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Hybrid stage 1 palliation (HS1P) is used as an alternative to the surgical Norwood for single ventricle patients and specific other conditions. Necrotizing enterocolitis (NEC) occurs in 5%-18% of infants after surgical Norwood, contributing to significant morbidity. We sought to compare the NEC incidences in HS1P versus Norwood patients. A single-center retrospective cohort study of all infants undergoing HS1P or Norwood over a 12-year period. Demographics, underlying cardiac diagnosis, surgical details, and NEC episodes were queried for each patient. The cumulative incidences of NEC between HS1P and Norwood patients were compared. A total of 305 infants were included; 200 Norwood and 105 HS1P. HS1P infants were more often premature (gestational age < 37 weeks; 23.8% vs 1.5%) and had lower birth weight (mean 2.8 ± 0.66 kg versus 3.3 ± 0.47 kg) than their Norwood counterparts. Most infants who underwent the Norwood procedure had hypoplastic left heart syndrome (79.5%), with variable underlying cardiac diagnosis for those who underwent HS1P. Incidence of NEC was significantly higher in the HS1P group (53.3% versus 37.0%, p = 0.01), with increased risk independent of birth weight or underlying cardiac diagnosis (adjusted odds ratio 1.8, p = 0.03). Infants after HS1P had a median of 2 episodes of NEC (interquartile range [IQR] 1-3) versus 1 episode in the Norwood group (IQR 1-2). Infants after HS1P are at higher risk of NEC in comparison to infants after the Norwood procedure. More studies are needed to help predict which infants after HS1P are at highest risk for NEC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Emerging evidence suggests that routine physical activity may improve exercise capacity, long-term outcomes, and quality of life in individuals with Fontan circulation. Despite this, it is unclear how active these individuals are and what guidance they receive from medical providers regarding physical activity. The aim of this study was to survey Fontan patients on personal physical activity behaviours and their cardiologist-directed physical activity recommendations to set a baseline for future targeted efforts to improve this., Methods: An electronic survey assessing physical activity habits and cardiologist-directed guidance was developed in concert with content experts and patients/parents and shared via a social media campaign with Fontan patients and their families., Results: A total of 168 individuals completed the survey. The median age of respondents was 10 years, 51% identifying as male. Overall, 21% of respondents spend > 5 hours per week engaged in low-exertion activity and only 7% spend > 5 hours per week engaged in high-exertion activity. In all domains questioned, pre-adolescents reported higher participation rates than adolescents. Nearly half (43%) of respondents reported that they do not discuss activity recommendations with their cardiologist., Conclusions: Despite increasing evidence over the last two decades demonstrating the benefit of exercise for individuals living with Fontan circulation, only a minority of patients report engaging in significant amounts of physical activity or discussing activity goals with their cardiologist. Specific, individualized, and actionable education needs to be provided to patients, families, and providers to promote and support regular physical activity in this patient population.

Patients with a single ventricle heart who had Fontan palliation (S/P Fontan) are at increased risk for acquired morbidity. Insulin resistance (IR) is a predictor of cardiac morbidity and mortality. A single-center, cross-sectional study using S/P Fontan and controls was designed to assess IR S/P Fontan. Group comparisons were made in IR via the Quantitative Insulin Index (QUICKI) and the natural log-transformed homeostasis model assessment, ln (HOMA-IR), without/with adjusting for age. A total of 89 patients (59 Fontan and 30 controls) were included. Fontan patients showed a significant decrease in QUICKI (0.34 ± 0.03 vs 0.37 ± 0.02) and an elevation of ln (HOMA-IR) (0.82 ± 0.62 vs 0.24 ± 0.44) compared to controls (both p < 0.0001); this remained significant even adjusting for age. With older age, there was a significant, progressive decrease in QUICKI (p = 0.01) and an increase in ln (HOMA-IR) (p = 0.02) S/P Fontan. Analysis excluding Fontan patients with obesity still showed a significant reduction of QUICKI and an elevation of ln (HOMA-IR) in Fontan patients compared to controls when adjusting for age (both p < 0.05). Using QUICKI, IR was present in 41 (69.5%) Fontan patients vs. 3 (10%) controls (p < 0.0001) and using HOMA-IR, IR was present in 32 (54.2%) vs 5 (16.7%) controls (p = 0.001). Fontan patients had significantly more IR compared to controls and the prevalence of IR increases with age. Since IR is known to correlate with long-term morbidity and mortality and can be ameliorated by therapies, we believe it is critical that IR be identified as early as possible in Fontan patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Frailty is a clinical syndrome common in adults with chronic disease with resultant vulnerability to adverse health outcomes. Little is known about frailty in pediatric patients, including those with single-ventricle heart disease. This study aimed to examine the prevalence of frailty and its associated risk factors in patients with Fontan circulation. A single-center, prospective cohort study assessed frailty in patients (10-21 years old) after Fontan palliation. Slowness, weakness, exhaustion, shrinkage, and diminished physical activity were evaluated and scored using a modified Fried frailty assessment comprised of validated pediatric tests. Providers estimated subjects' degree of frailty. Patient-reported quality of life (QOL) was assessed. Of 54 participants (median age 15.3 years, 61% male), 18 (33%) were identified as frail, while 26 (48%) were pre-frail. Patients frequently exhibited frailty in the domains of slowness (93%), weakness (41%), and diminished physical activity (39%). There was poor correlation between frailty scores and provider estimates of frailty (Kappa = 0.11). Frail subjects had lower PedsQL physical functioning scores (mean 62.8 ± SD 18.5 in Frail vs. 75.7 ± 16.0 in No/pre-Frail; p = 0.01). Factors associated with frailty included protein-losing enteropathy (p = 0.03) and at least one hospitalization in the last year (p = 0.047). One-third of pediatric patients after Fontan palliation were frail which was associated with lower physical functioning and higher healthcare utilization. Providers poorly recognized frailty. These findings highlight the need for improved screening and support for an at-risk population where frailty is not easily identified., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Hybrid stage I palliation has been used in many clinical scenarios including initial palliation in single ventricle heart disease, a bridge to biventricular repair, a bridge to transplant, and as a destination therapy. There is considerable hybrid stage I palliation practice variation, which we aimed to better understand in this study., Methods: Survey-based assessment of practice variation related to hybrid stage I palliation was sent to congenital heart centers across the United States and Canada., Results: Of the 106 centers surveyed, responses were received from 54 centers (50.9%). Of respondents, 45 centers perform hybrid stage I palliation. Centers most commonly (97.7%) perform hybrid stage I palliation on "high-risk" patients with single ventricle heart disease. Regarding the technical aspects of hybrid stage I palliation, most centers (95.3%) accomplish restrictive pulmonary blood flow using pulmonary artery bands and primarily use changes in oxygen saturation (34.1%) to identify appropriate restriction. Ductal stents are most often used (67.4%) to maintain ductal patency. Only 10 centers (23.3%) routinely enlarge the atrial septal defect. Indications for atrial septal defect intervention varied widely. Most centers (71.9%) discharge patients home to follow with a formal "interstage" program., Conclusions: There is significant variation in practice patterns for hybrid stage I palliation indications, technical aspects, and postoperative care. Therefore, generalizability of single-center studies on outcomes after hybrid stage I palliation is limited. Future multicenter studies are needed to best delineate which patients benefit most from hybrid stage I palliation and to further define optimal approaches to caring for these patients., Competing Interests: J.D.Z. is a consultant for Medtronic Inc and Gore Medical, and serves on the Data Safety Monitoring Board for Encore Medical. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2024 The Author(s).)

