What is the weakest point of a secured aortic cannula in central extracorporeal membrane oxygenation?

PURPOSE: The purpose of this study was to compare techniques for securing the aortic extracorporeal membrane oxygenation (ECMO) cannula, using in vitro models. METHODS: Two models were studied: a tissue model using porcine aortas and a stand model replacing the aorta with a metal stand to study the system independent of the tissue. Interventions in each model were divided into three experimental groups: Group 1 (3-0 Prolene® + 20-French Medtronic Arterial Cannula EOPA™), Group 2 (4-0 Prolene® + 16-French Medtronic Arterial Cannula DLP Pediatric), and Group 3 (5-0 Prolene® + 8-French Medtronic Arterial Cannula DLP Pediatric). In separate experiments, both gradual and rapid forces were applied to the cannulas, starting with 9.8 Newtons and increasing exponentially if the cannula remained secured. Additionally, the method of securing the tourniquet and the number of ties securing the tourniquet to the cannula were evaluated. RESULTS: In the tissue model, even with a minimum force of 9.8 Newtons, the suture pulled through the aortic tissue, leaving sutures and ties intact. In the stand model, two purse-string sutures secured by two ligaclips held the cannula reliably and withstood higher total force. Dislodgement was prevented at forces close to 60 Newtons with only two hemostatic clips included in cannulation. CONCLUSIONS: The weakest part of the aortic ECMO cannulation system using in vitro experiments was the tissue. Assuming that these experiments translate in vivo, it is therefore critical to prevent any pull on the cannulas by securing ECMO cannulas and ECMO tubing to both the patient and the patient's bed. Sutures with a larger diameter withstand more force. Two medium hemostatic clips can secure Prolene® sutures within snares as safely as a mosquito hemostat. Two polypropylene purse-string sutures secured by two hemostatic clips were most reliable at greater forces. The rationale for publishing our experiments in this manuscript is to (1) communicate our quantification of possible contributing factors to this rare and likely catastrophic complication of unintended decannulation, (2) increase awareness about this potential complication, and (3) increase vigilance to assure prevention of this dreaded complication.

Closing the gap between acceptable and ideal in catheterisation for paediatric and congenital heart disease-A global view.

In recent issues of the Journal of the Society for Cardiovascular Angiography and Interventions and the Journal of the American College of Cardiology: Cardiovascular Interventions, Holzer and colleagues presented an Expert Consensus Document titled: "PICS / AEPC / APPCS / CSANZ / SCAI / SOLACI: Expert consensus statement on cardiac catheterization for pediatric patients and adults with congenital heart disease." This Expert Consensus Document is a massively important contribution to the community of paediatric and congenital cardiac care. This document was developed as an Expert Consensus Document by the Pediatric and Congenital Interventional Cardiovascular Society, the Association for European Paediatric and Congenital Cardiology, the Asia-Pacific Pediatric Cardiac Society, the Cardiac Society of Australia and New Zealand, the Society for Cardiovascular Angiography and Interventions, and the Latin American Society of Interventional Cardiology, as well as the Congenital Cardiac Anesthesia Society and the American Association of Physicists in Medicine.As perfectly stated in the Preamble of this Expert Consensus Document, "This expert consensus document is intended to inform practitioners, payors, hospital administrators and other parties as to the opinion of the aforementioned societies about best practices for cardiac catheterisation and transcatheter management of paediatric and adult patients with congenital heart disease, with added accommodations for resource-limited environments." And, the fact that the authorship of this Expert Consensus Document includes global representation is notable, commendable, and important.This Expert Consensus Document has the potential to fill an important gap for this patient population. National guideline documents for specific aspects of interventions in patients with paediatric heart disease, including training guidelines, do exist. However, this current Expert Consensus Document authored by Holzer and colleagues provides truly globally applicable standards on cardiac catheterisation for both paediatric patients and adults with congenital heart disease (CHD).Our current Editorial provides different regional perspectives from senior physicians dedicated to paediatric and congenital cardiac care who are practicing in Europe, the Asia-Pacific region, Latin America, Australia/New Zealand, and North America. Establishing worldwide standards for cardiac catheterisation laboratories for children and adults with CHD is a significant stride towards improving the quality and consistency of care. These standards should not only reflect the current state of medical knowledge but should also be adaptable to future advancements, ultimately fostering better outcomes and enhancing the lives of individuals affected by CHD worldwide.Ensuring that these standards are accessible and adaptable across different healthcare settings globally is a critical step. Given the variability in resources and infrastructure globally, the need exists for flexibility and tailoring to implement recommendations.The potential impact of the Expert Consensus Document and its recommendations is likely significant, but heterogeneity of healthcare systems will pose continuing challenges on healthcare professionals. Indeed, this heterogeneity of healthcare systems will challenge healthcare professionals to finally close the gap between acceptable and ideal in the catheterisation of patients with paediatric and/or congenital heart disease.

