and further by disease severity., Results: Of 98 participants, 77 (78.6%) were SARS-CoV-2 positive during pregnancy. Among individuals with SARS-CoV-2 infection, severity was asymptomatic in 20 (26.0%), mild in 13 (16.9%), moderate in 4 (5.2%), severe in 38 (49.4%), and critical in 2 (2.6%). The D-dimer concentration at delivery did not significantly differ between those with a SARS-CoV-2 positive result compared with those without (mean 2.03 µg/mL [95% confidence interval {CI} 1.72-2.40] vs. 2.37 µg/mL [95% CI 1.65-3.40]; p  = 0.43). Three individuals (4%) with SARS-CoV-2 infection and none (0%) without infection were LAC positive ( p  = 0.59). There were no clinically apparent thromboses in either group. D-dimer concentrations and LAC positive results did not differ by COVID-19 severity., Conclusion: Thrombotic markers did not differ in pregnant individuals by SARS-CoV-2 infection; however, high rates of LAC positivity were detected., Key Points: · Thrombotic markers did not differ in pregnant individuals by SARS-CoV-2 infection.. · Higher than expected rates of LAC positivity were detected.. · There were no clinically apparent thromboses.., Competing Interests: C.C.Y. has authored a U.S. patent (patent no. 10,232,023 B2, “Methods for treatment of and prophylaxis against inflammatory disorders”) held by the University of Utah for the use of neonatal neutrophil extracellular traps (NET)-inhibitory factor, for which PEEL Therapeutics Inc. holds the exclusive license., (Thieme. All rights reserved.)

Retinopathy of prematurity (ROP), a blinding condition affecting preterm infants, is an interruption of retinal vascular maturation that is incomplete when born preterm. Although ROP demonstrates delayed onset following preterm birth, representing a window for therapeutic intervention, there are no curative or preventative measures available for this condition. The in utero environment, including placental function, is increasingly recognized for contributions to preterm infant disease risk. The current study identified a protective association between acute placental inflammation and preterm infant ROP development using logistic regression, with the most significant association found for infants without gestational exposure to maternal preeclampsia and those with earlier preterm birth. Expression analysis of proteins with described ROP risk associations demonstrated significantly decreased placental high temperature requirement A serine peptidase-1 (HTRA-1) and fatty acid binding protein 4 protein expression in infants with acute placental inflammation compared with those without. Within the postnatal peripheral circulation, HTRA-1 and vascular endothelial growth factor-A demonstrated inverse longitudinal trends for infants born in the presence of, compared with absence of, acute placental inflammation. An agnostic approach, including whole transcriptome and differential methylation placental analysis, further identify novel mediators and pathways that may underly protection. Taken together, these data build on emerging literature showing a protective association between acute placental inflammation and ROP development and identify novel mechanisms that may inform postnatal risk associations in preterm infants., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Endoaortic balloon occlusion (EABO) and transthoracic cross-clamping have been shown to have comparable safety profiles for aortic occlusion in minimally invasive mitral valve surgery (MIMVS). However, few studies have focused exclusively on the totally endoscopic robotic approach. We sought to compare outcomes for patients undergoing totally endoscopic robotic mitral valve surgery with aortic occlusion via EABO and transthoracic clamping after a period where EABO was unavailable required us to use the transthoracic clamp. Retrospective review identified 113 patients who underwent robotic mitral valve surgery at our facility between 2019 and 2021 with EABO (n = 71) or transthoracic clamping (n = 42). Relevant data were extracted and compared. Preoperative characteristics were similar other than a higher rate of coronary artery disease [EABO: 69.0% (49/71) vs clamp: 45.2% (19/42), p = .02] and chronic lung disease [EABO: 38.0% (27/71) vs clamp: 9.5% (4/42), p < .01] in the EABO group. Median percutaneous cardiopulmonary bypass time, operative time, and cross-clamp time were comparable. Similar rates of postoperative bleeding complications were observed, and no aortic complications were observed. One patient in each group underwent conversion to an open approach. 30-day mortality and readmission rates were comparable. EABO and transthoracic clamp were associated with similar bleeding and aortic outcomes, and mortality and readmission rates were comparable at thirty days postoperatively. Our findings support the comparable safety of the two techniques, which is well documented in studies encompassing all MIMVS techniques, within the specific context of the totally endoscopic robotic approach., (© 2023. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Protease-activated receptor 4 (PAR4) (gene F2RL3) harbors a functional dimorphism, rs773902 A/G (encoding Thr120/Ala120, respectively) and is associated with greater platelet aggregation. The A allele frequency is more common in Black individuals, and Black individuals have a higher incidence of ischemic stroke than White individuals. However, it is not known whether the A allele is responsible for worse stroke outcomes. To directly test the in vivo effect of this variant on stroke, we generated mice in which F2rl3 was replaced by F2RL3, thereby expressing human PAR4 (hPAR4) with either Thr120 or Ala120. Compared with hPAR4 Ala120 mice, hPAR4 Thr120 mice had worse stroke outcomes, mediated in part by enhanced platelet activation and platelet-neutrophil interactions. Analyses of 7,620 Black subjects with 487 incident ischemic strokes demonstrated the AA genotype was a risk for incident ischemic stroke and worse functional outcomes. In humanized mice, ticagrelor with or without aspirin improved stroke outcomes in hPAR4 Ala120 mice, but not in hPAR4 Thr120 mice. P selectin blockade improved stroke outcomes and reduced platelet-neutrophil interactions in hPAR4 Thr120 mice. Our results may explain some of the racial disparity in stroke and support the need for studies of nonstandard antiplatelet therapies for patients expressing PAR4 Thr120.

