Public Attitudes to Xenotransplantation: A National Survey in the United States.

PURPOSE: Xenotransplantation presents a potential clinical alternative to the shortage of human organs for transplantation. Before clinical trials occur in the United States, public assessments are crucial to understand potential barriers to acceptance. The purpose of this study was to explore barriers, and identify characteristics associated with attitudes toward xenotransplantation. METHODS: A survey assessing demographic characteristics and attitudes toward xenotransplantation was distributed to a nationally representative sample of adults ≥ 18 years old in the United States. Regression analysis was employed to identify characteristics associated with attitudes toward xenotransplantation. FINDINGS: Between May 25 and June 14, 2023, 5008 respondents completed the survey. Importantly, half of respondents expressed low or no knowledge of either transplantation or xenotransplantation. Approximately 40% expressed discomfort with receiving a pig organ for themselves or a loved one. Despite a lack of xenotransplant outcome data, 36% were open to experimental xenotransplantation if they needed a transplant. However, 57% rated lack of current evidence of success or fear complications as top concerns. Regression models consistently associated being younger, female, not needing an organ, or being member of a racially minority group with lower acceptance. CONCLUSION: This survey is the largest to date exploring public attitudes toward xenotransplantation. Despite overall acceptance, concerns persist. Increasing public acceptance is key as the field progresses advances.

Outcomes for Children With Vascular Ring Repair Using a Simple Surgical Approach.

INTRODUCTION: Vascular Rings (VRs) are congenital malformations of the aortic arch that can compress the trachea and esophagus producing symptoms. Approximately, 5%-10% of patients experience persistent symptoms postrepair and 9% require reintervention. There are various approaches to repair-simple ligation and division of the ring or more complex procedures. Our objective was to describe outcomes for VR repair using a "simple" surgical approach. METHODS: We identified patients who underwent VR repair from 2012 to 2022 at our institution. Clinical and surgical data, demographics, intraoperative, and postoperative outcomes were extracted from their electronic medical records. Outcomes were analyzed and regression analysis was used to identify risk factors for residual symptoms after repair. RESULTS: Ninety three patients with VR repair were included. Prevalence of symptoms were reduced following surgery (80% preoperative versus 13% postoperative, P 0.03). Tracheomalacia also decreased from 16% to 7% postrepair. No deaths were reported in our cohort and 2% of our patients required reintervention. Multivariable regression analysis showed that preoperative tracheomalacia was associated with having persistent symptoms after VR repair (odds ratio 6.2, 95% CI 1.02-37.6). CONCLUSIONS: Our institutional experience using a simple surgical approach showed a significant decrease in symptoms, a very low reintervention rate and no mortality. Preoperative tracheomalacia can be a risk factor for persistent symptoms postrepair. We believe a simple surgical approach for children with complete VR repair can be effective in relieving symptoms.

Standardization of the Norwood Procedure Improves Outcomes in a Medium-Sized Volume Center.

The Norwood operation has become common practice to palliate patients with hypoplastic left heart structures. Surgical technique and postoperative care have improved; yet, there remains significant attrition prior to stage II palliation. The objective of this study is to report outcomes before and after standardizing our approach to the Norwood operation. Patients who underwent the Norwood operation at Children's of Alabama were identified, those who underwent hybrid palliation operations were excluded. Pre- (2015-2020) and post- (2020-January 2023) standardization groups were compared and outcomes analyzed. Ninety-one patients were included (pre-standardization 44 (48.3%) and 47 (51.7%) post-standardization). There were no differences in baseline and intraoperative characteristics at Norwood between the pre- and post-standardization groups. Compared with pre-standardization, post-standardization was associated with decreased time to extubation (OR 0.87, 95%CI 0.79-0.96), inotrope duration (OR 0.92, 95%CI 0.86-0.98) and hospital length of stay (OR 0.98, 95%CI 0.96-0.99). There was a trend toward decreased cardiac arrest, reintervention rates, and interstage mortality for the post-standardization group. A standardized approach to complex neonatal cardiac operations such as the Norwood procedure may improve morbidity and decrease hospital resource utilization. We recommend establishing protocols at an institutional level to optimize outcomes in such high-risk patient populations.