Background: Hybrid stage I palliation (HS1P) has been utilized for patients with single ventricle (SV) congenital heart disease (CHD). To date, reports on the use of HS1P for other indications including biventricular (BiV) CHD have been limited. Methods: We performed a single-center retrospective cohort study of patients who underwent HS1P with an anticipated physiologic outcome of BiV repair, or with an undetermined SV versus BiV outcome. Patient characteristics and outcomes from birth through definitive repair or palliation were collected and reported with descriptive statistics. Results: Nineteen patients underwent HS1P with anticipated BiV repair. Extracardiac and intracardiac risk factors (ICRF) were common. Ultimately, 13 (68%) patients underwent BiV repair, 1 (5%) underwent SV palliation, and 5 (26%) died prior to further palliation or repair. Resolution of ICRF tracked with BiV outcome (6/6, 100%), persistence of ICRF tracked with SV outcome or death (3/3, 100%). Twenty patients underwent HS1P with an undetermined outcome. Ultimately, 13 (65%) underwent BiV repair, 6 (30%) underwent SV palliation, and 1 (5%) underwent transplant. There were no deaths. Intracardiac risk factors were present in 15 of 20 patients (75%); BiV repair only occurred when all ICRF resolved (67%). Post-HS1P complications and reinterventions occurred frequently in both groups, through all phases of care. Conclusions: Hybrid stage 1 palliation can be used to defer BiV repair and to delay decision between SV palliation and BiV repair. Resolution of ICRF was associated with ultimate outcome. In this high-risk group, complications are common, and mortality especially in the marginal BiV patient is high., 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: Patient and caregiver education following pediatric heart transplant (HTx) is a cornerstone of post-HTx care. Despite the importance of post-HTx education, there are no standardized guidelines for topics and content. Education practices vary across clinicians and centers. Patient and caregiver priorities regarding post-HTx education are unknown. This national survey study aimed to characterize adolescent HTx recipient, caregiver, and clinician values specific to post-HTx educational topics., Methods: A cross-sectional, national electronic survey was performed. Eligible participants included pediatric HTx recipients between the ages of 13-18, adult caregivers of pediatric HTx recipients, and pediatric HTx clinicians. An investigator-designed survey was developed to assess the importance of 20 educational topics. Average scores on educational topics were compared between HTx recipients/caregivers and HTx clinicians using two-sample t-tests., Results: 120 survey responses were included, with a majority completed by HTx caregivers (N = 73; 61%) and clinicians (N = 43; 36%). Of the 20 educational topics assessed, there was a significant difference (p < 0.05) between educational values of HTx recipients/caregivers compared to HTx clinicians for 40% (N = 8) of the topics. For each educational topic that revealed a significant difference, HTx recipients/caregivers consistently placed greater value on the educational topic compared to HTx clinicians., Conclusions: Priorities regarding post-HTx education do not always align between HTx recipients/caregivers and HTx clinicians. Results suggest that HTx recipients/caregivers place higher value on educational topics regarding daily life after HTx compared to HTx clinicians. We hope these findings better inform the approach to post-HTx education and care for future pediatric HTx patients., (© 2024 The Author(s). Pediatric Transplantation published by Wiley Periodicals LLC.)

Augmented reality (AR) visualization of 3D rotational angiography (3DRA) provides 3D representations of cardiac structures with full visualization of the procedural environment. The purpose of this study was to evaluate the feasibility of converting 3DRAs of congenital heart disease patients to AR models, highlight the workflow for 3DRA optimization for AR visualization, and assess physicians' perceptions of their use. This single-center study prospectively evaluated 30 retrospectively-acquired 3DRAs that were converted to AR, compared to Computer Models (CM). Median patient age 6.5 years (0.24-38.8) and weight 20.6 kg (3.4-107.0). AR and CM quality were graded highly. RV pacing was associated with higher quality of both model types (p = 0.02). Visualization and identification of structures were graded as "very easy" in 81.1% (n = 73) and 67.8% (n = 61) of AR and CM, respectively. Fifty-nine (66%) grades 'Agreed' or 'Strongly Agreed' that AR models provided superior appreciation of 3D relationships; AR was found to be least beneficial in visualization of aortic arch obstruction. AR models were thought to be helpful in identifying pathology and assisting in interventional planning in 85 assessments (94.4%). There was significant potential seen in the opportunity for patient/family counseling and trainee/staff education with AR models. It is feasible to convert 3D models of 3DRAs into AR models, which are of similar image quality as compared to CM. AR models provided additional benefits to visualization of 3D relationships in most anatomies. Future directions include integration of interventional simulation, peri-procedural counseling of patients and families, and education of trainees and staff with AR models., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Hybrid stage I palliation (HS1P) is an alternative approach for initial palliation in hypoplastic left heart syndrome (HLHS) patients. Unlike surgical stage I palliation where atrial septectomy is routinely performed, atrial septal intervention (ASI) during HS1P is variable. In this study, we described our experience with ASI in single ventricle (SV) patients who underwent HS1P and identified factors associated with need for ASI after HS1P., Methods: Data were retrospectively collected for all HLHS patients who underwent HS1P at our center over the past 12 years. We evaluated ASIs performed during the HS1P (intra-HS1P ASI) and ASIs performed during the period from HS1P to the subsequent surgical stage, either interval Norwood stage I or comprehensive stage II (post-HS1P ASI). Patient factors and procedural data were compared to identify factors associated with undergoing post-HS1P ASI and the impact of ASI on patient outcomes was evaluated., Results: Of 50 SV patients included, 23 (46%) underwent intra-HS1P ASI and 26 (52%) underwent post-HS1P ASI. Need for post-HS1P ASI was lower among patients who had an intra-HS1P ASI as compared to those who did not (30% vs. 70%; p = 0.005). There were no significant differences in short or Midterm outcomes between patients who underwent intra-HS1P ASI or post-HS1P ASI and their counterparts., Conclusions: ASI is common both during and after HS1P but is generally well tolerated and type of ASI does not significantly impact overall patient outcomes. Our findings suggest that the current approach of individualizing management of ASI in the HS1P population is effective and safe., (© 2024 The Author(s). Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Background: Neurocognitive impairment and quality of life are two important long-term challenges for patients with complex CHD. The impact of re-interventions during adolescence and young adulthood on neurocognition and quality of life is not well understood., Methods: In this prospective longitudinal multi-institutional study, patients 13-30 years old with severe CHD referred for surgical or transcatheter pulmonary valve replacement were enrolled. Clinical characteristics were collected, and executive function and quality of life were assessed prior to the planned pulmonary re-intervention. These results were compared to normative data and were compared between treatment strategies., Results: Among 68 patients enrolled from 2016 to 2020, a nearly equal proportion were referred for surgical and transcatheter pulmonary valve replacement (53% versus 47%). Tetralogy of Fallot was the most common diagnosis (59%) and pulmonary re-intervention indications included stenosis (25%), insufficiency (40%), and mixed disease (35%). There were no substantial differences between patients referred for surgical and transcatheter therapy. Executive functioning deficits were evident in 19-31% of patients and quality of life was universally lower compared to normative sample data. However, measures of executive function and quality of life did not differ between the surgical and transcatheter patients., Conclusion: In this patient group, impairments in neurocognitive function and quality of life are common and can be significant. Given similar baseline characteristics, comparing changes in neurocognitive outcomes and quality of life after surgical versus transcatheter pulmonary valve replacement will offer unique insights into how treatment approaches impact these important long-term patient outcomes.

Introduction: Dry eye disease (DED) is multifactorial and characterized by a loss of tear film homeostasis that causes a cycle of tear film instability, tear hyperosmolarity, and inflammation. While artificial tears are the traditional mainstay of treatment, addressing the underlying pathophysiology could relieve symptoms and prevent progression. Increasing evidence indicates a role for oral nutritional supplementation in multiple ophthalmic diseases, including DED. Lutein, zeaxanthin, curcumin, and vitamin D3 have demonstrated protective and anti-inflammatory properties in ocular models. This prospective, randomized, double-blind, parallel, placebo-controlled study evaluated the efficacy and safety of a proprietary blend of lutein, zeaxanthin isomers, curcumin, and vitamin D3 (LCD) as a daily supplement in adult participants with DED., Methods: Participants were randomized to receive one LCD supplement capsule (lutein 20 mg, zeaxanthin isomers 4 mg, curcumin 200 mg curcuminoids, and vitamin D3 600 IU) or placebo per day for 8 weeks (LCD, n=77; placebo, n=78). Primary outcomes were changes in tear volume (Schirmer's test) and ocular symptoms (Ocular Surface Disease Index [OSDI])., Results: The study met its primary endpoints: the LCD group demonstrated significantly better Schirmer's test scores and improvement in overall OSDI score, versus placebo, at Day 56 (p<0.001 for both). Scores for total OSDI, and symptoms and vision domains, significantly improved by Day 14 for LCD versus placebo, (p<0.05 for all) and were maintained to Day 56 (p<0.001). In addition, the LCD group demonstrated significantly improved tear film break-up time (TBUT) and tear film osmolarity, versus placebo, by Day 56 (p<0.001), along with significant improvements in corneal and conjunctival staining (p<0.001 for both), and inflammation (matrix metalloproteinase-9; p<0.001 for each eye). Total Standard Patient Evaluation of Eye Dryness (SPEED) score, and scores for the frequency and severity domains, were significantly improved by Day 14 for LCD versus placebo (p<0.05 for all) and maintained to Day 56 (p<0.001). There was no difference between groups for artificial tear usage. The supplement was well-tolerated., Discussion: Once-daily LCD supplementation significantly improved tear production, stability and quality, reduced ocular surface damage and inflammation, and improved participants' symptoms. LCD supplementation could offer a useful adjunct to artificial tears for patients with DED (NCT05481450)., Competing Interests: RR and KB are employees of Bausch + Lomb Incorporated. AM, DR and MP and employees of OmniActive Health Technologies. NG, JG, JP and LP are advisory board committee members for Bausch + Lomb. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gioia, Gerson, Ryan, Barbour, Poteet, Jennings, Sharp, Lowery, Wilson, Morde, Rai, Padigaru and Periman.)