Introduction: The robotic platform reduces the invasiveness of cardiac surgical procedures, thus facilitating earlier discharge in select patients. We sought to evaluate the characteristics, perioperative management, and early outcomes of patients who underwent postoperative day 1 or 2 (POD1-2) discharge after robotic cardiac surgery at our institution., Methods: Retrospective review of 169 patients who underwent robotic cardiac surgery at our facility between 2019 and 2021 identified 57 patients discharged early on POD1 (n = 19) or POD2 (n = 38) and 112 patients who underwent standard discharge (POD3 or later). Relevant data were extracted and compared., Results: In the early discharge group, median patient age was 62 [IQR: 55, 66] (IQR = interquartile range) years, and 70.2% (40/57) were male. Median Society of Thoracic Surgeons predictive risk of mortality score was 0.36 [IQR: 0.25, 0.56] %. The most common procedures performed were mitral valve repair [66.6%, (38/57)], atrial mass resection [10.5% (6/57)], and coronary artery bypass grafting [10.5% (6/57)]. The only significant differences between the POD1 and POD2 groups were shorter operative time, higher rate of in-operating room extubation, and shorter ICU length of stay in the POD1 group. Lower in-hospital morbidity and comparable 30-day mortality and readmission rates were observed between the early and standard discharge groups., Conclusions: POD1-2 discharge after various robotic cardiac operations afforded lower morbidity and similar 30-day readmission and mortality rates compared to discharge on POD3 or later. Our findings support the feasibility of POD1-2 discharge after robotic cardiac surgery for patients with low preoperative risk, an uncomplicated postoperative course, and appropriate postoperative management protocols., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: COVID-19 severity and its late complications continue to be poorly understood. Neutrophil extracellular traps (NETs) form in acute COVID-19, likely contributing to morbidity and mortality., Objectives: This study evaluated immunothrombosis markers in a comprehensive cohort of acute and recovered COVID-19 patients, including the association of NETs with long COVID., Methods: One-hundred-seventy-seven patients were recruited from clinical cohorts at 2 Israeli centers: acute COVID-19 (mild/moderate, severe/critical), convalescent COVID-19 (recovered and long COVID), along with 54 non-COVID controls. Plasma was examined for markers of platelet activation, coagulation, and NETs. Ex vivo NETosis induction capability was evaluated after neutrophil incubation with patient plasma., Results: Soluble P-selectin, factor VIII, von Willebrand factor, and platelet factor 4 were significantly elevated in patients with COVID-19 versus controls. Myeloperoxidase (MPO)-DNA complex levels were increased only in severe COVID-19 and did not differentiate between COVID-19 severities or correlate with thrombotic markers. NETosis induction levels strongly correlated with illness severity/duration, platelet activation markers, and coagulation factors, and were significantly reduced upon dexamethasone treatment and recovery. Patients with long COVID maintained higher NETosis induction, but not NET fragments, compared to recovered convalescent patients., Conclusions: Increased NETosis induction can be detected in patients with long COVID. NETosis induction appears to be a more sensitive NET measurement than MPO-DNA levels in COVID-19, differentiating between disease severity and patients with long COVID. Ongoing NETosis induction capability in long COVID may provide insights into pathogenesis and serve as a surrogate marker for persistent pathology. This study emphasizes the need to explore neutrophil-targeted therapies in acute and chronic COVID-19., Competing Interests: Declaration of competing interests N.K., S.S., S.N., A.D., A.S., H.P., E.P., A.F.C., J.D.S., and M.G. are current or former employees of Peel Therapeutics and hold share options in the company. K.M. and A.S. received consulting fees for scientific advice to Peel Therapeutics and hold stock options in the company. C.C.Y. authors a US patent (patent no. 10,232,023 B2) held by the University of Utah for the use of NET-inhibitory peptides for the "treatment of and prophylaxis against inflammatory disorders," for which Peel Therapeutics, Inc. holds the exclusive license. C.C.Y. and J.D.S. are co-inventors on patent application WO2021226111A1 for NET-inhibitory peptides to treat and prevent immunothrombosis in COVID-19 acute respiratory distress syndrome. S.P., A.R.P, I.L., S.I.C.M., R.A., N.C., R.K., A.J., A.R. and E.B. have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Barbed nonabsorbable sutures have been widely adopted for tissue closure in noncardiac robotic surgery to improve intraoperative efficiency. Here, we examine the profile in robotic mitral valve repair (rMVR), which utilized barbed nonabsorbable sutures. To our knowledge, this is the first report to describe clinical outcomes for rMVR with barbed nonabsorbable sutures., Methods: A retrospective review identified 90 patients who underwent rMVR using barbed nonabsorbable sutures at our center between 2019 and 2021. The primary outcome measure was dehiscence, while other relevant outcomes included 30-day readmission and 30-day mortality., Results: In addition to fixation of the mitral annuloplasty band, barbed nonabsorbable sutures were employed commonly in concomitant pericardiectomy closure (100.0%, 90 of 90), atriotomy closure (100.0%, 90 of 90), and left atrial appendage closure (if eligible; 98.8%, 83 of 84). One patient who underwent mitral valve annuloplasty using only barbed nonabsorbable suture required reoperation for annuloplasty ring dehiscence. Immediate postoperative ring dehiscence was not observed in any patients after the routine reinforcement of barbed nonabsorbable sutures with everting pledgeted polyester sutures, and no additional patients required reoperation for suture-related complications. Clinical signs of dehiscence were not observed after pericardiectomy, atriotomy, or left atrial appendage closure with barbed nonabsorbable sutures. The 30-day readmission rate was 3.3% (3 of 90), and 30-day mortality was 0% (0 of 90)., Conclusions: These data suggest the initial feasibility of barbed nonabsorbable sutures in robotic cardiac surgery, specifically within rMVR. Further research is necessary to explore the long-term safety and efficacy profile of such approach.

