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Scedosporium apiospermum previously known as Monospermum apiospermum is a ubiquitous fungus found in soil, polluted water and sewage. It causes broad spectrum of diseases, including soft tissue infections, septic arthritis, osteomyelitis, ophthalmic infections, sinusitis, pneumonia, meningitis, brain abscesses, endocarditis and disseminated infection. In recent years, it has been shown to be pathogenic for both immunocompetent and immunosuppressed patients. It is a significant opportunist with very high levels of antifungal resistance. We report here a case of invasive lung infection due to S. apiospermum in an immunocompetent patient who responded to antifungal therapy and surgical treatment.

Objective: To describe the safety and effectiveness of treating pediatric patients who have pulmonary arterial hypertension (PAH) with selexipag in a real-world, multicenter cohort, given that data supporting its use in pediatric PAH are sparse., Study Design: We report a multicenter, retrospective, cohort study of children with PAH treated with selexipag. Demographic and clinical variables were extracted from the medical records. Clinical parameters were analyzed at 3 timepoints: before selexipag, 3-12 months after selexipag, and >12 months follow-up., Results: Eighty-seven patients were included, 32 received selexipag as add-on to background therapy, and 55 transitioned from another prostanoid. The median starting and final doses were 4.7 and 28.5 μg/kg/dose twice daily, respectively. Add-on patients demonstrated improved indexed pulmonary to systemic vascular resistance ratio after selexipag initiation (PVRi/SVRi, 0.62v0.53; P = .034) with a lower average mean pulmonary artery pressure (46 vs 39 mm Hg; P = NS), and oxygen consumption (maximal oxygen consumption during cardiopulmonary exercise testing [VO 2 max] 27.8 mL/kg/min vs 30.9 mL/kg/min; P = NS). Transition patients demonstrated stable mean pulmonary artery pressure (47 mm Hg vs 45 mm Hg; P = NS) and a lower mean indexed pulmonary vascular resistance (10.9 Wood units∗m 2 vs 8.2 Wood units∗m 2 ; P = NS) but late functional worsening in some with VO 2 max decreased at follow-up (26.0 mL/kg/min vs 19.5 mL/kg/min). Side effects were noted in 40% of the cohort, but prompted discontinuation in only 2%., Conclusions: In a large, multicenter cohort, the oral prostacyclin agonist selexipag demonstrates favorable tolerability and effectiveness. Add-on patients demonstrated early hemodynamic improvement. Transition patients demonstrated early stability with risk of late functional worsening, highlighting the importance of ongoing monitoring., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture., Competing Interests: Declaration of interests W.K.C. is on the Board of Directors of Prime Medicine. The authors declare no additional competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the feasibility of using actigraphy to measure physical activity (pA) and heart rate variability (HRV) as study endpoints in pediatric pulmonary arterial hypertension (PAH) and to compare their performance to 6-minute-walk distance (6MWD), a common primary endpoint used in PAH clinical trials in adults and children who can walk and understand the test process., Study Design: We conducted a prospective, multicenter, noninterventional study in pediatric PAH patients and healthy children. Actiheart and Fitbit Charge 2 recorded pA and heart rate data. HRV was defined as SD of daily heart rate. Actigraphy pA and HRV and 6MWD from the same subjects were analyzed to compare children with PAH with controls, and Panama functional classification (FC) III vs II. Power/sample size simulations were conducted to detect hypothetical treatment effect equivalent to differences seen between FC III and FC II., Results: We enrolled 116 children: 90 and 98 adhered with Actiheart and Fitbit, respectively. Actigraphy daily pA was ∼36% lower (P < .05) and daily HRV was ∼18% lower (P < .05) in children with PAH (n = 62) than healthy controls (n = 54). Daily pA and daily HRV trended ∼17% lower in FC III than FC II, whereas 6MWD showed little difference. Simulation at 80% power showed that pA required 175 subjects per group and HRV required 40 per group to detect the difference/effect, whereas 6MWD required over our maximum sample size of 200., Conclusions: Actigraphy is a feasible measure in pediatric PAH. Compared with 6MWD, pA and HRV may be more sensitive in differentiating Panama FC III from II. HRV may improve actigraphy's utility in pediatric PAH., Competing Interests: Declaration of Competing Interest This study was supported by an U.S. Food and Drug Administration Chief Scientist Challenge Grant FY16. ClinicalTrials.Gov-NCT02909608., (Published by Elsevier Inc.)