The Academic Impact of Congenital Heart Surgeons' Society (CHSS) Studies.

PURPOSE: We reviewed all 64 articles ever published by The Congenital Heart Surgeons' Society (CHSS) Data Center to estimate the academic impact of these peer-reviewed articles. MATERIALS AND METHODS: The Congenital Heart Surgeons' Society has performed research based on 12 Diagnostic Inception Cohorts. The first cohort (Transposition) began enrolling patients on January 1, 1985. We queried PubMed to determine the number of publications that referenced each of the 64 journal articles generated by the datasets of the 12 Diagnostic Inception Cohorts that comprise the CHSS Database. Descriptive summaries of the data were tabulated using mean with standard deviation and median with range. RESULTS: Sixty-four peer-reviewed papers have been published based on the CHSS Database. Fifty-nine peer-reviewed articles have been published based on the 12 Diagnostic Inception Cohorts, and five additional articles have been published based on Data Science. Excluding the recently established Diagnostic Inception Cohort for patients with Ebstein malformation of tricuspid valve, the number of papers published per cohort ranged from 1 for coarctation to 11 for transposition of the great arteries. The 11 articles generated from the CHSS Transposition Cohort were referenced by a total of 111 articles (median number of references per journal article = 9 [range = 0-22, mean = 10.1]). Overall, individual articles were cited by an average of 11 (mean), and a maximum of 41 PubMed-listed publications. Overall, these 64 peer-reviewed articles based on the CHSS Database were cited 692 times in PubMed-listed publications. The first CHSS peer-reviewed article was published in 1987, and during the 35 years from 1987 to 2022, inclusive, the annual number of CHSS publications has ranged from 0 to 7, with a mean of 1.8 publications per year (median = 1, mode = 1). CONCLUSION: Congenital Heart Surgeons' Society studies are widely referenced in the pediatric cardiac surgical literature, with over 10 citations per published article. These cohorts provide unique information unavailable in other sources of data. A tool to access this analysis is available at: [https://data-center.chss.org/multimedia/files/2022/CAI.pdf].

Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2.

COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles' inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses.

An Analysis of 186 Transplants for Pediatric or Congenital Heart Disease: Impact of Pretransplant VAD.

BACKGROUND: We reviewed our management strategy and outcome data for all 181 patients with pediatric or congenital heart disease who received 186 heart transplants from January 1, 2011, to March 1, 2022, and evaluated the impact of pretransplant ventricular assist device (VAD). METHODS: Continuous variables are presented as mean (SD); median [interquartile range] (range). Categorical variables are presented as number (percentage). Univariable associations with long-term mortality were assessed with Cox proportional hazards models. Impact of pretransplant VAD on survival was estimated with multivariable models. RESULTS: Pretransplant VAD was present in 53 of 186 transplants (28.5%). Patients with VAD were younger (years): 4.8 (5.6); 1 [0.5-8] (0.1-18) vs 12.1 (12.7); 10 [0.7-17] (0.1-58); P = .0001. Patients with VAD had a higher number of prior cardiac operations: 3.0 (2.3); 2 [1-4] (1-12) vs 1.8 (1.9); 2 [0-3] (0-8); P = .0003. Patients with VAD were also more likely to receive an ABO-incompatible transplant: 10 of 53 (18.9%) vs 9 of 133 (6.8%); P = .028. Univariable associations with long-term mortality included: In multivariable analysis, pretransplant VAD did not impact survival while controlling for each one of the factors shown in univariable analysis to be associated with long-term mortality. Kaplan-Meier 5-year survival (95% CI) was 85.8% (80.0%-92.1%) for all patients, 84.3% (77.2%-92.0%) without pretransplant VAD, and 91.1% (83.1%-99.9%) with pretransplant VAD. CONCLUSIONS: Our single-institution analysis of 181 patients receiving 186 heart transplants for pediatric or congenital heart disease over 11.25 years reveals similar survival in patients with (n = 51) and without (n = 130) pretransplant VAD. The presence of a pretransplant VAD is not a risk factor for mortality after transplantation for pediatric or congenital heart disease.