Introduction: Expanding the heart donor pool to include patients with hepatitis B virus (HBV) could help ameliorate the organ shortage in heart transplantation. We performed a systematic review and meta-analysis to evaluate the management and recipient outcomes of D+/R- and D-/R+ heart transplants., Methods: An electronic search was performed to identify all relevant studies published on heart transplants involving HBV+ donors and/or HBV+ recipients. A comparison was performed between two groups where heart transplants were performed a) D+/R- (n = 98) versus b) D-/R+ (n = 65)., Results: Overall, 13 studies were selected, comprising 163 patients. Mean patient age was 55 y (95% CI: 39, 78) and 79% (69, 86) were male. Active post-transplant HBV infection requiring antiviral treatment occurred in 11% (1, 69) of D+/R- recipients and 33% (9, 71) of D-/R+ recipients. Post-transplant antiviral therapy was given to 80% (6, 100) of D+/R- recipients compared to 72% (42, 90) of D-/R+ recipients (P = 0.84). Hepatitis-related mortality was observed in no D+/R- recipients and 7% (2, 27) of D-/R+ recipients. Survival 1-y post-transplant was comparable between both groups at 83% (83, 92) and 81% (61, 92) for D+/R- and D-/R+ transplants, respectively., Conclusions: Our review found that HBV D+/R- heart transplantation was associated with fewer active hepatitis infections and lower hepatitis-related mortality than D-/R+ transplantation, with comparable survival at 1 y. Additional studies utilizing HBV nucleic acid testing (NAT) to compare outcomes with HBsAg+ and anti-HBc+ donors are crucial to reach more definitive conclusions about the risk of donor-derived infections in this context., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The integrated 6-year thoracic surgery (I-6) residency model was developed in part to promote early interest in cardiothoracic surgery in diverse trainees. To determine gaps in and opportunities for recruitment of women and minority groups in the pipeline for I-6 residency, we quantified rates of progression at each training level and trends over time., Methods: We obtained 2015 to 2019 medical student, I-6 applicant, and I-6 resident gender and race/ethnicity demographic data from the American Association of Medical Colleges and Electronic Residency Application Service public databases and Accreditation Council for Graduate Medical Education Data Resource Books. We performed χ 2 , Fisher exact, and Cochran-Armitage tests for trend to compare 2015 and 2019., Results: Our cross-sectional analysis found increased representation of women and all non-White races/ethnicities, except Native American, at each training level from 2015 to 2019 (P < .001 for all). The greatest trends in increases were seen in the proportions of women (28% vs 22%, P = .46) and Asian/Pacific Islander (25% vs 15%, P = .08) applicants. There was also an increase in the proportions of women (28% vs 24%, P = .024) and White (61% vs 58%, P = .007) I-6 residents, with a trend for Asian/Pacific Islanders (20% vs 17%, P = .08). The proportions of Hispanic (5%) and Black/African American (2%) I-6 residents in 2019 remained low., Conclusions: I-6 residency matriculation is not representative of medical student demographics and spotlights a need to foster early interest in cardiothoracic surgery among all groups underrepresented in medicine while ensuring that we mitigate bias in residency recruitment., (Copyright © 2023 The Society of Thoracic Surgeons. All rights reserved.)

A 61-year-old male presented via referral for mitral regurgitation and was deemed an appropriate robotic surgery candidate for complex mitral valve repair with the maze procedure and patent foramen ovale and left atrial appendage closures, using all percutaneous cannulation. We report upon the first case in the literature that describes the use of only 4 robotic ports, with no working port used.

