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.

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.

Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.

Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.

Analysis of UNOS: Berlin Heart Bridge-to-Transplant in Acquired versus Congenital Heart Disease.

BACKGROUND: We evaluated long-term survival in pediatric patients bridged-to-transplant with Berlin Heart, comparing those with congenital heart disease (CHD) to those with acquired heart disease (AHD). METHODS: The United Network for Organ Sharing Database was queried for patients (<18years) who received a heart transplant in the United States and were preoperatively supported with Berlin Heart. Patients were stratified by AHD versus CHD diagnosis. Univariable and multivariable analysis was performed to assess baseline characteristics and post-transplant survival. RESULTS: This cohort included 806 patients (n=573 AHD, n=233 CHD). CHD and AHD patients were of similar size (weight[kg], 12.8±9.27 versus 15.3±13.6, p=0.107) and most were aged<1 year (34.9%, n=281) or 1-5 years (45.3%, n=365). Ventricular assist device configuration differed between CHD and AHD patients-70.4%[n=164] versus 75%[n=430] were supported with left ventricular assist device, 9.9%[n=23] versus 0.7%[n=4] were supported with right ventricular assist device, and 19.7%[n=46] versus 24.3%[n=139] were supported with biventricular assist device (p<0.001). CHD patients were more often male (57.1%[n=133] versus 46.9%[n=269], p=0.011) and had worse estimated 5-year post-transplant survival at 74.3%(95% CI=67.5%-81.7%) compared to 85.8%(95% CI=82.5%-89.2%) in patients with AHD. However, for patients who survived the first year post-transplant, post-transplant survival was similar between groups (p>0.05 at 2-,3-,4-, and 5-years). In multivariable analysis, CHD diagnosis was significantly associated with an increased risk for mortality (HR=1.645, 95% CI=1.075-2.487, p=0.021). CONCLUSIONS: After controlling for demographic variations and pretransplant risk factors, patients with CHD bridged-to-transplant with Berlin Heart had worse long-term survival than patients with AHD bridged-to-transplant with Berlin Heart.

Longitudinal Cognitive and Motor Delay after Pediatric Heart Transplantation and Associated Survival.

BACKGROUND: We investigated factors associated with the longitudinal presence of neurodevelopmental delays in pediatric heart transplant (HTx) recipients. METHODS: The United Network for Organ Sharing Registry was queried for patients <18 years who received a first-time isolated HTx between March 2008 and December 2022. Two patient cohorts were developed, those with/without: 1) definitive motor delay (MD) and 2) definitive cognitive delay (CD). RESULTS: A total of 3847(n=3267[no MD], n=580[definitive MD]) and 3446(n=2689[no CD], n=757[definitive CD]) patients were included across MD and CD cohorts, respectively. Cohorts shared 3189 patients. Compared to intracohort non-delayed patients, definitive MD and CD cohorts each independently had higher rates of congenital heart disease, ventilator support at transplant, and stroke prior to discharge (p<0.001 for all). Patients with a definitive delay at follow-up had worse longitudinal survival, with hazard ratios of 2.82(95% CI: 2.32-3.44, p<0.001) and 1.67(95% CI: 1.32-2.05, p<0.001) for MD and CD cohorts, respectively. Both stroke prior to discharge and symptomatic cerebrovascular disease at listing were predictors of CD and MD at follow-up. Definitive MD and CD cohorts each independently had higher rates of stroke prior to discharge (MD cohort, 57/580=9.8% versus 48/3267=1.5%; CD cohort, 53/757=7.0% versus 42/2689=1.6%, p<0.001 for both), and symptomatic cerebrovascular disease at listing was a predictor of CD and MD at follow-up (CD cohort, OR=4.16[95% CI: 2.62-6.58]; MD cohort, OR=3.30[95% CI: 2.06-5.22]. CONCLUSIONS: Patients with MD and/or CD following HTx share several characteristics (including increased stroke prior to discharge) and have decreased longitudinal survival compared to their non-delayed counterparts.

Fate of Abstracts Presented at Annual Meetings of The Society of Thoracic Surgeons from 2015 to 2019.