Motivation: Due to the link between microglial morphology and function, morphological changes in microglia are frequently used to identify pathological immune responses in the central nervous system. In the absence of pathology, microglia are responsible for maintaining homeostasis, and their morphology can be indicative of how the healthy brain behaves in the presence of external stimuli and genetic differences. Despite recent interest in high throughput methods for morphological analysis, Sholl analysis is still widely used for quantifying microglia morphology via imaging data. Often, the raw data are naturally hierarchical, minimally including many cells per image and many images per animal. However, existing methods for performing downstream inference on Sholl data rely on truncating this hierarchy so rudimentary statistical testing procedures can be used., Results: To fill this longstanding gap, we introduce a parametric hierarchical Bayesian model-based approach for analyzing Sholl data, so that inference can be performed without aggressive reduction of otherwise very rich data. We apply our model to real data and perform simulation studies comparing the proposed method with a popular alternative., Availability and Implementation: Software to reproduce the results presented in this article is available at: https://github.com/vonkaenelerik/hierarchical&#95;sholl. An R package implementing the proposed models is available at: https://github.com/vonkaenelerik/ShollBayes., (© The Author(s) 2024. Published by Oxford University Press.)

Recent studies have suggested worse outcomes in patients exposed to hyperoxia while supported on veno-arterial extracorporeal membrane oxygenation (VA-ECMO). However, there are no data regarding the effect of reducing hyperoxia exposure in this population by adjusting the fraction of inspired oxygen (FiO 2 ) of the sweep gas of the ECMO circuit. A retrospective review of 143 patients less than 1 year of age requiring VA-ECMO following cardiac surgery from 2007 to 2018 was completed. 64 patients had a FiO 2 of the sweep gas < 100% with an average PaO 2 of 210 mm Hg in the first 48 h of support [vs 405 mm Hg in the group with a FiO 2  = 100% (p < 0.0001)]. There was no difference in mortality at 30 days after surgery or other markers of end-organ injury with respect to whether the FiO 2 was adjusted. At least one PaO 2 value < 200 mm Hg in the first 24 h on ECMO in patients with a FiO 2  < 100% trended toward a significant association (OR = 0.45, 95% CI = 0.21-1.01) with decreased risk of 30-day mortality when compared to those patients with a FiO 2  = 100% and all PaO 2 values > 200 mm Hg. Only 47% of patients with a FiO 2  < 100% had an average PaO 2 less than 200 mm Hg which indicates that the intervention of reducing the FiO 2 of the sweep gas was not entirely effective at reducing hyperoxia exposure. Future research is needed for developing clinical protocols to avoid hyperoxia and to identify mechanisms for hyperoxia-induced injury on VA-ECMO., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Heart failure is the leading cause of morbidity and mortality in patients with Fontan circulation. Sodium-glucose-cotransporter 2 inhibitors (SGLT2i) have become a mainstay of heart failure therapy in adult patients, however, there remains a paucity of literature to describe its use in pediatric heart failure patients, especially those with single ventricle physiology. We describe our early experience using SGLT2i in patients with single ventricle congenital heart disease surgically palliated to the Fontan circulation. We conducted a single-center retrospective chart review of all patients with Fontan circulation who were initiated on an SGLT2i from January 1, 2022 to March 1, 2023. Patient demographics, diagnoses, clinical status, and other therapies were collected from the electronic medical record. During the study period, 14 patients (median age 14.5 years, range 2.0-26.4 years) with Fontan circulation were started on a SGLT2i. Mean weight was 54 kg (range 11.6-80.4 kg). Median follow-up since SGLT2i initiation was 4.1 months (range 13 days-7.7 months). Four patients had a systemic left ventricle and 10 had a systemic right ventricle. Half the patients had Fontan Circulatory Failure with reduced Ejection Fraction (FCFrEF) of the systemic ventricle and the other half had Fontan Circulatory Failure with preserved Ejection Fraction (FCFpEF) of the systemic ventricle. In addition, 3 patients experienced Protein Losing Enteropathy (PLE) and 2 patients had plastic bronchitis, one of whom also was diagnosed with chylothorax. There were no genitourinary infections, hypoglycemia, ketoacidosis, hypotension or other significant adverse effects noted in our patient population. One patient experienced significant diuresis and transient acute kidney injury. Patients with FCFrEF showed a decrease in natriuretic peptide levels. Given the lack of proven therapies, demonstrated benefits of SGLT2i in other populations, and some suggestion of efficacy in Fontan circulation, further study of SGTLT2i in patients with Fontan circulation is warranted., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests.

Background: Burnout is well characterised in physicians and residents but not in paediatric cardiology fellows, and few studies follow burnout longitudinally. Training-specific fears have been described in paediatric cardiology fellows but also have not been studied at multiple time points. This study aimed to measure burnout, training-specific fears, and professional fulfilment in paediatric cardiology fellows with the attention to time of year and year-of-training., Methods: This survey-based study included the Professional Fulfillment Index and the Impact of Events Scale as well as an investigator-designed Fellow Fears Questionnaire. Surveys were distributed at three-time points during the academic year to paediatric cardiology fellows at a large Midwestern training programme. Fellow self-reported gender and year-of-training were collected. Descriptive analyses were performed., Results: 10/17 (59%) of fellows completed all surveys; 60% were female, 40% in the first-year class, 40% in the second-year class, and 20% in the third-year class. At least half of the fellows reported burnout at each survey time point, with lower mean professional fulfilment scores. The second-year class, who rotate primarily in the cardiac ICU, had higher proportions of burnout than the other two classes. At least half of fellows reported that they "often" or "always" worried about not having enough clinical knowledge or skills and about work-life balance., Conclusions: Paediatric cardiology fellows exhibit high proportions of burnout and training-specific fears. Interventions to mitigate burnout should be targeted specifically to training needs, including during high-acuity rotations.

Managed honey bee (Apis mellifera) populations play a crucial role in supporting pollination of food crops but are facing unsustainable colony losses, largely due to rampant disease spread within agricultural environments. While mounting evidence suggests that select lactobacilli strains (some being natural symbionts of honey bees) can protect against multiple infections, there has been limited validation at the field-level and few methods exist for applying viable microorganisms to the hive. Here, we compare how two different delivery systems-standard pollen patty infusion and a novel spray-based formulation-affect supplementation of a three-strain lactobacilli consortium (LX3). Hives in a pathogen-dense region of California are supplemented for 4 weeks and then monitored over a 20-week period for health outcomes. Results show both delivery methods facilitate viable uptake of LX3 in adult bees, although the strains do not colonize long-term. Despite this, LX3 treatments induce transcriptional immune responses leading to sustained decreases in many opportunistic bacterial and fungal pathogens, as well as selective enrichment of core symbionts including Bombilactobacillus, Bifidobacterium, Lactobacillus, and Bartonella spp. These changes are ultimately associated with greater brood production and colony growth relative to vehicle controls, and with no apparent trade-offs in ectoparasitic Varroa mite burdens. Furthermore, spray-LX3 exerts potent activities against Ascosphaera apis (a deadly brood pathogen) likely stemming from in-hive dispersal differences, whereas patty-LX3 promotes synergistic brood development via unique nutritional benefits. These findings provide a foundational basis for spray-based probiotic application in apiculture and collectively highlight the importance of considering delivery method in disease management strategies., (© 2023. The Author(s).)