Pharmacogenomics of coronary artery response to intravenous gamma globulin in kawasaki disease.

Kawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that can result in acute vasculitis. The mechanism of coronary artery aneurysms (CAA) in KD despite intravenous gamma globulin (IVIG) treatment is not known. We performed a Whole Genome Sequencing (WGS) association analysis in a racially diverse cohort of KD patients treated with IVIG, both using AHA guidelines. We defined coronary aneurysm (CAA) (N = 234) as coronary z ≥ 2.5 and large coronary aneurysm (CAA/L) (N = 92) as z ≥ 5.0. We conducted logistic regression models to examine the association of genetic variants with CAA/L during acute KD and with persistence >6 weeks using an additive model between cases and 238 controls with no CAA. We adjusted for age, gender and three principal components of genetic ancestry. The top significant variants associated with CAA/L were in the intergenic regions (rs62154092 p < 6.32E-08 most significant). Variants in SMAT4, LOC100127, PTPRD, TCAF2 and KLRC2 were the most significant non-intergenic SNPs. Functional mapping and annotation (FUMA) analysis identified 12 genomic risk loci with eQTL or chromatin interactions mapped to 48 genes. Of these NDUFA5 has been implicated in KD CAA and MICU and ZMAT4 has potential functional implications. Genetic risk score using these 12 genomic risk loci yielded an area under the receiver operating characteristic curve (AUC) of 0.86. This pharmacogenomics study provides insights into the pathogenesis of CAA/L in IVIG-treated KD and shows that genomics can help define the cause of CAA/L to guide management and improve risk stratification of KD patients.

Close contacts of xenograft recipients: Ethical considerations due to risk of xenozoonosis.

With decades of pre-clinical studies culminating in the recent clinical application of xenotransplantation, it would appear timely to provide recommendations for operationalizing oversight of xenotransplantation clinical trials. Ethical issues with clinical xenotransplantation have been described for decades, largely centering on animal welfare, the risks posed to the recipient, and public health risks posed by potential spread of xenozoonosis. Much less attention has been given to considerations relating to potentially elevated risks faced by those who may care for or otherwise have close contact with xenograft recipients. This paper examines the ethical and logistical issues raised by the potential exposure to xenozoonotic disease faced by close contacts of xenotransplant recipients-defined herein as including but not limited to caregivers, household contacts, and sexual partners-which warrants special attention given their increased risk of exposure to infection compared to the general public. We discuss implications of assent or consent by these close contacts to potentially undergo, along with the recipient, procedures for infection screening and possible quarantine. We then propose several options and recommendations for operationalizing oversight of xenotransplantation clinical trials that could account for and address close contacts' education on and agency regarding the risk of xenozoonosis.

Pharmacogenomics of Coronary Artery Response to Intravenous Gamma Globulin in Kawasaki Disease.