Background: Treatment of neonatal peritonitis and sepsis is challenging. Following infection, neutrophils elaborate neutrophil extracellular traps (NETs)-extracellular lattices of decondensed chromatin decorated with antimicrobial proteins. NETs, however, can augment pathogenic inflammation causing collateral damage. We hypothesized that NET inhibition would improve survival in experimental neonatal infectious peritonitis., Methods: We induced peritonitis in 7 to 10-day-old mice by intraperitoneal injection with cecal slurry. We targeted NETs by treating mice with neonatal NET-Inhibitory Factor (nNIF), an endogenous NET-inhibitor; Cl-amidine, a PAD4 inhibitor; DNase I, a NET degrading enzyme, or meropenem (an antibiotic). We determined peritoneal NET and cytokine levels and circulating platelet-neutrophil aggregates. Survival from peritonitis was followed for 6 days., Results: nNIF, Cl-amidine, and DNase I decreased peritoneal NET formation and inflammatory cytokine levels at 24 h compared to controls. nNIF, Cl-amidine, and DNase I decreased circulating platelet-neutrophil aggregates, and NET-targeting treatments significantly increased survival from infectious peritonitis compared to controls. Finally, nNIF administration significantly improved survival in mice treated with sub-optimal doses of meropenem even when treatment was delayed until 2 h after peritonitis induction., Conclusions: NET inhibition improves survival in experimental neonatal infectious peritonitis, suggesting that NETs participate pathogenically in neonatal peritonitis and sepsis., Impact: 1. Neutrophil extracellular trap formation participates pathogenically in experimental neonatal infectious peritonitis. 2. NET-targeting strategies improve outcomes in a translational model of neonatal infectious peritonitis. 3. NET inhibition represents a potential target for drug development in neonatal sepsis and infectious peritonitis., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Introduction: Neutrophil extracellular traps (NETs) clear pathogens but may contribute Q8 pathogenically to host inflammatory tissue damage during sepsis. Innovative therapeutic agents targeting NET formation and their potentially harmful collateral effects remain understudied., Methods: We investigated a novel therapeutic agent, neonatal NET-Inhibitory Factor (nNIF), in a mouse model of experimental sepsis - cecal ligation and puncture (CLP). We administered 2 doses of nNIF (1 mg/ kg) or its scrambled peptide control intravenously 4 and 10 hours after CLP treatment and assessed survival, peritoneal fluid and plasma NET formation using the MPO-DNA ELISA, aerobic bacterial colony forming units (CFU) using serial dilution and culture, peritoneal fluid and stool microbiomes using 16S rRNA gene sequencing, and inflammatory cytokine levels using a multiplexed cytokine array. Meropenem (25 mg/kg) treatment served as a clinically relevant treatment for infection., Results: We observed increased 6-day survival rates in nNIF (73%) and meropenem (80%) treated mice compared to controls (0%). nNIF decreased NET formation compared to controls, while meropenem did not impact NET formation. nNIF treatment led to increased peritoneal fluid and plasma bacterial CFUs consistent with loss of NET-mediated extracellular microbial killing, while nNIF treatment alone did not alter the peritoneal fluid and stool microbiomes compared to vehicle-treated CLP mice. nNIF treatment also decreased peritoneal TNF-a inflammatory cytokine levels compared to scrambled peptide control. Furthermore, adjunctive nNIF increased survival in a model of sub-optimal meropenem treatment (90% v 40%) in CLP-treated mice., Discussion: Thus, our data demonstrate that nNIF inhibits NET formation in a translationally relevant mouse model of sepsis, improves survival when given as monotherapy or as an adjuvant with antibiotics, and may play an important protective role in sepsis., Competing Interests: CY authors a US patent (patent no. 10,232,023 B2) held by the University of Utah for the use of NET-inhibitory peptides for the “treatment of and prophylaxis against inflammatory disorders,” for which Peel Therapeutics, Inc. holds the exclusive license. JS is shareholder and employed by Peel Therapeutics, Inc. The authors declare that this study received funding from Peel Therapeutics, Inc. in the form of a sponsored research agreement. The funder had the following involvement in the study: through co-author JS, help writing portions of this article., (Copyright © 2023 de Araujo, Denorme, Stephens, Li, Cody, Crandell, Petrey, Queisser, Rustad, Evangelista, Kay, Schiffman, Campbell and Yost.)

Previous studies have shown that the endoaortic balloon occlusion (EABO) can provide satisfactory aortic cross-clamping with comparable surgical outcomes to thoracic aortic clamping in the setting of minimally invasive and robotic cardiac surgery. We described our approach to EABO use in totally endoscopic and percutaneous robotic mitral valve surgery. Preoperative computed tomography angiography is required to evaluate the quality and size of the ascending aorta, identify access sites for peripheral cannulation and endoaortic balloon insertion, and screen for other vascular anomalies. Continuous bilateral upper extremity arterial pressure and cranial near-infrared spectroscopy monitoring are essential to detect obstruction of the innominate artery due to distal balloon migration. Transesophageal echocardiography is needed for continuous monitoring of balloon positioning and antegrade cardioplegia delivery. Direct fluorescent visualization of the endoaortic balloon on the robotic camera allows for verification of balloon and efficient repositioning if needed. The surgeon should assess hemodynamic and imaging information simultaneously during the balloon inflation and delivery of antegrade cardioplegia. Aortic root pressure, systemic blood pressure, and balloon catheter tension affect the position of the inflated endoaortic balloon in the ascending aorta. The surgeon should eliminate all slack in the balloon catheter and lock it into position to prevent proximal balloon migration after the completion of antegrade cardioplegia. Using scrupulous preoperative imaging assessment and continuous intraoperative monitoring, the EABO can achieve adequate cardiac arrest in totally endoscopic robotic cardiac surgery, even in patients with previous sternotomy without compromise of surgical outcomes.