Patients with d-looped transposition of the great arteries (d-TGA), especially those without an adequate atrial septal defect, can experience severe hypoxemia and hemodynamic compromise in the neonatal period. This can be mitigated by urgent balloon atrial septostomy (BAS). However, some patients with d-TGA are born at centers without this capability. The aim of this retrospective study of d-TGA patients who had urgent or emergent BAS at our institution between 2010 and 2021 was to evaluate time from birth to BAS for infants born at a tertiary care center as compared to those requiring transport from other institutions and to examine correlation between time to BAS and patient outcomes. Our primary outcome was time from birth to BAS. Secondary outcomes included hospital and ICU length of stay, mortality, and evidence of pulmonary or neurologic abnormalities including pulmonary hypertension, abnormal neuroimaging, or seizures. Of 96 patients, 67 (70%) were born at our institution. The median time to BAS was 4 h for patients born at our institution vs. 14.1 h for those born elsewhere (p < .0001). A longer time from birth to BAS was associated with longer ICU (r = 0.21, p = 0.046) and hospital length of stay (r = 0.24, p = 0.02) and increased likelihood of elevated right ventricular pressure on post-operative discharge echocardiogram (p = 0.01). There were no differences in mortality between the groups. Therefore, prenatal planning for patients with known d-TGA should include a delivery plan with access to urgent BAS., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Despite high disease morbidity and mortality and complex treatment decisions, little is known about the medical and end-of-life decision-making preferences of adolescents and young adults (AYA) with advanced heart disease. AYA decision-making involvement is associated with important outcomes in other chronic illness groups., Objective: To characterize decision-making preferences of AYAs with advanced heart disease and their parents and determine factors associated with these preferences., Design, Setting, and Participants: Cross-sectional survey between July 2018 and April 2021 at a single-center heart failure/transplant service at a Midwestern US children's hospital. Participants were AYAs aged 12 to 24 years with heart failure, listed for heart transplantation, or posttransplant with life-limiting complications and a parent/caregiver. Data were analyzed from May 2021 to June 2022., Main Outcomes and Measures: Single-item measure of medical decision-making preferences, MyCHATT, and Lyon Family-Centered Advance Care Planning Survey., Results: Fifty-six of 63 eligible patients enrolled in the study (88.9%) with 53 AYA-parent dyads. Median (IQR) patient age was 17.8 (15.8-19.0) years; 34 (64.2%) patients were male, and 40 patients (75.5%) identified as White and 13 patients (24.5%) identified as members of a racial or ethnic minority group or multiracial. The greatest proportion of AYA participants (24 of 53 participants [45.3%]) indicated a preference for active, patient-led decision-making specific to heart disease management, while the greatest proportion of parents (18 of 51 participants [35.3%]) preferred they and physician(s) make shared medical decisions on behalf of their AYA, representing AYA-parent decision-making discordance (χ2 = 11.7; P = .01). Most AYA participants stated a preference to discuss adverse effects or risks of treatment (46 of 53 participants [86.8%]), procedural and/or surgical details (45 of 53 participants [84.9%]), impact of condition on daily activities (48 of 53 participants [90.6%]), and their prognosis (42 of 53 participants [79.2%]). More than half of AYAs preferred to be involved in end-of-life decisions if very ill (30 of 53 participants [56.6%]). Longer time since cardiac diagnosis (r = 0.32; P = .02) and worse functional status (mean [SD] 4.3 [1.4] in New York Heart Association class III or IV vs 2.8 [1.8] in New York Heart Association class I or II; t-value = 2.7; P = .01) were associated with a preference for more active, patient-led decision-making., Conclusions and Relevance: In this survey study, most AYAs with advanced heart disease favored active roles in medical decision-making. Interventions and educational efforts targeting clinicians, AYAs with heart disease, and their caregivers are needed to ensure they are meeting the decision-making and communication preferences of this patient population with complex disease and treatment courses.

Objectives: Approximately 0.2% to 2.7% of children with congenital heart disease require a tracheostomy after cardiac surgery with the majority having single ventricle (SV) type heart lesions. Tracheostomy in SV patients is reported to be associated with high mortality. We hypothesized that short- and long-term survival of patients with SV heart disease would vary according to tracheostomy indication., Methods: This is a single center, 20-year, retrospective review of all patients with SV heart disease who underwent tracheostomy. Demographic, cardiac anatomy, surgical, intensive care unit, and hospital course data were collected. The primary outcome was survival following tracheostomy. Secondary outcome was the completion of staged palliation to Fontan., Results: In total, 25 patients with SV heart disease who underwent tracheostomy were included. Indications for tracheostomy included one or more of the following: tracheobronchomalacia (n = 8), vocal cord paralysis (n = 7), tracheal/subglottic stenosis (n = 6), primary respiratory insufficiency (n = 4), diaphragm paralysis (n = 3), suboptimal hemodynamics (n = 2), and other upper airway issues (n = 1). Survival at six months, one year, five years, and ten years was 76%, 68%, 63%, and 49%, respectively. Most patients completed Fontan palliation (64%). Patients who underwent tracheostomy for suboptimal hemodynamics and/or respiratory insufficiency had a higher mortality risk compared to those with indications of upper airway obstruction or diaphragm paralysis (hazard ratio 4.1, 95% confidence interval 1.2-13.7; P  = .02)., Conclusions: Mortality risk varies according to tracheostomy indication in patients with SV heart disease. Tracheostomy may allow staged surgical palliation to proceed with acceptable risk if it was indicated for anatomic or functional airway dysfunction.

Objectives: Virtual reality has emerged as a unique educational modality for medical trainees. However, incorporation of virtual reality curricula into formal training programmes has been limited. We describe a multi-centre effort to develop, implement, and evaluate the efficacy of a virtual reality curriculum for residents participating in paediatric cardiology rotations., Methods: A virtual reality software program ("The Stanford Virtual Heart") was utilised. Users are placed "inside the heart" and explore non-traditional views of cardiac anatomy. Modules for six common congenital heart lesions were developed, including narrative scripts. A prospective case-control study was performed involving three large paediatric residency programmes. From July 2018 to June 2019, trainees participating in an outpatient cardiology rotation completed a 27-question, validated assessment tool. From July 2019 to February 2020, trainees completed the virtual reality curriculum and assessment tool during their cardiology rotation. Qualitative feedback on the virtual reality experience was also gathered. Intervention and control group performances were compared using univariate analyses., Results: There were 80 trainees in the control group and 52 in the intervention group. Trainees in the intervention group achieved higher scores on the assessment (20.4 ± 2.9 versus 18.8 ± 3.8 out of 27 questions answered correctly, p = 0.01). Further analysis showed significant improvement in the intervention group for questions specifically testing visuospatial concepts. In total, 100% of users recommended integration of the programme into the residency curriculum., Conclusions: Virtual reality is an effective and well-received adjunct to clinical curricula for residents participating in paediatric cardiology rotations. Our results support continued virtual reality use and expansion to include other trainees.