Background: Necrotizing enterocolitis (NEC) is a complication that can affect infants with congenital heart disease (CHD). The objective of this study is to determine whether breast milk, which is associated with decreased incidence of NEC in preterm infants, is protective in infants with CHD. Methods: Retrospective case-control study of infants ≥ 33 weeks gestational age with CHD who underwent cardiac surgery during their admission to the Infant Cardiac Unit from 2008 to 2017. Cases were defined as infants with modified Bell's stage ≥ II NEC. Controls were matched by date of birth, gestational age, and pre- or postcardiac surgery feed initiation. Results: A total of 926 infants with gestational age ≥ 33 weeks and CHD were admitted; 18 cases of NEC were identified and compared with 84 controls. Breast milk intake was higher in controls, but this difference was not statistically significant. Single ventricle (SV) physiology was identified as an independent risk factor for NEC by multivariable analysis. Analysis of infants with SV physiology demonstrated that median age at time of surgery was 9 days (interquartile range [IQR], 7-12) in NEC cases and 5 days (IQR, 4-9) in controls ( P  = .02). Conclusions: While this study is inconclusive with regard to feeding composition and risk of NEC in infants with CHD, the trend toward greater intake of breast milk in the control group suggests that breast milk may be protective for these infants. Infants with SV physiology are at high risk for NEC. Earlier time to stage I palliation may be a modifiable risk factor for NEC., 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.

Hematopoietic stem cell transplant (HSCT) is a potentially curative therapy for children with sickle cell disease (SCD). The effects of HSCT on ventricular function are not well characterized in children with SCD. Echocardiograms from children with SCD who underwent HSCT between 2007 and 2017 were retrospectively analyzed before and 1-year after HSCT. Left ventricular (LV) volumes, mass, and ejection fraction were calculated by the 5/6 area*length method. LV end-diastolic and systolic dimensions, septal, and posterior wall thickness, and fractional shortening were measured by M-mode. Mitral and tricuspid inflow Dopplers (E and A waves) as well as mitral, tricuspid, and septal tissue Dopplers (E', A') were assessed. E/A, E'/A' and E/E' ratios were calculated. Biventricular strain imaging was performed using speckle-tracking echocardiography. Peak global systolic longitudinal and circumferential LV strain, and global longitudinal right ventricular strain, as well as early and late diastolic strain rate, were measured on LV apical 4-chamber, LV short-axis mid-papillary, and RV apical views, respectively. Forty-seven children (9.7 ± 5.5 years, 60% male) met inclusion criteria. Pre-HSCT, subjects had mild LV dilation with normal LV systolic function by conventional measure of ejection fraction and fractional shortening. There was a significant reduction in LV volume, mass, and ejection fraction after HSCT, but measurements remained within normal range. LV longitudinal and circumferential strain were normal pre-HSCT and showed no significant change post-HSCT. RV strain decreased after HSCT, but the absolute change was small, and mean values were normal both pre- and post-HSCT. Conventional measures of diastolic function were all normal pre-HSCT. Post-HSCT there was a reduction in select parameters, but all parameters remained within normal range. Early and late diastolic strain rate parameters showed no significant change from pre- to post-HSCT. At one-year after HSCT in children with SCD conventional measures of systolic and diastolic function are within normal limits. Except for a small decrease in RV systolic strain with values remaining within normal limits, systolic strain and diastolic strain rate values did not significantly change 1-year after HSCT., (© 2024. The Author(s).)