Objective: Prior studies have demonstrated robotic excision of cardiac tumors as a safe and effective treatment option. The procedure is performed with five incisions: three robotic arm ports, one atrial retractor port, and one working port. We report our unique initial experience in robotic tumor removal. To our knowledge, this is one of the first reports demonstrating cardiac myxoma and fibroelastoma removal with use of exclusively 8-mm ports., Methods: All data for robotic cardiac tumor resection at our institution from June 2019 to December 2021 were retrospectively collected; 18 cases were included, including 13 cardiac myxomas and five fibroelastomas. Baseline demographics, intraoperative characteristics, and surgical outcomes were recorded. Descriptive statistics were calculated; continuous variables were reported as median [interquartile range], and categorical variables were reported as percentages., Results: Median patient age was 64 [55, 70] years old. The cohort consisted of primarily female (67%) and white (83%) patients. Median body mass index was 26.3 [23.0, 31.5] kg/m 2 . 11% of patients were current tobacco users and 50% had hypertension. All patients underwent myxoma or fibroelastoma removal with the use of five 8-mm robotic ports. Each patient underwent percutaneous cannulation via the femoral arteries. Aortic occlusion was achieved via an endoaortic balloon (67%) or transthoracic cross-clamp (33%). Cross-clamp time was 30 [26, 41] minutes. Concomitant procedures performed during myxoma removal included patent foramen ovale closure (28%), mitral valve repair (8%), left atrial appendage closure (8%), Cox-maze procedure (6%), and coronary artery bypass grafting (6%). All cardiac tumors were packaged with use of the endo-bag and subsequently removed through the working port. Maximal myxoma and fibroelastoma diameters were 2.5 [1.7, 3.5] and 0.6 [0.4, 0.7] cm, respectively. Procedural cardiopulmonary bypass time was 77 [65, 84] minutes. No intraoperative mortality, reoperation for bleeding, or postoperative cardiac issues were recorded. One in-hospital mortality occurred as the result of a thrombotic event in the context of a hypercoagulable state unrelated to the patient's operation. No other mortalities were observed at 30 days. Hospital length of stay was 4.5 [3.0, 7.8] days., Conclusions: In our study, the robotic platform facilitated safe and effective cardiac tumor excision. Our results highlight the efficacy of 8-mm port sizing and the concurrent use of other minimally invasive techniques, including percutaneous cannulation, in this patient population. In general, patients prefer the least invasive treatment option available. Our findings emphasize the importance of training cardiac surgeons to perform robotic procedures using the least invasive means possible to provide patients with various options for their treatment., (© 2022 Wiley Periodicals LLC.)

Objective: To analyze preoperative cardiopulmonary support and define preoperative stability relative to timing of surgical repair for CDH neonates not on ECMO., Study Design: We retrospectively analyzed repeated measures of oxygenation index (OI; Paw*FiO 2 ×100/PaO 2 ) among 158 neonates for temporal preoperative trends. We defined physiologic stability using OI and characterized ventilator days and discharge age relative to delay in repair beyond physiologic stability., Results: The OI in the first 24 h of life was temporally reliable and representative of the preoperative mean (ICC 0.70, 95% CI 0.61-0.77). A pre-operative OI of ≤ 9.4 (AUC 0.95) was predictive of survival. Surgical delay after an OI ≤ 9.4 resulted in increased ventilator days (1.4, 95% CI 1.1-1.9) and discharge age (1.5, 95% CI 1.2-2.0). When prospectively applied to a subsequent cohort, an OI ≤ 9.4 was again reflective of physiologic stability prior to repair., Conclusion: OI values are temporally reliable and change minimally after 24 h age. Delay in surgical repair of CDH beyond initial stability increases ventilator days and discharge age without a survival benefit., Level of Evidence: Prognosis study, Level III., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Published by Elsevier Inc.)

A 76-year-old male patient was referred to our institution with moderate-to-severe aortic and mitral insufficiency. The patient underwent totally endoscopic robot-assisted aortic valve replacement and mitral valve repair. In this article, we present our lateral approach to the robotic double valve surgery.

Ischemic stroke prompts a strong inflammatory response, which is associated with exacerbated outcomes. In this study, we investigated mechanistic regulators of neutrophil extracellular trap (NET) formation in stroke and whether they contribute to stroke outcomes. NET-forming neutrophils were found throughout brain tissue of ischemic stroke patients, and elevated plasma NET biomarkers correlated with worse stroke outcomes. Additionally, we observed increased plasma and platelet surface-expressed high-mobility group box 1 (HMGB1) in stroke patients. Mechanistically, platelets were identified as the critical source of HMGB1 that caused NETs in the acute phase of stroke. Depletion of platelets or platelet-specific knockout of HMGB1 significantly reduced plasma HMGB1 and NET levels after stroke, and greatly improved stroke outcomes. We subsequently investigated the therapeutic potential of neonatal NET-inhibitory factor (nNIF) in stroke. Mice treated with nNIF had smaller brain infarcts, improved long-term neurological and motor function, and enhanced survival after stroke. nNIF specifically blocked NET formation without affecting neutrophil recruitment after stroke. Importantly, nNIF also improved stroke outcomes in diabetic and aged mice and was still effective when given 1 hour after stroke onset. These results support a pathological role for NETs in ischemic stroke and warrant further investigation of nNIF for stroke therapy.