Health-related quality of life (HRQOL) is an important clinical and research trial endpoint in adult heart failure and has been shown to predict mortality and hospitalizations in adult heart failure populations. HRQOL has not been adequately studied in the growing pediatric and young adult heart failure population. This study described HRQOL in adolescents and young adults (AYAs) with heart failure and examined primary disease, sex, race, and other correlates of HRQOL in this sample. Participants in this cross-sectional, single-center study included adolescent and young adults with heart failure and a parent/guardian. Patients and their parent/proxies completed the PedsQL, a well-established measure of HRQOL in pediatric chronic illness populations. HRQOL is impaired in AYAs with heart failure resulting from dilated, hypertrophic, or other cardiomyopathy, congenital heart disease, or post-transplant with rejection/complications. Patients identifying as white endorsed poorer total HRQOL than non-white patients (p = 0.002). Subscale analysis revealed significant correlations between female sex (p = 0.01) and white race (p = 0.01) with poorer self-reported physical functioning. Family income was unrelated to HRQOL. Functional status was strongly associated with total (p = 0.0003) and physical HRQOL (p < 0.0001). Sociodemographic and disease-specific risk and resilience factors specific to HRQOL in AYAs with heart failure include primary cardiac disease, race, sex, and functional status. Building upon extensive work in adult heart failure, utilization, and study of HRQOL as a clinical and research trial outcome is necessary in pediatric heart failure. Developing targeted interventions for those at greatest risk of impaired HRQOL is an important next step., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Kommerell diverticulum (KD) is a dilated proximal aberrant right or left subclavian artery associated with either right or left aortic arches (RAA-ARSA or LAA-ALSA). Although case series suggest that KD may be a liability for vascular complications, the risk, pattern of dilation throughout the life span, and differences between arch sides are not known., Methods: This study was a single-center retrospective review of patients of all ages with KD on cross-sectional imaging. Maximal short-axis diameter of KD (KDmax), absolute and indexed to descending aortic diameter (DAo), was correlated with age. Comparisons were made between arch sides. Patients with vascular complications were described., Results: A total of 104 patients with KD were included: 68 (65%) with RAA-ALSA, 36 (35%) with LAA-ARSA, 43 (41%) asymptomatic. Although KDmax was correlated with age (RAA-ALSA r = 0.84; [P< .0001]; LAA-ARSA r = 0.51 [P = .001]), KDmax indexed to DAo was not (RAA-ALSA r = 0.14 [P = .27]; LAA-ARSA r = -0.22 [P = .21]). Patients with RAA-ALSA had larger KDmax indexed to DAo (1.02 ± 0.20 mm/mm vs 0.89 ± 0.18 mm/mm; P = .002) and more symptoms (75% vs 28%; P < .0001), and they were younger (median, 9.5 years vs 61.7 years; P < .0001). Six patients (58 to 80 years of age) had vascular complications, and all 6 had LAA-ARSA and risk factors for acquired aneurysms., Conclusions: In older patients, KDmax indexed to DAo was not larger, thus arguing against isolated KD dilation with age. Diverticula from RAA-ALSA and LAA-ARSA demonstrated different phenotypes, a finding suggesting different disease processes and likely different risk. The incidence of vascular complications was lower than in previous reports, and these complications occurred exclusively in patients with LAA-ARSA and aneurysm risk factors. This finding suggests that conservative management of asymptomatic KD is often reasonable, especially in patients with RAA-ALSA., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Infants who require open heart surgery are at increased risk for developmental delays including gross motor impairments which may have implications for later adaptive skills and cognitive performance. We sought to evaluate the feasibility and efficacy of a tummy time intervention to improve motor skill development in infants after cardiac surgery., Methods: Infants <4 months of age who underwent cardiac surgery were randomly assigned to tummy time with or without outpatient reinforcement or standard of care prior to hospital discharge. The Alberta Infant Motor Scale (AIMS) was administered to each infant prior to and 3 months after discharge. Groups were compared, and the association between parent-reported tummy time at home and change in motor scores at follow-up was examined., Results: Parents of infants (n = 64) who had cardiac surgery at a median age of 5 days were randomly assigned to tummy time instruction (n = 20), tummy time + outpatient reinforcement (n = 21) or standard of care (n = 23). Forty-nine (77%) returned for follow-up. At follow-up, reported daily tummy time was not significantly different between groups (p = 0.17). Fifteen infants had <15 minutes of tummy time daily. Infants who received >15 minutes of tummy time daily had a significantly greater improvement in motor scores than infants with <15 minutes of tummy time daily (p = 0.01)., Conclusion: In infants following cardiac surgery, <15 minutes of tummy time daily is associated with increased motor skill impairment. Further research is needed to elucidate the best strategies to optimise parental compliance with tummy time recommendations.

In single-ventricle patients with native-to-neoaortic anastomoses, the native aortic root serves as a conduit to the coronary arteries. Thrombosis of the native aortic root has been described only in small, limited reports. We described our center's experience with this rare adverse event. All single-ventricle patients who underwent native-to-neoaortic anastomosis from 2002 to 2017 were compiled from institutional databases. Chart review identified cases of native aortic root thrombosis. Of 467 patients, there were 9 (2%) cases of native aortic root thrombosis; all had hypoplastic left heart syndrome. Timing of thrombosis varied and occurred following each stage of single-ventricle palliation. For treatment, 8 patients received systemic anticoagulation and one patient did not receive any treatment. One patient also underwent percutaneous thrombectomy. Three patients (33.3%) died during the follow-up period. Among survivors, 4/6 had right ventricular systolic function that was mildly depressed or worse at a median follow-up of 8.3 years (interquartile range 1.3-10.8). Native aortic root thrombosis is a rare complication occurring at various stages of single-ventricle palliation. In this series, 6 of 9 patients (66.6%) survived; however, ventricular function was often compromised. No risk factors were identified to focus preventative therapies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Prolonged pleural effusions are common post Fontan operation and are associated with morbidity. Fontan pleural effusions have elevated proinflammatory cytokines. Little is known about the chest tube drainage after a superior cavopulmonary connection. We examined the chest tube drainage and the inflammatory profiles in post-operative superior cavopulmonary connection patients., Methods: This prospective cohort study enrolled 25 patients undergoing superior cavopulmonary connection and 10 age-similar controls. Data are also compared to 25 previously published Fontan patients and their 15 age-similar controls. Chest tube samples were analysed with a 17-cytokine BioPlex Assay. Descriptive statistics and univariate comparisons were made between groups., Results: Duration of chest tube drainage was significantly shorter in superior cavopulmonary connection patients (median 4 days, [interquartile range 3-5 days]) versus Fontan patients (10 days, [7-11 days], p < 0.0001). Cytokine concentrations were higher on post-operative day 1 in superior cavopulmonary connection patients versus Fontan patients (all p ≤ 0.01), however levels were comparable to age-similar controls. While proinflammatory IL 8, MIP-1β, and TNF-α concentrations increased in chest tube drainage of Fontan patients from post-operative day 1 to last chest tube day (all p < 0.0001), there was no change in these biomarkers in superior cavopulmonary connection patients, their controls, or Fontan controls., Conclusions: Our study demonstrates that after superior cavopulmonary connection, proinflammatory cytokines in the chest tube drainage remain similar to biventricular controls of both age groups, unlike the significant rise over time observed in Fontan patients. Inflammation within the chest tube drainage is likely not innate to single ventricle patients.

Under-diagnosis of pediatric hypertension remains pervasive due to difficulty recognizing elevated systolic blood pressures (SBPs). We performed a retrospective review comparing recognition of and response to elevated SBPs ≥95th percentile before and after development of a clinical decision support tool (CDST) in an academic pediatric system. Of 44,351 encounters, 477 had elevated SBPs with documented recognition of an elevated SBP in 17.9% of encounters pre-CDST that increased to 33.7% post-CDST ( P = .001). Post-CDST, 75.5% of elevated SBPs had repeat measurement, with 90.8% of initially elevated SBPs normalizing to <95th percentile. If repeat measurement was obtained and SBP remained elevated, documented recognition increased from 14.0 to 83.3% ( P < .0001). These data support using the CDST is associated with increased identification of elevated SBPs in children with greatest improvements associated with repeat SBP measurement. This suggests targeted training and support systems at medical intake would be high yield for increasing recognition of elevated SBP.

Background: We sought to describe QOL in children with VAD and to identify factors associated with impaired QOL., Methods: There were 82 children (6-19 years) in the Pediatric Interagency Registry for Mechanical Circulatory Support who completed the PedsQL +/- a VAD-specific QOL assessment pre-VAD implant (n = 18), 3 months post-VAD (n = 63), and/or 6 months post-VAD (n = 38). Significantly impaired QOL is a score >1 SD below norms., Results: Study patients were 59% male, 67% Caucasian, with cardiomyopathy diagnosis in 82%, and median age at implant of 14 y (IQR 11-17). PedsQL scores were lower than norms for physical (p < .0001) and psychosocial (p < .01) QOL in pre- and post-VAD groups. Compared to chronic health condition and complex or severe heart disease groups, PedsQL scores were lower for physical and psychosocial QOL in the pre-VAD group (p < .0001); however, psychosocial QOL was not significantly different in post-VAD groups. Psychosocial QOL was impaired in 67%, 40%, and 24% in pre-VAD, 3-month, and 6-month post-VAD groups, respectively. Total and psychosocial QOL scores were significantly higher in the 3-month and 6-month post-VAD group than pre-VAD (all p ≤ .02). VAD patients were most bothered by their inability to participate in usual play activities. Impaired QOL 3 months post-VAD was associated with inotropic support >2 weeks/ongoing post-VAD (p = .04)., Conclusion: Physical QOL is significantly impaired in most children pre- and post-VAD. However, psychosocial QOL is not significantly impaired in most children post-VAD suggesting VAD implantation may improve psychosocial QOL in children., (© 2022 Wiley Periodicals LLC.)