It is increasingly recognised that diverse genetic respiratory disorders present as severe pulmonary hypertension (PH) in the neonate and young infant, but many controversies and uncertainties persist regarding optimal strategies for diagnosis and management to maximise long-term outcomes. To better define the nature of PH in the setting of developmental lung disease (DEVLD), in addition to the common diagnoses of bronchopulmonary dysplasia and congenital diaphragmatic hernia, we established a multidisciplinary group of expert clinicians from stakeholder paediatric specialties to highlight current challenges and recommendations for clinical approaches, as well as counselling and support of families. In this review, we characterise clinical features of infants with DEVLD/DEVLD-PH and identify decision-making challenges including genetic evaluations, the role of lung biopsies, the use of imaging modalities and treatment approaches. The importance of working with team members from multiple disciplines, enhancing communication and providing sufficient counselling services for families is emphasised to create an interdisciplinary consensus., Competing Interests: Conflict of interest: E.D. Austin reports grants from the NIH and a leadership role with TBX4Life. C. Galambos reports leadership roles with PPHNet and TBX4Life. D. Yung reports grants from Merck, Janssen and the NIH. S.O. Vargas reports grants from the Chan Zuckerberg Initiative, consultancy fees from Vertex Pharmaceuticals, lecture fees from the American Academy of Allergy, Asthma & Immunology, participation on a data safety monitoring board or advisory board with Millipore Sigma, and a leadership role with the Society for Pediatric Pathology. E.O. Jackson reports support for attending meetings from Seattle Children's Hospital. E.C. Whalen reports consultancy fees from the Pulmonary Hypertension Association Care Center and a leadership role with PPHNet. N.M. Villafranco reports support for attending meetings from the Children's Hospital of Philadelphia. S.H. Abman reports grants from the NHLBI (U01 HL12118), consultancy fees from Chiesi, and participation on a data safety monitoring board or advisory board with Bayer Pharmaceuticals and the NHLBI. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

This is a single-center retrospective study to assess the safety and tolerability of continuous inhaled iloprost use as rescue therapy for refractory pulmonary hypertension (PH) in critically ill neonates and infants. A retrospective chart review was performed on 58 infants and data were collected at baseline, 1, 6, 12, 24, 48 and 72 h of iloprost initiation. Primary outcomes were change in heart rate (HR), fraction of inspired oxygen (FiO 2 ), mean airway pressures (MAP), blood pressure (BP) and oxygenation index (OI). Secondary outcomes were need for extracorporeal membrane oxygenation (ECMO) and death. 51 patients treated for >6 h were analyzed in 2 age groups, neonate (≤28 days: n = 32) and infant (29-365 days: n = 19). FiO 2 ( p < 0.001) and OI ( p = 0.01) decreased, while there were no significant changes in MAP, BP and HR. Of the fifteen patients placed on ECMO, seven were bridged off ECMO on iloprost and eight died. Twenty-four out of fifty-one patients (47%) recovered without requiring ECMO, while twelve (23%) died. Iloprost as add-on therapy for refractory PH in critically ill infants in the NICU has an acceptable tolerability and safety profile. Large prospective multicenter studies using iloprost in the neonatal ICU are necessary to validate these results.

Pulmonary vasodilator treatment can improve hemodynamics, right ventricular function, symptoms, and survival in pediatric pulmonary hypertension (PH). However, clinical trial data are lacking due to many constraints. One major limitation is the lack of relevant trial endpoints reflective of hemodynamics or functional status in patients in whom standard exercise testing is impractical, unreliable, or not reproducible. The Kids Mod PAH trial (Mono- vs. Duo Therapy for Pediatric Pulmonary Arterial Hypertension) is an ongoing multicenter, Phase III, randomized, open-label, pragmatic trial to compare the safety and efficacy of first-line combination therapy (sildenafil and bosentan) to first-line monotherapy (sildenafil alone) in 100 pediatric patients with PH across North America. Investigators will measure participants' physical activity with a research-grade, wrist-worn actigraphy device at multiple time points as an exploratory secondary outcome. Vector magnitude counts per minute and activity intensity will be compared between the treatment