Background: Kawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that can result in acute vasculitis. The pathological walls of afflicted coronary arteries show propensity for forming thrombosis and aneurysms. The mechanism of coronary artery aneurysms (CAA) despite intravenous gamma globulin (IVIG) treatment is not known. Methods: We performed a Whole Genome Sequencing (WGS) association analysis in a racially diverse cohort of KD patients treated with IVIG, both using AHA guidelines. We defined coronary aneurysm (CAA) (N = 234) as coronary z>2.5 and large coronary aneurysm (CAA/L) (N = 92) as z>5.0. We conducted logistic regression models to examine the association of genetic variants with CAA/L during acute KD and with persistence >6 weeks using an additive model between cases and 238 controls with no CAA. We adjusted for age, gender and three principal components of genetic ancestry. We performed functional mapping and annotation (FUMA) analysis and further assessed the predictive risk score of genomic risk loci using the area under the receiver operating characteristic curve (AUC). Results: The top significant variants associated with CAA/L were in the intergenic regions (rs62154092 p<6.32E-08 most significant). Variants in SMAT4, LOC100127 , PTPRD, TCAF2 and KLRC2 were the most significant non-intergenic SNPs. FUMA identified 12 genomic risk loci with eQTL or chromatin interactions mapped to 48 genes. Of these NDUFA5 has been implicated in KD CAA and MICU and ZMAT4 has potential functional implications. Genetic risk score using these 12 genomic risk loci yielded an AUC of 0.86. Conclusions: This pharmacogenomics study provides insights into the pathogenesis of CAA/L in IVIG-treated KD patients. We have identified multiple novel SNPs associated with CAA/L and related genes with potential functional implications. The study shows that genomics can help define the cause of CAA/L to guide management and improve risk stratification of KD patients.

Pediatric Cardiac Xenotransplantation: Recommendations for the Ethical Design of Clinical Trials.

For children with complex congenital heart problems, cardiac allotransplantation is sometimes the best therapeutic option. However, availability of hearts for pediatric patients is limited, resulting in a long and growing waitlist, and a high mortality rate while waiting. Cardiac xenotransplantation has been proposed as one therapeutic alternative for neonates and infants, either in lieu of allotransplantation or as a bridge until an allograft becomes available. Scientific and clinical developments in xenotransplantation appear likely to permit cardiac xenotransplantation clinical trials in adults in the coming years. The ethical issues around xenotransplantation of the heart and other organs and tissues have recently been examined, but to date, only limited literature is available on the ethical issues that are attendant with pediatric heart xenotransplantation. Here, we summarize the ethical issues, focusing on (1) whether cardiac xenotransplantation should proceed in adults or children first, (2) pediatric recipient selection for initial xenotransplantation trials, (3) special problems regarding informed consent in this context, and (4) related psychosocial and public perception considerations. We conclude with specific recommendations regarding ethically informed design of pediatric heart xenotransplantation trials.

Hybrid Thrombectomy and Central Extracorporeal Membrane Oxygenation for Massive Pulmonary Embolism in a Child.

We describe a hybrid thrombectomy and central extracorporeal membrane oxygenation for a child in cardiogenic shock due to a massive pulmonary embolism.

Ethically Advancing Pediatric Cardiac Xenotransplant.

This Viewpoint examines how pediatrics should prepare for the prospect of cardiac xenotransplant, including its ethical implications.

Revisiting the Use of Ulysses Contracts in Xenotransplantation.

BACKGROUND: Xenotransplantation clinical trials may begin soon. A persistent risk of xenotransplantation, known for decades, is the possibility that a xenozoonotic infection could be transferred from a xenograft to its recipient and then to other human contacts. Because of this risk, guidelines and commentators have advocated for xenograft recipients to agree to either long-term or lifelong surveillance mechanisms. METHODS: For the past few decades, one solution that has been proposed to ensure that xenograft recipients will comply with surveillance protocols is the use of a heavily modified Ulysses contract, which we review. RESULTS: These contracts are most often used in psychiatry, and their application to xenotransplantation has been espoused several times with minimal criticism. CONCLUSIONS: In this article, we argue against the applicability of Ulysses contracts in xenotransplantation based upon (1) the telos of the advance directive that may not be applicable to this clinical context, (2) the suspect nature of enforcing Ulysses contracts in xenotransplantation, and (3) the ethical and regulatory hurdles that such enforcement would require. Although our focus is on the US regulatory landscape in preparation for clinical trials, there are applications globally.

Central Extracorporeal Membrane Oxygenation Support Following Calcium Channel Blocker Overdose in Children.