BACKGROUND: Society of Thoracic Surgeons (STS) annual meetings provide opportunities to disseminate cardiothoracic research. We assessed rates of publication of STS abstracts as manuscripts in peer-reviewed journals over five years and determined factors associated with successful publication. METHODS: The STS "Annual Meeting Archive" was searched online for abstract books from STS annual meetings from 2015-2019. Abstract books were reviewed for information about presented abstracts. A PubMed and Google search was then performed to identify corresponding peer-reviewed journal publications. RESULTS: A total of 1451 abstracts were presented at STS annual meetings from 2015-2019. Overall publication rate of accepted abstracts as manuscripts in peer-reviewed journals was 1097/1451=75.60%. Most published manuscripts were published in The Annals of Thoracic Surgery (750/1097=68.37%). Median duration between abstract presentation and peer-reviewed journal publication was 313[IQR=212.5-458] days. Only 29/1451=2.00% of abstracts won an award, and all 29 of these award-winning abstracts were published as a manuscript. Oral presentation was associated with increased odds of publication compared to poster presentation (OR=1.28[95% CI=1.04-1.71], p=0.021). Median 5-year impact factor of peer-reviewed journals containing these manuscripts was 5.04[IQR=5.04-5.04], and corresponding manuscripts were cited a median of 4[IQR=1-9] times. Overall, 836/1097=76.20% of manuscripts published in peer-reviewed scientific journals had a corresponding North American author. CONCLUSIONS: Annual STS meetings are a forum for the presentation of high-quality research. The rate of publication of accepted STS abstracts as manuscripts in peer-reviewed journals is >75%, comparing favorably with national meetings of other surgical societies, and >2/3 of published manuscripts are published in STS's official journal.

Comprehensive Approach to the Management of Patients With Hypoplastic Left Heart Syndrome: Analysis of 100 Consecutive Neonates.

BACKGROUND: We report our comprehensive approach to the management of patients with hypoplastic left heart syndrome (HLHS) and describe our outcomes in 100 consecutive neonates. METHODS: We stratified 100 consecutive neonates (January 1, 2015 to September 1, 2023, inclusive) into 3 pathways. Pathway 1: 77 of 100 (77%) were standard risk and underwent an initial Norwood Stage 1. Pathway 2: 10 of 100 (10%) were high-risk with noncardiac risk factors and underwent an initial Hybrid Stage 1. Pathway 3: 13 of 100 (13%) were high-risk with cardiac risk factors: 10 underwent an initial Hybrid Stage 1 + Ventricular Assist Device insertion (HYBRID+VAD), and 3 were supported with prostaglandin as a planned bridge to primary cardiac transplantation. RESULTS: The overall 1-year mortality for the entire cohort of 100 patients was 9% (9 of 100). Pathway 1: Operative Mortality in Pathway 1 for the initial Norwood Stage 1 was 2.6% (2 of 77). Of the 75 survivors of Norwood Stage 1, 72 underwent successful Glenn, 2 underwent successful biventricular repair, and 1 underwent successful cardiac transplantation. Pathway 2: Operative Mortality in Pathway 2 for the initial Hybrid Stage 1 without VAD was 10% (1 of 10). Of 9 survivors of Hybrid Stage 1, 4 underwent successful cardiac transplantation, 1 died while awaiting cardiac transplantation, 3 underwent Comprehensive Stage 2 (with 1 Operative Mortality after Comprehensive Stage 2), and 1 underwent successful biventricular repair. Pathway 3: Of 10 patients supported with initial HYBRID+VAD in Pathway 3, 7 (70%) underwent successful cardiac transplantation and are alive today, and 3 (30%) died on VAD while awaiting transplantation. Median VAD support time was 134 days (range, 56-226 days). Of 3 patients who were bridged to transplant with prostaglandin, 2 underwent successful transplantation and 1 died while awaiting transplantation. CONCLUSIONS: A comprehensive approach to the management of patients with HLHS is associated with an Operative Mortality after Norwood of 2.6% (2 of 77) and an overall 1-year mortality of 9% (9 of 100). Ten patients (10%) were stabilized with HYBRID+VAD while awaiting transplantation. VAD facilitates survival on the waiting list during prolonged waiting times.

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.