Introduction: Extracorporeal carbon dioxide removal (ECCO 2 R) provides respiratory support to patients suffering from hypercapnic respiratory failure by utilizing an extracorporeal shunt and gas exchange membrane to remove CO 2 from either the venous (VV-ECCO 2 R) or arterial (AV-ECCO 2 R) system before return into the venous site. AV-ECCO 2 R relies on the patient's native cardiac function to generate pressures needed to deliver blood through the extracorporeal circuit. VV-ECCO 2 R utilizes a mechanical pump and can be used to treat patients with inadequate native cardiac function. We sought to evaluate the existing evidence comparing the subgroups of patients supported on VV and AV-ECCO 2 R devices., Methods: A literature search was performed to identify all relevant studies published between 2000 and 2019. Demographic information, medical indications, perioperative variables, and clinical outcomes were extracted for systematic review and meta-analysis., Results: Twenty-five studies including 826 patients were reviewed. 60% of patients (497/826) were supported on VV-ECCO 2 R. The most frequent indications were acute respiratory distress syndrome (ARDS) [69%, (95%CI: 53%-82%)] and chronic obstructive pulmonary disease (COPD) [49%, (95%CI: 37%-60%)]. ICU length of stay was significantly shorter in patients supported on VV-ECCO 2 R compared to AV-ECCO 2 R [15 (95%CI: 7-23) vs. 42 (95%CI: 17-67) days, p = 0.05]. In-hospital mortality was not significantly different [27% (95%CI: 18%-38%) vs. 36% (95%CI: 24%-51%), p = 0.26]., Conclusion: Both VV and AV-ECCO 2 R provided clinically meaningful CO 2 removal with comparable mortality., (© 2021 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Platelet-neutrophil interactions regulate ischemic vascular injury. Platelets are activated by serine proteases that cleave protease-activated receptor (PAR) amino termini, resulting in an activating tethered ligand. Neutrophils release cathepsin G (CatG) at sites of injury and inflammation, which activates PAR4 but not PAR1, although the molecular mechanism of CatG-induced PAR4 activation is unknown. We show that blockade of the canonical PAR4 thrombin cleavage site did not alter CatG-induced platelet aggregation, suggesting CatG cleaves a different site than thrombin. Mass spectrometry analysis using PAR4 N-terminus peptides revealed CatG cleavage at Ser67-Arg68. A synthetic peptide, RALLLGWVPTR, representing the tethered ligand resulting from CatG proteolyzed PAR4, induced PAR4-dependent calcium flux and greater platelet aggregation than the thrombin-generated GYPGQV peptide. Mutating PAR4 Ser67or Arg68 reduced CatG-induced calcium flux without affecting thrombin-induced calcium flux. Dog platelets, which contain a conserved CatG PAR4 Ser-Arg cleavage site, aggregated in response to human CatG and RALLLGWVPTR, while mouse (Ser-Gln) and rat (Ser-Glu) platelets were unresponsive. Thus, CatG amputates the PAR4 thrombin cleavage site by cleavage at Ser67-Arg68 and activates PAR4 by generating a new functional tethered ligand. These findings support PAR4 as an important CatG signaling receptor and suggest a novel therapeutic approach for blocking platelet-neutrophil-mediated pathophysiologies., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Major airway surgery can pose a complex problem to perioperative central airway management. Adjuncts to advanced ventilation strategies have included cardiopulmonary bypass, veno-arterial, or veno-venous extracorporeal life support. We performed a systematic review to assess the existing evidence utilizing these strategies., Methods: An electronic search was conducted to identify studies written in English reporting the use of extracorporeal life support (ECLS) during central airway surgery. Thirty-six articles consisting of 78 patients were selected and patient-level data were analyzed., Results: Median patient age was 47 [IQR: 34-53] and 59.0% (46/78) were male. Indications for surgery included central airway or mediastinal cancer in 57.7% (45/78), lesion or injury in 15.4% (12/78), and stenosis in 12.8% (10/78). Support was initiated pre-operatively in 9.9% (7/71) and at the time of induction in 55.3% (42/76). It was most commonly used at the time of tracheal resection/repair [93.2% (68/73)], intubation of the tracheal stump [94.4% (68/72)], and re-anastomosis [94.2% (65/69)]; 13.7% (10/73) patients were supported post-operatively. The most commonly performed surgery was tracheal repair or resection in 70.3% (52/74). Median hospital stay was 12 [8, 25] days and in-hospital mortality was 7.9% (6/76). There was no significant difference in survival between the three groups (p = .54)., Conclusions: Extracorporeal membrane oxygenation offers versatility in timing, surgical approach, and ECLS runtime that makes it a viable addition to the surgical armamentarium for treating complex central airway pathologies., (© 2021 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Minimally invasive cardiac surgery (MICS) has evolved in its practice over the past several years. Percutaneous cannulation is a technique that can be used during MICS to facilitate cardiopulmonary bypass. This manuscript describes the stepwise approach to percutaneous cannulation and decannulation in robotic mitral valve surgery.