Refractory vasodilatory shock (RVS) following massive calcium channel blocker (CCB) overdose remains a challenging clinical entity. Peripheral venoarterial extracorporeal membrane oxygenation (ECMO) has proven useful in several cases of CCB intoxication, however, its use in the pediatric population poses unique challenges given the generally small size of pediatric peripheral vasculature in comparison to the high flow rates necessary for adequate mechanical circulatory support. As a result of these challenges, our group has adopted a "primary" central ECMO cannulation approach to the treatment of children and adolescents admitted to our center with profound RVS after CCB ingestion. We present four cases within the last year using this approach. All patients were successfully discharged from the hospital with no late morbidity at most recent follow-up. Central ECMO support in cases of massive vasodilatory shock following CCB overdose is safe and effective and should be considered early in the clinical course of these critically ill patients.

Seasonality and geographical distribution of Kawasaki disease among Black children in the Southeast United States.

Introduction: Kawasaki Disease (KD) is a leading cause of pediatric acquired heart disease in the United States, affecting up to 7,000 children annually. Seasonal variation, an epidemiological characteristic of KD, has previously been reported predominantly among Asian children; however, little is known about the epidemiology and seasonality of KD of Black children within the U.S. Methods: Electronic medical records were abstracted from 529 hospitalized KD patients admitted to a single tertiary center in Alabama between 2005 and 2019. Medical charts were reviewed to confirm KD diagnosis following American Heart Association criteria. Cases were stratified by the month of diagnosis date to assess seasonality, and statewide distribution of incidence is reported at county level using geographical spatial analysis. Comparisons were performed between Black patients and White patients with KD. Results: The average number of KD cases per year was 35. Approximately, 60% were males and 44% were White children (N = 234), 45% were Black children (N = 240) and 11% were other races (N = 55). Black children were younger than White children at KD admission (median age 32 vs. 41 months respectively, p = 0.02). Overall, the highest rates of cases occurred between January and April. When stratifying by race, cases started to rise in December among White children with the highest rates between February and April with a peak in March. Among Black children cases were high during the winter season (January-April) with a peak in April. Similarly high rates also occurred in June, July and November. There were no differences in geographical distribution of cases by race. Conclusion: KD incidence among White children in Alabama follows a seasonal cycle similar to other regions in the U.S. However, sustained incidence and additional peaks outside of the usual KD seasonality were seen among Black children with KD. Further studies are needed to investigate differential triggers between races.

Hybrid Norwood for Hypoplastic Left Heart Syndrome With Rare Aortic Arch Anatomy.

We describe the hybrid Norwood as first-stage palliation for a patient with hypoplastic left heart syndrome, right aortic arch, right descending aorta, bilateral ductus arteriosus, and left innominate artery arising from the left ductus.

Surgical Experience With Nine Cases of Obstructed Right Aortic Arch.

BACKGROUND: Right-sided aortic arch obstruction is an extremely rare congenital anomaly. A variety of surgical approaches have been described. This study reviews our institutional experience over the last 30 years. METHODS: Our surgical database at the University of Alabama at Birmingham and Children's Hospital of Alabama from 1992 to 2022 was reviewed to include all patients who underwent surgical repair for right-sided aortic arch obstruction. RESULTS: A total of nine patients underwent surgical repair for right-sided aortic arch obstruction. Surgical approach was via thoracotomy (n = 2, 22%), sternotomy (n = 5, 56%), or combined (n = 2, 22%). Primary extended end-to-end anastomosis was utilized for patients with discrete coarctation (n = 1, 11%), reverse subclavian flap for coarctation with associated distal arch hypoplasia (n = 2, 22%), GORE-TEX® tube graft for circumflex aorta (n = 1, 11%), and aortic arch advancement (n = 5, 56%) with or without patch augmentation for those with an interrupted or severely hypoplastic aortic arch. Reintervention was required in one patient (11%) for recoarctation. All patients were discharged in good condition. There was no hospital mortality and at 10.5 years (mean) follow-up there was one late death. CONCLUSION: Right aortic arch obstruction is a rare entity. Surgical approach should be tailored to the anatomy and associated intracardiac defects. Preoperative imaging with a CT angiogram is useful for operative planning. Sternotomy with single-stage primary repair is safe, effective, and our preferred surgical approach for patients with right aortic arch obstruction and associated intracardiac pathology.