Recent studies have shown that the aryl hydrocarbon receptor (AhR) is expressed in the brain's native immune cells, known as microglia. However, while the impact of exposure to AhR ligands is well studied in the peripheral immune system, the impact of such exposure on immune function in the brain is less well defined. Microglia serve dual roles in providing synaptic and immunological support for neighboring neurons and in mediating responses to environmental stimuli, including exposure to environmental chemicals. Because of their dual roles in regulating physiological and pathological processes, cortical microglia are well positioned to translate toxic stimuli into defects in cortical function via aberrant synaptic and immunological functioning, mediated either through direct microglial AhR activation or in response to AhR activation in neighboring cells. Here, we use gene expression studies, histology, and two-photon in vivo imaging to investigate how developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a high-affinity and persistent AhR agonist, modulates microglial characteristics and function in the intact brain. Whole cortical RT-qPCR analysis and RNA-sequencing of isolated microglia revealed that gestational and lactational TCDD exposure produced subtle, but durable, changes in microglia transcripts. Histological examination and two-photon in vivo imaging revealed that while microglia density, distribution, morphology, and motility were unaffected by TCDD exposure, exposure resulted in microglia that responded more robustly to focal tissue injury. However, this effect was rectified with depletion and repopulation of microglia. These results suggest that gestational and lactational exposure to AhR ligands can result in long-term priming of microglia to produce heightened responses towards tissue injury which can be restored to normal function through microglial repopulation., (Copyright © 2022. Published by Elsevier Inc.)

In patients with congenitally corrected transposition of the great arteries (ccTGA) and hemodynamically significant concomitant lesions, physiologic repair may be undertaken, in which the circulation is septated but the morphologic right ventricle (RV) remains the systemic ventricle. Patients without significant concomitant lesions may be observed without surgery, with a similar physiologic result. We compared cardiovascular magnetic resonance measures of ventricular size and function in patients with physiologically repaired and unrepaired ccTGA. Patients with ccTGA who underwent cardiovascular magnetic resonance at our center between September 2007 and July 2019 were analyzed. In 38 patients identified (12, physiologically repaired; 26, unrepaired; mean age 34.5 [18.7 to 52.0] years), there was a higher proportion of RV ejection fraction ≤45% in physiologically repaired (75% vs unrepaired 35%, p = 0.02). Physiologically repaired patients had worse left ventricle global longitudinal strain (-14.9% ± 5.0% vs unrepaired patients -18.4% ± 2.7%, p = 0.04). The difference in tricuspid regurgitant fraction between groups did not achieve statistical significance (physiologically repaired 27.4 ± 11.1% vs unrepaired patients 19.2 ± 13.0%, p = 0.08). Evaluation for late gadolinium enhancement was more commonly undertaken in physiologically repaired patients (8 of 12 vs unrepaired 7 of 26, p = 0.03) and present more frequently in the left ventricle in physiologically repaired patients in patients evaluated (6 of 8 vs unrepaired 0 of 7, p = 0.01). In conclusion, ventricular function is decreased in patients with ccTGA undergoing physiologic repair compared with those without previous surgery. These cohorts should be considered separately when using ventricular function as an outcome. RV dysfunction is concerning for long-term outcomes following physiologic repair., Competing Interests: Disclosures Dr. Agarwal's disclosures are listed in the "Article Footnotes" section at the end of this proof. The remainder of the authors have nothing to disclose. This statement may be formated in the Journal's prefered language., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: We aimed to describe the incidence, risk factors, and clinical outcomes of pericardial effusions within 6 months after pediatric heart transplantation (HT)., Methods: A single-center retrospective cohort study was performed on all pediatric HT recipients from 2004 to 2018. Logistic regression was used to identify factors associated with pericardial effusions post-HT, and survival was compared using log-rank test., Results: During the study period, 97 HTs were performed in 93 patients. Fifty patients (52%) had a ≥small pericardial effusion within 6 months, 16 of which were, or became, ≥moderate in size. Pericardial drain was placed in 8 patients. In univariate analysis, larger recipient body surface area (p = .01) and non-congenital heart disease (p = .002) were associated with pericardial effusion development. Donor/recipient size ratios, post-HT hemodynamics, and rejection did not correlate with pericardial effusion development. In multivariable analysis, non-congenital heart disease (adjusted odds ratio 3.3, p = .01) remained independently associated with development of pericardial effusion. There were no significant differences in post-HT survival between patients with and without ≥small (p = .68) or ≥moderate pericardial effusions (p = .40)., Conclusions: Pericardial effusions are common after pediatric HT. Patients with cardiomyopathy, or non-congenital heart disease, were at higher risk for post-HT pericardial effusions. Pericardial effusions increased morbidity but had no effect on mortality in our cohort. The risk factors identified may be used for anticipatory guidance in pediatric HT., (© 2021 Wiley Periodicals LLC.)

L-carnitine tartrate has been shown to improve relatively short-term recovery among athletes. However, there is a lack of research on the longer-term effects in the general population., Objective: The primary objectives of this randomized double-blind, placebo-controlled trial were to evaluate the effects of daily L-carnitine tartrate supplementation for 5 weeks on recovery and fatigue., Method: In this study, eighty participants, 21- to 65-years-old, were recruited. Participants were split into two groups of forty participants each, a placebo, and a L-carnitine Tartrate group. Seventy-three participants completed a maintenance exercise training program that culminated in a high-volume exercise challenge., Results: Compared to placebo, L-carnitine tartrate supplementation was able to improve perceived recovery and soreness ( p = 0.021), and lower serum creatine kinase ( p = 0.016). In addition, L-carnitine tartrate supplementation was able to blunt declines in strength and power compared to placebo following an exercise challenge. Two sub-analyses indicated that these results were independent of gender and age. Interestingly, serum superoxide dismutase levels increased significantly among those supplementing with L-carnitine tartrate., Conclusions: These findings agree with previous observations among healthy adult subjects and demonstrate that L-carnitine tartrate supplementation beyond 35 days is beneficial for improving recovery and reducing fatigue following exercise across gender and age.