Neutrophil extracellular traps (NETs) are important components of innate immunity. Neonatal neutrophils (polymorphonuclear leukocytes [PMNs]) fail to form NETs due to circulating NET-inhibitory peptides (NIPs), cleavage fragments of α1-antitrypsin (A1AT). How fetal and neonatal blood NIPs are generated remains unknown, however. The placenta expresses high-temperature requirement serine protease A1 (HTRA1) during fetal development, which can cleave A1AT. We hypothesized that placentally expressed HTRA1 regulates the formation of NIPs and that NET competency changed in PMNs isolated from neonatal HTRA1 knockout mice (HTRA1-/-). We found that umbilical cord blood plasma has elevated HTRA1 levels compared with adult plasma and that recombinant and placenta-eluted HTRA1 cleaves A1AT to generate an A1AT cleavage fragment (A1ATM383S-CF) of molecular weight similar to previously identified NIPs that block NET formation by adult neutrophils. We showed that neonatal mouse pup plasma contains A1AT fragments that inhibit NET formation by PMNs isolated from adult mice, indicating that NIP generation during gestation is conserved across species. Lipopolysaccharide-stimulated PMNs isolated from HTRA1+/+ littermate control pups exhibit delayed NET formation after birth. However, plasma from HTRA1-/- pups had no detectable NIPs, and PMNs from HTRA1-/- pups became NET competent earlier after birth compared with HTRA1+/+ littermate controls. Finally, in the cecal slurry model of neonatal sepsis, A1ATM383S-CF improved survival in C57BL/6 pups by preventing pathogenic NET formation. Our data indicate that placentally expressed HTRA1 is a serine protease that cleaves A1AT in utero to generate NIPs that regulate NET formation by human and mouse PMNs., (© 2021 by The American Society of Hematology.)

Background: Pneumonia and diarrhea are among the leading causes of death worldwide, and epidemiological studies have demonstrated that diarrhea is associated with an increased risk of subsequent pneumonia. Our aim was to determine the impact of intestinal infection on innate immune responses in the lung., Methods: Using a mouse model of intestinal infection by Salmonella enterica serovar Typhimurium ( S . Typhimurium [ ST ]), we investigated associations between gastrointestinal infections and lung innate immune responses to bacterial ( Klebsiella pneumoniae ) challenge., Results: We found alterations in frequencies of innate immune cells in the lungs of intestinally infected mice compared with uninfected mice. On subsequent challenge with K. pneumoniae, we found that mice with prior intestinal infection have higher lung bacterial burden and inflammation, increased neutrophil margination, and neutrophil extracellular traps, but lower overall numbers of neutrophils, compared with mice without prior intestinal infection. Total numbers of dendritic cells, innate-like T cells, and natural killer cells were not different between mice with and without prior intestinal infection., Conclusions: Together, these results suggest that intestinal infection impacts lung innate immune responses, most notably neutrophil characteristics, potentially resulting in increased susceptibility to secondary pneumonia., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Alpha-1-acid glycoprotein (AGP-1) is a positive acute phase glycoprotein with uncertain functions. Serum AGP-1 (sAGP-1) is primarily derived from hepatocytes and circulates as 12-20 different glycoforms. We isolated a glycoform secreted from platelet-activating factor (PAF)-stimulated human neutrophils (nAGP-1). Its peptide sequence was identical to hepatocyte-derived sAGP-1, but nAGP-1 differed from sAGP-1 in its chromatographic behavior, electrophoretic mobility, and pattern of glycosylation. The function of these 2 glycoforms also differed. sAGP-1 activated neutrophil adhesion, migration, and neutrophil extracellular traps (NETosis) involving myeloperoxidase, peptidylarginine deiminase 4, and phosphorylation of ERK in a dose-dependent fashion, whereas nAGP-1 was ineffective as an agonist for these events. Furthermore, sAGP-1, but not nAGP-1, inhibited LPS-stimulated NETosis. Interestingly, nAGP-1 inhibited sAGP-1-stimulated neutrophil NETosis. The discordant effect of the differentially glycosylated AGP-1 glycoforms was also observed in platelets where neither of the AGP-1 glycoforms alone stimulated aggregation of washed human platelets, but sAGP-1, and not nAGP-1, inhibited aggregation induced by PAF or ADP, but not by thrombin. These functional effects of sAGP-1 correlated with intracellular cAMP accumulation and phosphorylation of the protein kinase A substrate vasodilator-stimulated phosphoprotein and reduction of Akt, ERK, and p38 phosphorylation. Thus, the sAGP-1 glycoform limits platelet reactivity, whereas nAGP-1 glycoform also limits proinflammatory actions of sAGP-1. These studies identify new functions for this acute phase glycoprotein and demonstrate that the glycosylation of AGP-1 controls its effects on 2 critical cells of acute inflammation., (©2020 Society for Leukocyte Biology.)