An Analysis of 183 Heart Transplants for Pediatric or Congenital Heart Disease-Impact of High Panel Reactive Antibody.

BACKGROUND: We reviewed our management strategy and outcome data for all 179 patients with pediatric and/or congenital heart disease who underwent 183 heart transplants from January 1, 2011, to December 31, 2021, and evaluated the impact of elevated panel reactive antibody (PRA). METHODS: High PRA was defined as PRA >10%. Univariate associations with long-term survival were assessed with Cox proportional hazards models. Impact of high PRA on survival was estimated with multivariable models. RESULTS: PRA >10% was present in 60 of 183 transplants (32.8%), who were more likely to have prior cardiac surgery, higher number of prior cardiac operations, prior sternotomy, prior heart transplant, and positive crossmatch (24 of 60 [40.0%] vs 11 of 123 [8.9%], P < .0001). Univariate associations with long-term survival include acquired heart disease vs congenital or retransplant (hazard ratio [HR], 0.18; 95% CI, 0.053-0.593; P = .005), prior cardiac surgery (HR, 5.6; 95% CI, 1.32-23.75; P = .020), number of prior cardiac operations (HR, 1.3 for each additional surgery; 95% CI, 1.12-1.50; P = .0004), single ventricle (HR, 2.4; 95% CI, 1.05-5.48; P = .038), and preoperative renal dysfunction (HR, 3.4; 95% CI, 1.43-7.49; P = .002). In multivariate analysis, high PRA does not impact survival when controlling for each of the factors shown in univariable analysis to be associated with long-term survival. The Kaplan-Meier method provided the following survival estimates at 1 year (95% CI) and 5 years (95% CI) after cardiac transplantation: All patients, 93.6% (89.9%-97.3%) and 85.8% (80.0%-92.1%); PRA <10%, 96.6% (93.4%-99.9%) and 86.7% (79.6%-94.3%); and PRA >10%, 86.7% (78.0%-96.4%) and 83.8% (74.0%-95.0%). Despite high PRA being associated with higher mortality at 1 year (14.9% vs 3.8%, P = .035), no significant difference exists in Kaplan-Meier overall survival at 5 years posttransplant in patients with and without high PRA (log-rank P = .4). CONCLUSIONS: In our cohort, 5-year survival in patients with high PRA (PRA >10%) is similar to that in patients without high PRA (PRA <10%), despite the presence of more risk factors in those with high PRA. Individualized immunomodulatory strategies can potentially mitigate the risk of high PRA.

Variation in Case-Mix Across Hospitals: Analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database.

BACKGROUND: The Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database was queried to document variation of patient characteristics, procedure types, and programmatic case-mix. METHODS: All index cardiac operations in patients less than 18 years of age in the STS Congenital Heart Surgery Database (July 2016 to June 2020) were eligible for inclusion except patients weighing ≤2.5 kg undergoing isolated patent ductus arteriosus closure. At the hospital level, we describe variations in patient and procedural characteristics known from previous analyses to be associated with outcomes. We also report variations across hospitals of programmatic case-mix. RESULTS: Data were analyzed from 117 sites (90 322 total operations, 87 296 total index cardiac operations eligible for STAT [STS-European Association for Cardio-Thoracic Surgery] 2020 Mortality Score). The median annual total index cardiac operations eligible for STAT 2020 Mortality Score per hospital was 157 (interquartile range [IQR], 94-276). Wide variability was documented in total annual index cardiac operations eligible for STAT 2020 Mortality Score per hospital (ratio 90th/10th percentile = 9.01), operations in neonates weighing <2.5 kg (ratio 90th/10th percentile = 4.09), operations in patients with noncardiac anatomic abnormalities (ratio 90th/10th percentile = 3.46), and operations in patients with preoperative mechanical ventilation (ratio 90th/10th percentile = 3.97). At the hospital level, the median percentage of all index cardiac operations in STAT 2020 Mortality Category 5 was 3.7% (IQR, 1.7%-4.9%), the median percentage of all index cardiac operations in STAT 2020 Mortality Category 4 or 5 was 24.4% (IQR, 19.0%-28.4%), the median hospital-specific mean STAT Mortality Category was 2.39 (IQR, 2.20-2.47), and the median hospital-specific mean STAT Mortality Score was 0.86 (IQR, 0.73-0.91). CONCLUSIONS: Substantial variation of patient characteristics, procedure types, and case-mix exists across pediatric and congenital cardiac surgical programs. Knowledge about programmatic case-mix augments data about indirectly standardized programmatic observed-to-expected (O/E) mortality. Indirectly standardized O/E ratios do not provide a complete description of a given pediatric and congenital cardiac surgical program. The indirectly standardized programmatic O/E ratios associated with a given program apply only to its specific case-mix of patients and may represent a quite different case-mix than that of another program.