Fontan palliation has improved survival for single ventricle patients, but long-term complications persist including cardiovascular dysfunction, neurohormonal abnormalities, and protein-losing enteropathy (PLE). Although chronic inflammation contributes to morbidity, an association between inflammation and vascular dysfunction has not been studied. We assessed inflammation and vascular function in 31 Fontan-palliated patients (52% male, median age 14.3 years), including 10 PLE+. Fontan circulation was associated with altered inflammatory cytokines (TNF-α: mean 2.5 ± 1.4 vs. 0.7 ± 0.2 pg/ml, p < 0.0001; sTNFR2: 371 ± 108 vs. 2694 ± 884 pg/ml, p < 0.0001) and vascular dysfunction [log-transformed reactive hyperemia index (lnRHI) 0.28 ± 0.19 vs. 0.47 ± 0.26, p < 0.01; augmentation index (AI) -2.9 ± 13.8 vs. -16.3 ± 12.0, p = 0.001; circulating endothelial progenitor cells (cEPCs) 5.0 ± 8.1 vs. 22.8 ± 15.9, p = 0.0002)]. Furthermore, PLE+ patients showed greater inflammation (IFN-γ 6.3 ± 2.2 vs. 11.5 ± 7.9 pg/ml, p = 0.01; sTNFR1: 1181 ± 420 vs. 771 ± 350 pg/ml, p = 0.01) and decreased arterial compliance (AI: 5.4 ± 17.1 vs. -6.8 ± 10.2, p = 0.02) than PLE- patients. Circulating EPCs, but not inflammatory cytokines, were inversely associated with arterial stiffness in Fontan patients. In conclusion, chronic inflammation and vascular dysfunction are observed after Fontan operation, with greater inflammation and arterial stiffness in Fontan patients with active PLE. However, there is no clear association between inflammatory cytokines and vascular dysfunction, suggesting these pathophysiologic processes are not mechanistically linked., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The Ross operation is an important option for children with critical aortic stenosis with residual disease, but operation in infancy is associated with significant morbidity and mortality. The aim of this study was to evaluate echocardiographic correlates of transplantation-free survival, reintervention, and left ventricular (LV) function in midterm follow-up., Methods: This retrospective, single-center study included all infants with critical aortic stenosis who underwent Ross by 1 year of age from January 2000 to September 2018. Serial echocardiograms were analyzed for LV ejection fraction (LVEF) and systolic and diastolic longitudinal strain. The primary outcome was mortality or transplantation; secondary outcomes were reintervention and abnormal LVEF (≤55%)., Results: Among 40 infants (30 male [75%]; median age at Ross, 51 days) with median follow-up duration of 3.3 years (interquartile range, 1.0-9.4 years), the primary outcome was met in 11 (28%). Rates of transplantation-free survival was 79%, 77%, and 69% at 1, 5, and 10 years after Ross. Predictors of transplantation or death included neonatal surgery, cross-clamp time, and preoperative left atrial dilatation and lower LVEF. Median freedom from reintervention was 7.1 years after Ross, with no identified associations. LV longitudinal strain improved 1 year after Ross (-21.1 ± 3.8% vs -17.4 ± 5.1%, P = .02), although LVEF did not reach significance. Lower LVEF at 1 year was related to pre-Ross left atrial dilatation (P = .02), abnormal LVEF (P = .04), and lower early diastolic longitudinal strain rate (P = .03). LVEF remained stable 3 years after Ross., Conclusions: Both transplantation-free survival and normalization of LV function after Ross in infancy are associated with preoperative LV systolic and diastolic measures, highlighting the prognostic value of echocardiography in this population. Further data are necessary in a larger, multicenter cohort to allow more precise risk stratification., (Copyright © 2020 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the use of early intervention services in infants with CHD after open-heart surgery and identify factors associated with receipt of services., Study Design: Surveys were administered to caregivers of infants who underwent open-heart surgery before 1 year of age at a single institution between July, 2017 and July, 2018. Information regarding the infant's use of early intervention services and the caregiver's experience with the programme was obtained. Clinical data were retrieved from the medical record review. Logistic regression identified factors associated with receipt of services., Results: The study included 158 eligible infants. Ninety-eight caregivers (62%) completed the surveys. Of those surveyed, 53.1% of infants were currently or previously enrolled in early intervention services. Infants most frequently received physical therapy (76.9%). The majority of caregivers found services to be moderately/very helpful (92.3%) and sufficient for their child (76.9%). In the univariate analysis, single-ventricle disease, known syndrome/genetic abnormality, extracardiac anomaly, and longer intensive care and hospital length of stay were associated with receipt of services. Single-ventricle disease (p = 0.004) and known syndrome/genetic abnormality (p < 0.0001) remained independently associated with receipt of services in the multivariable analysis., Conclusion: Amongst infants at risk for neurodevelopmental deficits, approximately half received services after open-heart surgery. Caregivers expressed satisfaction with the programme. While infants with single-ventricle disease and a known syndrome/genetic abnormality were more likely to receive early intervention services, many at-risk infants with CHD failed to receive services. Further research is needed to identify barriers to early intervention services and promote developmental outcomes.

Background: Understanding the impact of the COVID-19 pandemic on paediatric non-COVID-19-related care, as well as patient and caregiver concerns and stressors, is critical for informing healthcare delivery. It was hypothesised that high care disruptions and psychological stress would be observed among paediatric and adult CHD patients in the early phase of the pandemic., Methods: A cross-sectional, international, electronic survey study was completed. Eligible participants included parents of children with acquired or CHD, adults with CHD, or caregivers of adults with CHD., Results: A total of 1220 participants from 25 countries completed the survey from 16 April to 4 May, 2020. Cardiac care disruption was significant with 38% reporting delays in pre-pandemic scheduled cardiac surgeries and 46% experiencing postponed cardiac clinic visits. The majority of respondents (75%) endorsed moderate to high concern about the patient with heart disease becoming ill from COVID-19. Worry about returning for in-person care was significantly greater than worry of harm to patient due to postponed care. Clinically significant psychological stress was high across the sample including children (50%), adults with CHD (42%), and caregivers (42%)., Conclusions: The early phase of the COVID-19 pandemic contributed to considerable disruptions in cardiac care for patients with paediatric and adult CHD. COVID-19-related fears are notable with potential to impact willingness to return to in-person care. Psychological stress is also very high necessitating intervention. Further study of the impact of delays in care on clinical outcomes is warranted.

Background: In patients with repaired tetralogy of Fallot (TOF), key echocardiogram report elements have been identified, but poor adherence has been demonstrated, particularly for quantitative assessment. We report a quality improvement effort to improve adherence at our institution, with a focus on increasing quantitative assessment of right ventricular (RV) function., Methods: Baseline compliance was established by a 3-month retrospective review of outpatient echocardiogram reports. Intervention 1 included presenting baseline data and reviewing the guidelines with echocardiogram laboratory staff (physicians and sonographers). Intervention 2, chosen to focus on quantitative assessment of RV function, involved recommending measurement of tricuspid annular plane systolic excursion (TAPSE) for all echocardiograms. Reporting rates were prospectively analyzed for 1 month after each intervention. To evaluate sonographer versus physician compliance, both study images (acquisition of TAPSE images) and reports were reviewed., Results: At baseline, adherence was poor (median 65% of elements reported), with lower rates for measurements versus descriptive elements (median 40% vs 78%, p<.0001). Following intervention 1, total reported elements improved (median 71% vs 65%, p=0.02) due to increase in measurements (median 50% vs 40%, p=0.02). Reports of quantitative RV function did not significantly change after either intervention, but sonographer compliance improved after intervention 1 (33% vs 14%, p=0.03), with further improvement after intervention 2 (53% vs 14%, p=0.001)., Conclusion: While education on lesion-specific guidelines may modestly improve adherence, standardization has a greater effect. However, interventions may have differential impact on sonographers versus attendings, and iterative interventions may be required to change practice patterns., (© 2021 Wiley Periodicals LLC.)

The ketogenic diet is a high-fat, very low-carbohydrate, moderate-protein diet that will induce a state of ketosis, but because of its restrictive nature, it may be difficult to adhere to, especially in adolescents. Supplementing with exogenous beta-hydroxybutyrate salts may induce a state of temporary ketosis without any undesirable side effects, thereby promoting the benefits of ketosis and minimizing adherence requirements to a ketogenic diet. To date, beta-hydroxybutyrate supplementation in healthy adolescents has not been explored. Therefore, the purpose of this study was to examine the safety of exogenous beta-hydroxybutyrate salt supplementation in a healthy adolescent population. In the present study, 22 healthy male and female adolescents consumed 3.75 g of beta-hydroxybutyrate salts or maltodextrin placebo twice daily for 90 days. Comprehensive blood safety analysis, bone densitometry, happiness and emotional intelligence surveys, and blood pressure were assessed at Pre, Day 45, and Day 90. There were no significant differences detected in subjects supplementing with beta-hydroxybutyrate salts, indicating that exogenous beta-hydroxybutyrate salts had no detrimental impact on fasting blood safety metrics, bone density, happiness, emotional intelligence, or blood pressure. We conclude that supplementing with exogenous beta-hydroxybutyrate salts is safe and well-tolerated by healthy adolescents.

Purpose: This study investigated the effects of marine phytoplankton supplementation (Oceanix®, Tetraselmis chuii) on 1) maximal isometric strength and immune function in healthy humans following a oneweek high-intensity resistance-training program and 2) the proinflammatory cytokine response to exercise in a rat model., Methods: In the human trial, 22 healthy male and female participants were randomly divided into marine phytoplankton and placebo groups. Following baseline testing, participants underwent a 14-day supplement loading phase before completing five consecutive days of intense resistance training. In the rat model, rats were randomly divided into four groups (n=7 per condition): (i) control, (ii) exercise, (iii) exercise + marine phytoplankton (2.55 mg/kg/day), or (iv) exercise + marine phytoplankton (5.1 mg/kg/day). Rats in the exercising groups performed treadmill exercise 5 days per week for 6 weeks., Results: In the human model, marine phytoplankton prevented significant declines in the isometric peak rate of force development compared to placebo. Additionally, salivary immunoglobulin A concentration was significantly lower following the resistance training protocol in the placebo group but not in the marine phytoplankton group. Marine phytoplankton in exercising rats decreased intramuscular levels and serum concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) and intramuscular concentrations of malondialdehyde., Conclusion: Marine phytoplankton prevented decrements in indices of functional exercise recovery and immune function. Mechanistically, these outcomes could be prompted by modulating the oxidative stress and proinflammatory cytokine response to exercise.