Objective: Coronavirus disease 2019 (COVID-19) is associated with derangement in biomarkers of coagulation and endothelial function and has been likened to the coagulopathy of sepsis. However, clinical laboratory metrics suggest key differences in these pathologies. We sought to determine whether plasma coagulation and fibrinolytic potential in patients with COVID-19 differ compared with healthy donors and critically ill patients with sepsis. Approach and Results: We performed comparative studies on plasmas from a single-center, cross-sectional observational study of 99 hospitalized patients (46 with COVID-19 and 53 with sepsis) and 18 healthy donors. We measured biomarkers of endogenous coagulation and fibrinolytic activity by immunoassays, thrombin, and plasmin generation potential by fluorescence and fibrin formation and lysis by turbidity. Compared with healthy donors, patients with COVID-19 or sepsis both had elevated fibrinogen, d-dimer, soluble TM (thrombomodulin), and plasmin-antiplasmin complexes. Patients with COVID-19 had increased thrombin generation potential despite prophylactic anticoagulation, whereas patients with sepsis did not. Plasma from patients with COVID-19 also had increased endogenous plasmin potential, whereas patients with sepsis showed delayed plasmin generation. The collective perturbations in plasma thrombin and plasmin generation permitted enhanced fibrin formation in both COVID-19 and sepsis. Unexpectedly, the lag times to thrombin, plasmin, and fibrin formation were prolonged with increased disease severity in COVID-19, suggesting a loss of coagulation-initiating mechanisms accompanies severe COVID-19., Conclusions: Both COVID-19 and sepsis are associated with endogenous activation of coagulation and fibrinolysis, but these diseases differently impact plasma procoagulant and fibrinolytic potential. Dysregulation of procoagulant and fibrinolytic pathways may uniquely contribute to the pathophysiology of COVID-19 and sepsis.

There is an urgent need to understand the pathogenesis of coronavirus disease 2019 (COVID-19). In particular, thrombotic complications in patients with COVID-19 are common and contribute to organ failure and mortality. Patients with severe COVID-19 present with hemostatic abnormalities that mimic disseminated intravascular coagulopathy associated with sepsis, with the major difference being increased risk of thrombosis rather than bleeding. However, whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters platelet function to contribute to the pathophysiology of COVID-19 remains unknown. In this study, we report altered platelet gene expression and functional responses in patients infected with SARS-CoV-2. RNA sequencing demonstrated distinct changes in the gene-expression profile of circulating platelets of COVID-19 patients. Pathway analysis revealed differential gene-expression changes in pathways associated with protein ubiquitination, antigen presentation, and mitochondrial dysfunction. The receptor for SARS-CoV-2 binding, angiotensin-converting enzyme 2 (ACE2), was not detected by messenger RNA (mRNA) or protein in platelets. Surprisingly, mRNA from the SARS-CoV-2 N1 gene was detected in platelets from 2 of 25 COVID-19 patients, suggesting that platelets may take-up SARS-COV-2 mRNA independent of ACE2. Resting platelets from COVID-19 patients had increased P-selectin expression basally and upon activation. Circulating platelet-neutrophil, -monocyte, and -T-cell aggregates were all significantly elevated in COVID-19 patients compared with healthy donors. Furthermore, platelets from COVID-19 patients aggregated faster and showed increased spreading on both fibrinogen and collagen. The increase in platelet activation and aggregation could partially be attributed to increased MAPK pathway activation and thromboxane generation. These findings demonstrate that SARS-CoV-2 infection is associated with platelet hyperreactivity, which may contribute to COVID-19 pathophysiology.

COVID-19 affects millions of patients worldwide, with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens, and they can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n = 33) and age- and sex-matched controls (n = 17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), platelet factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-inhibitory factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19, with intubation (P < .0001) and death (P < .0005) as outcome. Illness severity correlated directly with plasma MPO-DNA complexes (P = .0360), whereas Pao2/fraction of inspired oxygen correlated inversely (P = .0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19, and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline, and COVID-19 plasma triggered NET formation, which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19, and NETs may represent targets for therapeutic intervention.

Background: Mortality and ECMO rates for congenital diaphragmatic hernia (CDH) remain ~30%. In 2016, we changed our CDH guidelines to minimize stimulation while relying on preductal oxygen saturation, lower mean airway pressures, stricter criteria for nitric oxide (iNO), and inotrope use. We compared rates of ECMO, survival, and survival without ECMO between the two epochs., Design/methods: Retrospective review of left-sided CDH neonates at the University of Utah/Primary Children's Hospital NICUs during pre (2003-2015, n = 163) and post (2016-2019, n = 53) epochs was conducted. Regression analysis controlled for defect size and intra-thoracic liver., Results: Following guideline changes, we identified a decrease in ECMO (37 to 13%; p = 0.001) and an increase in survival without ECMO (53 to 79%, p = 0.0001). Overall survival increased from 74 to 89% (p = 0.035)., Conclusion(s): CDH management guideline changes focusing on minimizing stimulation, using preductal saturation and less aggressive ventilator/inotrope support were associated with decreased ECMO use and improved survival.

Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19., Competing Interests: Disclosures: M.R. Looney reported "other" from Neutrolis outside the submitted work. R.E. Schwartz is a Sponsored Advisory Board Member for Miromatrix Inc. J.D. Spicer reported personal fees from Bristol Myers Squibb, personal fees from Astra Zeneca, personal fees from Merck, personal fees from Trans-Hit Bio, and non-financial support from Astra Zeneca outside the submitted work. C.C. Yost reports a grant from PEEL Therapeutics, Inc. during the conduct of the study; in addition, C.C. Yost authors a US patent (patent no. 10,232,023 B2) held by the University of Utah for the use of NET-inhibitory peptides for "treatment of and prophylaxis against inflammatory disorders." PEEL Therapeutics, Inc. has exclusive licensing rights. M. Egeblad reported "other" from Santhera during the conduct of the study; and consulted for CytomX in 2019. No other disclosures were reported., (© 2020 Barnes et al.)