A Multidisciplinary Surgical Approach to Mediastinal Masses in Children.

The aim of this study is to demonstrate the safety and advantages of a multidisciplinary approach to surgical resection of mediastinal masses in children. Eight patients underwent resection of a mediastinal mass by a team involving both a pediatric general surgeon and pediatric cardiothoracic surgeon. One patient required rapid initiation of cardiopulmonary bypass to complete the tumor resection and repair an aortic injury that occurred when removing adherent tumor from the structure. Perioperative outcomes were excellent for all patients. This series shows that a multidisciplinary surgical approach can be potentially life saving.

Association Between Venous Homografts and Allosensitization After Norwood Procedure.

BACKGROUND: Right ventricle (RV) to pulmonary artery (PA) shunts have become the shunt of choice at many centers for use during the Norwood procedure for single ventricle palliation. Some centers have begun to use cryopreserved femoral or saphenous venous homografts as an alternative to polytetrafluoroethylene (PTFE) for shunt construction. The immunogenicity of these homografts is unknown, and potential allosensitization could have significant implications on transplant candidacy. METHODS: All patients undergoing Glenn procedure at our center between 2013 and 2020 were screened. Patients who initially underwent Norwood procedure with either PTFE or venous homograft RV-PA shunt and had available pre-Glenn serum were included in the study. The primary outcome of interest was panel reactive antibody (PRA) level at the time of Glenn surgery. RESULTS: Thirty-six patients met inclusion criteria (N = 28 PTFE, N = 8 homograft). Patients in the homograft group had significantly higher median PRA levels at the time of Glenn surgery (0% [IQR 0-18] PTFE vs 94% [IQR 74-100] homograft, P = .003). There were no other differences between the two groups. CONCLUSIONS: Despite potential improvements in PA architecture, the use of venous homografts for RV-PA shunt construction at the time of Norwood procedure is associated with significantly elevated PRA level at the time of Glenn surgery. Centers should carefully consider the use of currently available venous homografts given the high percentage of these patients who may require future transplantation.

Health-Related Quality of Life After Single Ventricle Palliation or Tetralogy of Fallot Repair.

Single ventricle (SV) cardiac lesions and tetralogy of Fallot (TOF) are both common forms of cyanotic congenital heart disease. With advances in perioperative care and longitudinal follow-up, survival of these patients has dramatically improved and the majority survive to adulthood. This study compares health-related quality of life (HRQoL) of adult SV and TOF patients to each other and the general population. HRQoL of all surviving, non-transplanted SV and TOF patients 21 years of age and older at our institution was assessed with the SF-36 questionnaire via phone. Additional data including demographic parameters and information related to comorbidities and healthcare utilization were also analyzed. Among 81 eligible SV patients and 207 TOF patients, 33 (41%) and 75 (36%) completed the SF-36 phone survey, respectively. The mean age of SV patients was 32 vs. 38 years in the TOF group (p=0.01). SV patients reported more hepatic, pulmonary, and renal comorbidities. TOF patients were more likely to complete advanced degrees and more likely to have children (p=0.03). SV physical functioning scores were worse compared to TOF. In other domains of the SF-36 questionnaire, SV and TOF scores were similar. Compared to the general population, both groups reported worse bodily pain and mental health, but other aspects of psychosocial and general health were comparable. Overall HRQoL is good for both SV and TOF patients through early and mid-adulthood. Some QoL metrics were modestly worse in the SV patients. While these patients may have some physical limitations, psychosocial wellbeing appears preserved.