Introduction: Highlights of HeartWeek 2013 at the Sixth World Congress of Paediatric Cardiology and Cardiac Surgery in Cape Town South Africa.

This December issue of Cardiology in the Young represents the 11th annual publication generated from the two meetings that compose "HeartWeek in Florida". "HeartWeek in Florida", the joint collaborative project sponsored by the Cardiac Center at the Children's Hospital of Philadelphia, Pennsylvania, together with Johns Hopkins All Children's Heart Institute of Saint Petersburg, Florida, averages over 1000 attendees every year and is now recognised as one of the major planks of continuing medical and nursing education for those working in the fields of diagnosis and treatment of cardiac disease in the foetus, neonate, infant, child,and adult. "HeartWeek in Florida" combines the International Symposium on Congenital Heart Disease,organised by All Children's Hospital and Johns Hopkins Medicine and entering its 14th year, with the Annual Postgraduate Course in Pediatric Cardiovascular Disease, organised by The Children's Hospital of Philadelphia and entering its 17th year.This December, 2013 issue of Cardiology in the Young highlights the sessions from HeartWeek 2013 that were held at The Sixth World Congress of Paediatric Cardiology and Cardiac Surgery in Cape Town, South Africa. We would like to acknowledge the tremendous contributions made to medicine by John Brown, and therefore we dedicate this HeartWeek 2013 issue of Cardiology in the Young to him.

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.

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 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.

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].

Human microdose evaluation of the novel EP1 receptor antagonist GSK269984A.

AIM: The primary objective was to evaluate the pharmacokinetics (PK) of the novel EP(1) antagonist GSK269984A in human volunteers after a single oral and intravenous (i.v.) microdose (100 µg). METHOD: GSK269984A was administered to two groups of healthy human volunteers as a single oral (n= 5) or i.v. (n= 5) microdose (100 µg). Blood samples were collected for up to 24 h and the parent drug concentrations were measured in separated plasma using a validated high pressure liquid chromatography-tandem mass spectrometry method following solid phase extraction. RESULTS: Following the i.v. microdose, the geometric mean values for clearance (CL), steady-state volume of distribution (V(ss) ) and terminal elimination half-life (t(1/2) ) of GSK269984A were 9.8 l h(-1) , 62.8 l and 8.2 h. C(max) and AUC(0,∞) were 3.2 ng ml(-1) and 10.2 ng ml(-1) h, respectively; the corresponding oral parameters were 1.8 ng ml(-1) and 9.8 ng ml(-1) h, respectively. Absolute oral bioavailability was estimated to be 95%. These data were inconsistent with predictions of human PK based on allometric scaling of in vivo PK data from three pre-clinical species (rat, dog and monkey). CONCLUSION: For drug development programmes characterized by inconsistencies between pre-clinical in vitro metabolic and in vivo PK data, and where uncertainty exists with respect to allometric predictions of the human PK profile, these data support the early application of a human microdose study to facilitate the selection of compounds for further clinical development.

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.

Report from The International Society for Nomenclature of Paediatric and Congenital Heart Disease: cardiovascular catheterisation for congenital and paediatric cardiac disease (Part 2 - Nomenclature of complications associated with interventional cardiology).

Interventional cardiology for paediatric and congenital cardiac disease is a relatively young and rapidly evolving field. As the profession begins to establish multi-institutional databases, a universal system of nomenclature is necessary for the field of interventional cardiology for paediatric and congenital cardiac disease. The purpose of this paper is to present the results of the efforts of The International Society for Nomenclature of Paediatric and Congenital Heart Disease to establish a system of nomenclature for cardiovascular catheterisation for congenital and paediatric cardiac disease, focusing both on procedural nomenclature and the nomenclature of complications associated with interventional cardiology. This system of nomenclature for cardiovascular catheterisation for congenital and paediatric cardiac disease is a component of The International Paediatric and Congenital Cardiac Code. This manuscript is the second part of the two-part series. Part 1 covered the procedural nomenclature associated with interventional cardiology as treatment for paediatric and congenital cardiac disease. Part 2 will cover the nomenclature of complications associated with interventional cardiology as treatment for paediatric and congenital cardiac disease.