arms. By directly and noninvasively measuring physical activity in the ambulatory setting, we aim to identify a novel, simple, inexpensive, and highly reproducible approach for quantitative assessment of exercise tolerance in pediatric PH. These data will increase the field's understanding of the effect of pulmonary vasodilator treatment on daily activity - a quantitative measure of functional status and wellbeing in pediatric PH and a potential primary outcome for future clinical trials in children with cardiopulmonary disorders., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Objectives: There are limited data documenting sources of medical information that families use to learn about paediatric cardiac conditions. Our study aims to characterise these resources and to identify any disparities in resource utilisation. We hypothesise there are significant variations in the resources utilised by families from different educational and socio-economic backgrounds., Methods: A survey evaluating what resources families use (websites, healthcare professionals, social media, etc.) to better understand paediatric cardiac conditions was administered to caretakers and paediatric patients at Morgan Stanley Children's Hospital. Patients with a prior diagnosis of CHD, cardiac arrhythmia, and/or heart failure were included. Caretakers' levels of education (fewer than 16 years vs. 16 years or more) and patients' medical insurance types (public vs. private) were compared with regard to the utilisation of resources., Results: Surveys completed by 137 (91%) caretakers and 27 (90%) patients were analysed. Websites were utilised by 72% of caretakers and 56% of patients. Both private insurance and higher education were associated with greater reported utilisation of websites, healthcare professionals, and personal networks (by insurance p = 0.009, p = 0.001, p = 0.006; by education p = 0.022, p < 0.001, p = 0.018). They were also more likely to report use of electronic devices (such as a computer) compared to those with public medical insurance and fewer than 16 years of education (p < 0.001, p < 0.001, respectively)., Conclusion: Both levels of education and insurance status are associated with the utilisation of informative resources and digital devices by families seeking to learn more about cardiac conditions in children.

Cardiopulmonary exercise testing (CPET) is an important tool in assessing the functional status of patients with pulmonary arterial hypertension (PAH). During CPET, continuous electrocardiography (ECG) is used as a marker of exercise-induced ischemia or arrhythmia. We hypothesize that ECG changes with exercise may be an early indicator of clinical worsening in PAH and could predict adverse outcomes. Clinical, hemodynamic, and CPET data of 155 children and young adult patients with PAH who underwent CPET between 2012 and 2019 in our pulmonary hypertension (PH) center were included in this retrospective analysis. ECGs were analyzed for ST depressions and T-wave inversions, along with coincident hemodynamic data. These data were correlated with adverse outcomes divided into 2 categories: severe worsening (death or receiving lung transplant) and mild to moderate worsening (PAH medication escalation, hospitalization, shunt creation, or listing for lung transplant). The median age was 19 years (range 7 to 40 years), 69% were female, and the average follow-up time was 5 years (range 1 to 8 years). A total of 63 patients (41%) had at least 1 adverse outcome. A total of 39 patients (25%) demonstrated significant ST-T-wave changes with exercise. Patients with ST-T-wave changes were 20% more likely to die or need lung transplant than those without. The multiple linear regression found that ST-T-wave changes were a predictor of elevated mean pulmonary arterial pressure (mPAP) found on catheterization (R = 0.489, p = 0.003), although not of pulmonary vascular resistance index (R = -0.112, p = 0.484). An mPAP of 55 mm Hg was the most sensitive and specific point in identifying when ST-T-wave changes with exercise begin to appear. In conclusion, ST-T-wave changes on exercise ECG are significantly associated with adverse outcomes in PH in a medium-term follow-up study, and the presence of ST-T-wave changes correlates with higher mPAP. These ECG changes with exercise may be used as early indicators of clinical worsening in PH and predictors of adverse outcomes., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pulmonary vein stenosis (PVS) in children is a challenging condition with poor outcomes. Post-operative stenosis can occur after repair of anomalous