Microglia, the immune cells of the brain, have a canonical role in regulating responses to neurological disease or injury, but have also recently been implicated as regulators of neurophysiological processes such as learning and memory. Given these dual immune and physiological roles, microglia are a likely mechanism by which external toxic stimuli are converted into deficits in neuronal circuitry and subsequently function. However, while it is well established that exposure to environmental toxicants negatively affects the peripheral immune system, it remains unknown whether and how such exposure causes neuroinflammation which, in turn, may negatively impact microglial functions in vivo. Here, we examined how acute 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in adulthood, which negatively impacts immune cells in the periphery, affects microglial characteristics in the cortex of the mouse. We found that microglia density, distribution, morphology, inflammatory signaling, and response to a secondary, pathological activation were unaffected by acute TCDD exposure. These results suggest that acute, peripheral TCDD exposure in adulthood is not sufficient to induce an overt inflammatory phenotype in cortical microglia., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Absent risk stratification, variable physiology of ductal-dependent congenital heart disease (DD-CHD) imparts risk of over-medicalization and unnecessary exclusion from early parental bonding., Methods: Single-center retrospective cohort study of term infants with isolated prenatally diagnosed DD-CHD expected to require immediate advanced resuscitation/intervention (2005-2017). Standardized documentation (2015 onward) included diagnosis, expected saturations, and allowability of postnatal parental bonding., Results: The study cohort (n = 386) included 289 patients in the pre-standardized documentation era and 97 in the post-era; the groups had similar characteristics. Fewer infants were born by cesarean in the later era (32% vs. 22%; p = 0.049). Decrease in any respiratory intervention (38-26%; p = 0.03) followed standardized documentation. More patients had any bonding time (22-74%; p < 0.0001), without increase in CPAP or intubation in the first two hours of life (6.9% vs. 7.2%; p = 0.92)., Conclusion: Standardized predelivery documentation for neonates with DD-CHD decreased unnecessary respiratory intervention and increased parental bonding.

Patients after the Ross procedure are at risk for right (RV) and left ventricular (LV) dysfunction due to neo-aortic and pulmonary dysfunction. While neo-aortic root dilatation has been related to LV dysfunction, the potential contributions of aortic stiffness and ventricular interactions have not been evaluated. Patients status post Ross procedure up to age 18 years with cardiac magnetic resonance (CMR) exam from 2007 to 2018 were retrospectively reviewed. Aortic pulse wave velocity (PWV) was calculated from phase contrast and angiogram images. RV and LV peak global longitudinal (GLS) and circumferential strain (GCS) were measured using tissue tracking software. Multivariable regression was performed for variables associated with parameters of LV function. In 58 patients (median age 20.5 years at CMR exam), male gender, longer time since Ross procedure, aortic root dilatation, and lower RV ejection fraction (EF) were associated with decreased LV EF. There was no association with LV late gadolinium enhancement or neo-aortic or conduit regurgitation. LV GCS and GLS also correlated with RV GCS, RV GLS and PWV. In multivariable analysis, the relation of RV and LV systolic function, but not aortic measurements, remained significant. In conclusion, in long-term follow-up after pediatric Ross procedure, RV function rather than aortic root size or aortic stiffness most closely relates to LV function. Ventricular interactions may impact decision-making on timing of conduit intervention, which could differ from established criteria in populations with only aortic or pulmonary valve disease. Further study is warranted to evaluate possible association with clinical outcome.

The purpose of this study was to investigate the impact of antioxidant-rich marine phytoplankton supplementation (Oceanix, OCX) on performance and muscle damage following a cross-training event in endurance-trained subjects. Additionally, an animal model was carried out to assess the effects of varying dosages of OCX, with exercise, on intramuscular antioxidant capacity., Methods: In the human trial, endurance-trained subjects (average running distance = 29.5 ± 2.6 miles × week -1 ) were randomly divided into placebo (PLA) and OCX (25 mg) conditions for 14 days. The subjects were pre-tested on a one-mile uphill run, maximal isometric strength, countermovement jump (CMJ) and squat jump (SJ) power, and for muscle damage (creatine kinase (CK)). On Day 12, the subjects underwent a strenuous cross-training event. Measures were reassessed on Day 13 and 14 (24 h and 48 h Post event). In the animal model, Wistar rats were divided into four groups ( n = 7): (i) Control (no exercise and placebo (CON)), (ii) Exercise (E), (iii) Exercise + OCX 1 (Oceanix, 2.55 mg/day, (iv) Exercise + OCX 2 (5.1 mg/day). The rats performed treadmill exercise five days a week for 6 weeks. Intramuscular antioxidant capacity (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px)) and muscle damage (CK and myoglobin (MYOB) were collected. The data were analyzed using repeated measures ANOVA and t -test for select variables. The alpha value was set at p < 0.05., Results: For the human trial, SJ power lowered in PLA relative to OCX at 24 h Post (-15%, p < 0.05). Decrements in isometric strength from Pre to 48 h Post were greater in the PLA group (-12%, p < 0.05) than in the OCX. Serum CK levels were greater in the PLA compared to the OCX (+14%, p < 0.05). For the animal trial, the intramuscular antioxidant capacity was increased in a general dose-dependent manner (E + Oc2 > E + Oc1 > E > CON). Additionally, CK and MYOB were lower in supplemented compared to E alone., Conclusions: Phytoplankton supplementation (Oceanix) sustains performance and lowers muscle damage across repeated exercise bouts. The ingredient appears to operate through an elevating oxidative capacity in skeletal muscle.

Background: Clinical genetics has evolved significantly to become an efficient and effective means of diagnosing disease. Genetic treatments are now being developed which are showing promising results. However, ophthalmic patients are not utilizing genetic testing as part of their diagnostic workups. This paper explores the patient experience at the Ocular Genetics Clinic (OGC) at the University of Arkansas for Medical Sciences (UAMS) Jones Eye Institute and discusses reasons why patients continue to not pursue genetic testing., Materials and Methods: We performed a retrospective chart review to understand the main reasons why patients were referred to the OGC between 2009 and 2018, with a detailed analysis of why patients did not pursue genetic testing., Results: Patients mainly did not undergo testing due to the cost of testing. However, patient availability, patient interest, and diagnostic workup also drove a significant amount of this lack of testing., Conclusions: Ocular genetic testing is becoming an increasingly beneficial tool for diagnosing ocular disease. However, to date, patients do not utilize this service fully. At the OGC, there are several main drivers for this lack of testing, namely finances, interest/availability, and diagnostic workup. As more ocular genetics clinics are established, it will be imperative to address reasons for forgoing genetic testing and to develop strategies to encourage patients to pursue this testing.

Objective: The objective was to evaluate and improve accuracy of anticipatory counseling regarding neonatal intervention for prenatally diagnosed tetralogy of Fallot (TOF) by assessing new and previously published predictors of neonatal intervention., Methods: This is a multi-center, retrospective study from three centers of 112 fetal TOF patients undergoing third trimester fetal echocardiograms from 2004 to 2017. Additional cardiac defects requiring neonatal intervention were excluded. Fetal echocardiographic, clinical, and consultation data were compared between neonatal and late intervention. Optimal echocardiographic values were determined., Results: Twenty-six infants (23%) required neonatal intervention. Those infants had significantly different pulmonary valve (PV) z-scores, PV:aortic valve (AoV) ratios, PV:AoV z-score differences (absolute difference between z-scores), and increased likelihood of abnormal ductal flow. Counseling during fetal echocardiogram regarding interventional timing was accurate for 50% needing neonatal intervention and 86% undergoing late intervention (P = .002). The best neonatal intervention predictors were PV:AoV ratio of <0.6 and counseling for neonatal intervention. PV:AoV z-score difference ≥5 provided 89% negative predictive value for excluding patients from neonatal repair., Conclusions: Third trimester fetal echocardiograms can predict interventional timing. The best predictors of neonatal intervention are PV:AoV ratio <0.6, PV:AoV z-score difference ≥5, and cardiologist counseling that neonatal intervention was likely., (© 2020 John Wiley & Sons, Ltd.)