Report from The International Society for Nomenclature of Paediatric and Congenital Heart Disease: cardiovascular catheterisation for congenital and paediatric cardiac disease (Part 1 - Procedural nomenclature).

Interventional cardiology for paediatric and congenital cardiac disease is a relatively young and rapidly evolving field. As the profession begins to establish multi-institutional databases, a universal system of nomenclature is necessary for the field of interventional cardiology for paediatric and congenital cardiac disease. The purpose of this paper is to present the results of the efforts of The International Society for Nomenclature of Paediatric and Congenital Heart Disease to establish a system of nomenclature for cardiovascular catheterisation for congenital and paediatric cardiac disease, focusing both on procedural nomenclature and on the nomenclature of complications associated with interventional cardiology. This system of nomenclature for cardiovascular catheterisation for congenital and paediatric cardiac disease is a component of The International Paediatric and Congenital Cardiac Code. This manuscript is the first part of a two-part series. Part 1 will cover the procedural nomenclature associated with interventional cardiology as treatment for paediatric and congenital cardiac disease. This procedural nomenclature of The International Paediatric and Congenital Cardiac Code will be used in the IMPACT Registry™ (IMproving Pediatric and Adult Congenital Treatment) of the National Cardiovascular Data Registry® of The American College of Cardiology. Part 2 will cover the nomenclature of complications associated with interventional cardiology as treatment for paediatric and congenital cardiac disease.

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.

Congenital heart surgery databases around the world: do we need a global database?

The question posed in the title of this article is: "Congenital Heart Surgery Databases Around the World: Do We Need a Global Database?" The answer to this question is "Yes and No"! Yes--we need to create a global database to track the outcomes of patients with pediatric and congenital heart disease. No--we do not need to create a new "global database." Instead, we need to create a platform that allows for the linkage of currently existing continental subspecialty databases (and continental subspecialty databases that might be created in the future) that will allow for the seamless sharing of multi-institutional longitudinal data across temporal, geographical, and subspecialty boundaries. This review article will achieve the following objectives: (A) Consider the current state of analysis of outcomes of treatments for patients with congenitally malformed hearts. (B) Present some principles that might make it possible to achieve life-long longitudinal monitoring and follow-up. (C) Describe the rationale for the creation of a Global Federated Multispecialty Congenital Heart Disease Database. (D) Propose a methodology for the creation of a Global Federated Multispecialty Congenital Heart Disease Database that is based on linking together currently existing databases without creating a new database. To perform meaningful multi-institutional analyses, any database must incorporate the following six essential elements: (1) Use of a common language and nomenclature. (2) Use of a database with an established uniform core dataset for collection of information. (3) Incorporation of a mechanism to evaluate the complexity of cases. (4) Implementation of a mechanism to assure and verify the completeness and accuracy of the data collected. (5) Collaboration between medical and surgical subspecialties. (6) Standardization of protocols for life-long longitudinal follow-up. Analysis of outcomes must move beyond recording 30-day or hospital mortality, and encompass longer-term follow-up, including cardiac and non-cardiac morbidities, and importantly, those morbidities impacting health-related quality of life. Methodologies must be implemented in our databases to allow uniform, protocol-driven, and meaningful long-term follow-up. We need to create a platform that allows for the linkage of currently existing continental subspecialty databases (and continental subspecialty databases that might be created in the future) that will allow for the seamless sharing of multi-institutional longitudinal data across temporal, geographical, and subspecialty boundaries. This "Global Federated Multispecialty Congenital Heart Disease Database" will not be a new database, but will be a platform that effortlessly links multiple databases and maintains the integrity of these extant databases. Description of outcomes requires true multi-disciplinary involvement, and should include surgeons, cardiologists, anesthesiologists, intensivists, perfusionists, neurologists, educators, primary care physicians, nurses, and physical therapists. Outcomes should determine primary therapy, and as such must be monitored life-long. The relatively small numbers of patients with congenitally malformed hearts requires multi-institutional cooperation to accomplish these goals. The creation of a Global Federated Multispecialty Congenital Heart Disease Database that links extant databases from pediatric cardiology, pediatric cardiac surgery, pediatric cardiac anesthesia, and pediatric critical care will create a platform for improving patient care, research, and teaching related to patients with congenital and pediatric cardiac disease.