pulmonary venous return (APVR) or stenosis within native veins. There is limited data on the outcomes of post-operative PVS. Our objective was to review our experience and assess surgical and transcatheter outcomes. Single-center retrospective study was performed including patients < 18 years who developed restenosis after baseline pulmonary vein surgery that required additional intervention(s) from 1/2005 to 1/2020. Non-invasive imaging, catheterization and surgical data were reviewed. We identified 46 patients with post-operative PVS with 11 (23.9%) patient deaths. Median age at index procedure was 7.2 months (range 1 month-10 years), and median follow-up was 10.8 months (range 1 day-13 years). Index procedure was surgical in 36 (78.3%) and transcatheter in 10 (21.7%). Twenty-three (50%) patients developed vein atresia. Mortality was not associated with number of affected veins, vein atresia, or procedure type. Single ventricle physiology, complex congenital heart disease (CCHD), and genetic disorders were associated with mortality. Survival rate was higher in APVR patients (p = 0.03). Patients with three or more interventions had a higher survival rate compared to patients with 1-2 interventions (p = 0.02). Male gender, necrotizing enterocolitis, and diffuse hypoplasia were associated with vein atresia. In post-operative PVS, mortality is associated with CCHD, single ventricle physiology, and genetic disorders. Vein atresia is associated with male gender, necrotizing enterocolitis, and diffuse hypoplasia. Multiple repeated interventions may offer a patient survival benefit; however, larger prospective studies are necessary to elucidate this relationship further., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Repair of systemic to pulmonary shunts is timed to prevent the development of irreversible pulmonary vascular disease, including in patients with other factors contributing to pulmonary hypertension. This study assessed outcomes of an individualised strategy for managing patients with mild-moderately elevated pulmonary vascular resistance (PVR) deemed borderline eligible for repair., Methods: A retrospective chart review was conducted of patients with systemic to pulmonary shunts and baseline indexed PVR (PVRi) ≥3 WU·m 2 treated at a single centre from 1 January 2005 to 30 September 2019. Data included demographics, World Health Organization functional class (WHO FC), medications and haemodynamic data at baseline and serial follow-up., Results: 30 patients (18 females) met criteria for inclusion. Median age at diagnosis of pulmonary arterial hypertension was 1.3 years (range 0.03-54 years) and at surgery was 4.1 years (range 0.73-56 years). Median follow-up time was 5.8 years (range 0.2-14.6 years) after repair. Most patients received at least one targeted pulmonary arterial therapy prior to repair and the majority (80%) underwent fenestrated shunt closure. There was a significant decrease in mean pulmonary arterial pressure (mPAP) (p<0.01), PVRi (p=0.0001) and PVR/systemic vascular resistance (p<0.01) between baseline and preoperative catheterisation and a decrease in PVRi (p<0.005), mPAP (p=0.0001) and pulmonary to systemic flow ratio (p<0.03) from baseline to most recent catheterisation. WHO FC improved from FC II-III at baseline to FC I post repair in most patients (p<0.003)., Conclusions: In carefully selected patients with systemic to pulmonary shunts and elevated PVR considered borderline for operability, the use of preoperative targeted therapy in conjunction with fenestrated or partial closure of intracardiac shunts is associated with improvement in WHO FC and clinical outcomes., Competing Interests: Conflict of interest: No disclosures for A.N. Linder, J. Hsia, S.V. Krishnan and E.A. Bacha. Conflict of interest: S. Crook receives salary support from the Babies Heart Fund. Conflict of interest: Columbia University Irving Medical Center has received research grant support from Janssen and United Therapeutics for studies for which U.S. Krishnan is the principal investigator. U.S. Krishnan has no financial conflicts. Conflict of interest: E.B. Rosenzweig's institution (Columbia University Irving Medical Center) has received research grant support from Actelion/Janssen Pharmaceuticals, Bayer, Insmed, SonVie and United Therapeutics, and E.B. Rosenzweig has research funding from the National Heart, Lung, and Blood Institute. Conflict of interest: U.S. Krishnan and E.B. Rosenzweig express gratitude to the Pediatric Pulmonary Hypertension Network for supporting care of patients with pulmonary hypertension., (Copyright ©The authors 2023.)