Palliation Plus Ventricular Assist Device Insertion in 15 Neonates and Infants With Functionally Univentricular Circulation.

BACKGROUND: We report 15 high-risk neonates and infants with functionally univentricular circulation stabilized with initial surgical palliation plus ventricular assist device (VAD) insertion (PALLIATION+VAD) in preparation for transplantation. METHODS: Fifteen functionally univentricular patients with ductal-dependent systemic circulation (8 hypoplastic left heart syndrome, 1 hypoplastic left heart syndrome-related malformation: 7 neonates, 2 infants) or ductal-dependent pulmonary circulation (6 hypoplastic right heart syndrome: 5 neonates, 1 infant) presented with anatomical and/or physiological features associated with increased risk for conventional univentricular palliation (large coronary sinusoids with ventricular-dependent coronary circulation, severe systemic atrioventricular valvar regurgitation, cardiogenic shock, or restrictive atrial septum). PALLIATION+VAD for patients with ductal-dependent systemic circulation was: VAD insertion plus application of bilateral pulmonary bands, stent placement in the arterial duct, and atrial septectomy, if needed. PALLIATION+VAD for patients with ductal-dependent pulmonary circulation was: VAD insertion plus stent placement in the arterial duct or systemic-to-pulmonary artery shunt with pulmonary arterioplasty, if needed. RESULTS: At PALLIATION+VAD, median age was 20 days (range, 4-143 days) and median weight was 3.47 kg (range, 2.43-4.86 kg). Ten patients (67%) survived and 5 patients (33%) died. All ten survivors are at home doing well after successful transplantation. Only 2 of 10 survivors (20%) required intubation >10 days after PALLIATION+VAD. Median length of VAD support for all 15 patients was 138 days (range, 56-226 days). CONCLUSIONS: High-risk neonates with functionally univentricular hearts who are suboptimal candidates for conventional palliation can be successfully stabilized with pulsatile VAD insertion along with initial palliation while awaiting cardiac transplantation; these patients may be extubated, enterally nourished, and optimized for transplantation while on VAD.

Development of a LC-MS/MS method for the quantification of toxic payload DM1 cleaved from BT1718 in a Phase I study.

Background: BT1718 is a novel bicyclic peptide anticancer drug targeting membrane type I matrix metalloproteinase to release its toxic payload DM1. A LC-MS/MS method was validated to quantify DM1 generated from BT1718 in a Phase I/IIa clinical trial. Materials & methods: Plasma samples underwent a reduction reaction to artificially cleave BT1718 into DM1 and its bicycle components. An alkylation step was carried out to stabilize the reaction products, and plasma proteins extracted using acetonitrile. LC-MS/MS analysis utilized a C18 column and Agilent 6460 triple quadrupole mass spectrometer (Agilent, Cheshire, UK). Results: The method was fully validated over a linear range of 200-50,000 ng/ml BT1718, with overall precision ≤10% and accuracy 89-102%. Conclusion: A novel method for quantifying DM1 yielded from BT1718 has been validated and is now being utilized clinically.

Myocardial revascularization: the evolution of the STS database and quality measurement for improvement.