Objective: To evaluate the feasibility, tolerability, and adherence with wearable actigraphy devices among infants and children with pulmonary arterial hypertension (PAH)., Study Design: This multicenter, prospective, observational study included children ages 0-6 years with and without PAH. Participants wore the ActiGraph wGT3X-BT on the hip and FitBit Inspire on the wrist during waking hours for 14 days. Steps, vector magnitude counts per minute, activity intensity, heart rate, and heart rate variability were compared between groups., Results: Forty-seven participants (18 PAH, 29 control) were enrolled from 10 North American sites. PAH patients were mostly functional class II (n = 16, 89%) and treated with oral medications at the time of enrollment. The number of wear days was not significantly different between the groups (ActiGraph: 10 [95% CI: 5.5, 12.2] in PAH vs 8 [4, 12] in control, P = .20; FitBit 13 [10, 13.8] in PAH vs 12 [8, 14] in control, P = .87). Complete data were obtained in 81% of eligible ActiGraph participants and 72% of FitBit participants. PAH participants demonstrated fewer steps, lower vector magnitude counts per minute, more sedentary activity, and less intense physical activity at all levels compared with control participants. No statistically significant differences in heart rate variability were demonstrated between the 2 groups., Conclusions: Measurement of physical activity and other end points using wearable actigraphy devices was feasible in young children with PAH. Larger studies should determine associations between physical activity and disease severity in young patients with PAH to identify relevant end points for pediatric clinical trials., Competing Interests: Declaration of Competing Interest Funding for the study was provided by the Department of Health and Human Services/Food and Drug Administration BAA-18-00 123, University of Colorado. The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pulmonary hypertension (PH) is a significant health problem that contributes to high morbidity and mortality in diverse cardiac, pulmonary, and systemic diseases in children. Evidence-based advances in PH care have been challenged by a paucity of quality endpoints for assessing clinical course and the lack of robust clinical trial data to guide pharmacologic therapies in children. While the landmark adult AMBITION trial demonstrated the benefit of up-front combination PH therapy with ambrisentan and tadalafil, it remains unknown whether upfront combination therapy leads to more rapid and sustained clinical benefits in children with various categories of PH. In this article, we describe the inception of the Kids Mod PAH Trial, a multicenter Phase III trial, to address whether upfront combination therapy (sildenafil and bosentan vs. sildenafil alone) improves PH outcomes in children, recognizing that marked differences between the etiology and therapeutic response between adults and children exist. The primary endpoint of this study is WHO functional class (FC) 12 months after initiation of study drug therapy. In addition to the primary outcome, secondary endpoints are being assessed, including a composite measure of time to clinical worsening, WHO FC at 24 months, echocardiographic assessment of PH and quantitative assessment of right ventricular function, 6-min walk distance, and NT-proBNP levels. Exploratory endpoints include selected biomarkers, actigraphy, and assessments of quality of life. This study is designed to pave the way for additional clinical trials by establishing a robust infrastructure through the development of a PPHNet Clinical Trials Network., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Background: Patients with pulmonary arterial hypertension have quality-of-life limitations, decreased exercise capacity, and poor prognosis if the condition is left untreated. Standard exercise testing is routinely performed to evaluate patients with pulmonary arterial hypertension but may be limited in its ability to monitor activity levels in daily living., Objective: To evaluate the validity of the commercial Fitbit Charge HR as a tool to assess real-time exercise capacity as compared with standard exercise testing., Methods: Ambulatory pediatric and adult patients were enrolled and given a Fitbit with instructions to continuously wear the device during waking hours. Patients underwent a 6-minute walk test, cardiopulmonary exercise test, and a 36-Item Short Form Health Survey on the day of enrollment and follow-up. Twenty-seven ambulatory patients with pulmonary arterial hypertension were enrolled, and 21 had sufficient data for analyses (median age, 25 years [range, 13-59 years]; 14 female participants)., Results: Daily steps measured by the Fitbit had a positive correlation with 6-minute walk distance (r = 0.72, P = .03) and an inverse trend with World Health Organization functional class. On the 36-Item Short Form Health Survey, 77% of patients reported improvement in vitality (P = .055). At follow-up, there was a strong correlation between number of steps recorded by Fitbit and role limitations because of physical problems (r = 0.88, P = .02) and weaker correlations with other quality-of-life markers., Conclusion: The findings of this pilot study suggest activity monitors may have potential as a simple and novel method of assessing longitudinal exercise capacity and activity levels in patients with pulmonary hypertension. Further study in larger cohorts of patients is warranted to determine which accelerometer measures correlate best with outcomes., (© 2023 The Author(s). Published by The Texas Heart Institute®.)