The Society of Thoracic Surgeons (STS) is a not-for-profit organization dedicated to helping clinicians and researchers provide optimal outcomes for patients undergoing heart, lung, and esophageal surgery. The organization was founded in 1964 and has grown to now include over 7300 members in over 90 countries. The STS created a national database that collects detailed clinical information on patients undergoing adult cardiac, pediatric and congenital cardiac, and general thoracic operations. The data collected are used to produce risk-adjusted, nationally benchmarked performance assessments and feedback; facilitate voluntary public reporting; support quality initiatives; develop evidence-based guidelines; monitor long-term clinical outcomes; track device performance; and promote high-quality research collaboratives.

The importance of patient-specific preoperative factors: an analysis of the society of thoracic surgeons congenital heart surgery database.

BACKGROUND: The most common forms of risk adjustment for pediatric and congenital heart surgery used today are based mainly on the estimated risk of mortality of the primary procedure of the operation. The goals of this analysis were to assess the association of patient-specific preoperative factors with mortality and to determine which of these preoperative factors to include in future pediatric and congenital cardiac surgical risk models. METHODS: All index cardiac operations in The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) during 2010 through 2012 were eligible for inclusion. Patients weighing less than 2.5 kg undergoing patent ductus arteriosus closure were excluded. Centers with more than 10% missing data and patients with missing data for discharge mortality or other key variables were excluded. Rates of discharge mortality for patients with or without specific preoperative factors were assessed across age groups and were compared using Fisher's exact test. RESULTS: In all, 25,476 operations were included (overall discharge mortality 3.7%, n=943). The prevalence of common preoperative factors and their associations with discharge mortality were determined. Associations of the following preoperative factors with discharge mortality were all highly significant (p<0.0001) for neonates, infants, and children: mechanical circulatory support, renal dysfunction, shock, and mechanical ventilation. CONCLUSIONS: Current STS-CHSD risk adjustment is based on estimated risk of mortality of the primary procedure of the operation as well as age, weight, and prematurity. The inclusion of additional patient-specific preoperative factors in risk models for pediatric and congenital cardiac surgery could lead to increased precision in predicting risk of operative mortality and comparison of observed to expected outcomes.

Functionally univentricular heart and the fontan operation: lessons learned about patterns of practice and outcomes from the congenital heart surgery databases of the European association for cardio-thoracic surgery and the society of thoracic surgeons.

BACKGROUND: "The term "functionally univentricular heart" describes a spectrum of congenital cardiovascular malformations in which the ventricular mass may not readily lend itself to partitioning that commits one ventricular pump to the systemic circulation and another to the pulmonary circulation." The purpose of this article is to review patterns of practice and outcomes in the Congenital Heart Surgery Databases (CHSDBs) of the European Association for Cardio-Thoracic Surgery (EACTS) and the Society of Thoracic Surgeons (STS) in patients with functionally univentricular hearts undergoing the Fontan operation. METHODS: We examined all index operations performed on patients with functionally univentricular hearts in the EACTS and STS-CHSDBs over 4 years from 2007 to 2010, inclusive. RESULTS: The most common diagnostic categories are hypoplastic left heart syndrome, tricuspid atresia, and double inlet left ventricle. The Fontan operation makes up 3.2% of all cardiac operations in the EACTS and STS-CHSDBs over 4 years from 2007 to 2010, inclusive. Of all the patients undergoing a Fontan procedure, 65.1% had an extracardiac Fontan, 21.5% had a lateral tunnel, and 5.8% had a Fontan revision or conversion (Re-do Fontan). In operations where fenestration status is known, 68.5% of the Fontan operations were fenestrated. During the four years of this analysis, only 5 patients had ventricular septation. Exclusive of Fontan revision or conversion (Re-do Fontan), all remaining Fontan operations had a discharge mortality of 2.3%. Fontan revision or conversion (Re-do Fontan) had a discharge mortality of 12.8%. CONCLUSIONS: The STS database is largest CHSDB in North America. The EACTS database is largest CHSDB in Europe. This review of data from EACTS and STS allows for unique documentation of practice patterns and outcomes. From this analysis, it is clear that patients with functionally univentricular hearts present a challenging problem; however, exclusive of Fontan revision or conversion (Re-do Fontan), the Fontan operation has a discharge mortality of 2.3%.

Identification of clinical candidates from the benzazepine class of histamine H3 receptor antagonists.

This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.

Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains.

The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.