Objective: To describe the types of congenital heart disease (CHD) in a congenital diaphragmatic hernia (CDH) cohort in a large volume center and evaluate surgical decision making and outcomes based on complexity of CHD and associated conditions., Study Design: A retrospective review of patients with CHD and CDH diagnosed by echocardiogram between 01/01/2005 and 07/31/2021. The cohort was divided into 2 groups based on survival at discharge., Results: Clinically important CHD was diagnosed in 19% (62/326) of CDH patients. There was 90% (18/20) survival in children undergoing surgery for both CHD and CDH as neonates, and 87.5 (22/24) in those undergoing repair initially for CDH alone. A genetic anomaly identified on clinical testing was noted in 16% with no significant association with survival. A higher frequency of other organ system anomalies was noted in nonsurvivors compared with survivors. Nonsurvivors were more likely to have unrepaired CDH (69% vs 0%, P < .001) and unrepaired CHD (88% vs 54%, P < .05), reflecting a decision not to offer surgery., Conclusions: Survival was excellent in patients who underwent repair of both CHD and CDH. Patients with univentricular physiology have poor survival and this finding should be incorporated into pre and postnatal counseling about eligibility for surgery. In contrast, patients with other complex lesions including transposition of the great arteries have excellent outcomes and survival at 5 years follow-up at a large pediatric and cardiothoracic surgical center., Competing Interests: Declaration of Competing Interest Supported by the National Institute of Health grant NICHDR-01 HD057036, P01HD068250, UL1 RR024156. The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Patients with pulmonary hypertension associated with congenital heart disease make up an increasing proportion of the total pulmonary hypertension population who bring with them added complexity because of underlying anatomical and hemodynamic abnormalities. Currently, no consensus recommendations are available on how to best manage this group of patients for either the primary cardiologist or pulmonary hypertension subspecialist, including timing of referral. The purposes of this document are (1) to describe the various pulmonary hypertension groups and subgroups associated with congenital heart disease, (2) to describe imaging modalities used in patient evaluation, (3) to elucidate medical and surgical management considerations, (4) to highlight disparities within this population, and (5) to identify gaps and future research needs of patients with pulmonary hypertension associated with congenital heart disease.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe life-threatening manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that often presents with acute cardiac dysfunction and cardiogenic shock. While recovery from acute illness is excellent, the long-term myocardial impact is unknown., Objective: To compare cardiac MRI findings in children 6-9 months after their hospitalization with MIS-C against MRI findings in healthy controls to assess for residual myocardial disease., Materials and Methods: We prospectively performed cardiac MRI on 13 children 6-9 months following their hospitalization with MIS-C: eight of these children had a history of left ventricle ejection fraction (LVEF) < 50%, persistent symptoms, or electrocardiogram (ECG) abnormalities and underwent clinical MRI; five of these children without cardiac abnormalities during their hospitalization underwent research MRIs. We compared their native T1 and T2 mapping values with those of 20 normal controls., Results: Cardiac MRI was performed at 13.6 years of age (interquartile range [IQR] 11.9-16.4 years) and 8.2 months (IQR 6.8-9.6 months) following hospitalization. Twelve children displayed normal ejection fraction: left ventricle (LV) 57.2%, IQR 56.1-58.4; right ventricle (RV) 53.1%, IQR 52.0-55.7. One had low-normal LVEF (52%). They had normal extracellular volume (ECV) and normal T2 and native T1 times compared to controls. There was no qualitative evidence of edema. One child had late gadolinium enhancement (LGE) with normal ejection fraction, no edema, and normal T1 and T2 times. When stratifying children who had MIS-C according to history of LVEF <55% on echocardiography, there was no difference in MRI values., Conclusion: Although many children with MIS-C present acutely with cardiac dysfunction, residual myocardial damage 6-9 months afterward appears minimal. Long-term implications warrant further study., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pulmonary hypertension (PH) is a multifactorial, progressive disease with poor outcomes. Group 2 PH is defined by pulmonary vascular disease with elevated pulmonary capillary wedge pressure including both left-sided obstructive lesions and diastolic heart failure (HF). Sildenafil was historically discouraged in this population as pulmonary vasodilation can lead to pulmonary edema. However, evidence suggests that sildenafil can help to treat the precapillary component of PH. This is a single center, retrospective pilot study of pediatric PH patients with left-sided HF who were treated with sildenafil for ≥ 4 weeks. HF patients without mechanical support (HF group) and HF patients with a left ventricular assist device (HF-VAD) were analyzed. The exploratory analysis described the safety and side effects of the drug. Echocardiographic parameters were compared before and after sildenafil treatment in a paired analysis. The changes in medical therapy during treatment, mechanical support, and mortality was reported; 19/22 patients tolerated sildenafil. Pulmonary edema in two patients resolved upon discontinuation of sildenafil. In the HF group, both the right atrial volume and right ventricular diastolic area decreased, and the tricuspid regurgitation (TR) S/D ratio decreased after therapy ( p = 0.02). Across both the groups, four patients weaned off milrinone and seven weaned off inhaled nitric oxide. Of the thirteen HF patients, four received a transplant, and all of the nine HF-VAD patients received a transplant. Sildenafil can be safely used in carefully selected patients with HF and mixed pre/postcapillary PH with judicious titration and inpatient surveillance, with patients showing improvements in echocardiographic parameters.

Background: The FUEL trial (Fontan Udenafil Exercise Longitudinal) demonstrated statistical improvements in exercise capacity following 6 months of treatment with udenafil (87.5 mg po BID). The effect of udenafil on echocardiographic measures of single ventricle function in this cohort has not been studied., Methods: The 400 enrolled participants were randomized 1:1 to udenafil or placebo. Protocol echocardiograms were obtained at baseline and 26 weeks after initiation of udenafil/placebo. Linear regression compared change from baseline indices of single ventricle systolic, diastolic and global function, atrioventricular valve regurgitation, and mean Fontan fenestration gradient in the udenafil cohort versus placebo, controlling for ventricular morphology (left ventricle versus right ventricle/other) and baseline value., Results: The udenafil participants (n=191) had significantly improved between baseline and 26 weeks visits compared to placebo participants (n=195) in myocardial performance index ( P =0.03, adjusted mean difference [SE] of changes between groups -0.03[0.01]), atrioventricular valve inflow peak E ( P =0.009, 3.95 [1.50]), and A velocities ( P =0.034, 3.46 [1.62]), and annular Doppler tissue imaging-derived peak e' velocity ( P =0.008, 0.60[0.23]). There were no significant differences in change in single ventricle size, systolic function, atrioventricular valve regurgitation severity, or mean fenestration gradient. Participants with a dominant left ventricle had significantly more favorable baseline values of indices of single ventricle size and function (lower volumes and areas, E/e' ratio, systolic:diastolic time and atrioventricular valve regurgitation, and higher annular s' and e' velocity)., Conclusions: FUEL participants who received udenafil demonstrated a statistically significant improvement in some global and diastolic echo indices. Although small, the changes in diastolic function suggest improvement in pulmonary venous return and/or augmented ventricular compliance, which may help explain improved exercise performance in that cohort., Registration: URL: https://clinicaltrials.gov; Unique Identifier: NCT02741115.

Background: Syncope in Group 1 pulmonary arterial hypertension (PAH) is an independent predictor of poor prognosis in adults, but this is not well studied in children. We hypothesise that syncope in children with PAH often occurs in association with a reactive pulmonary vascular bed with sudden vasoconstriction in response to adverse stimuli. In the current study, we sought to determine the association of syncope with acute vasoresponsiveness and outcomes in children with Group 1 PAH., Methods: A retrospective chart review of children with PAH at a single pulmonary hypertension centre from 1 January 2005 to 31 October 2018 was performed. Data included demographics, symptoms, imaging, haemodynamics, and outcomes at baseline and follow-up., Results: 169 children had Group 1 PAH; 47 (28%) had syncope at presentation or follow-up. Children with significant shunts were excluded from the analysis. Children with syncope were older at diagnosis (7.5 versus 5.0 years; p=0.002) and had a higher incidence of chest pain (p=0.022) and fatigue (p=0.003). They had higher pulmonary vascular resistance at baseline (14.9 versus 9.1 WU·m 2 ; p=0.01). More children with syncope were vasoresponders to inhaled nitric oxide (33% versus 22%; p=0.08-NS). Children with syncope and acute vasoresponsiveness had the highest survival, and non-responders with syncope on medications had the worst long-term survival., Conclusions: Children with syncope had higher rates of vasoreactivity compared to those without. This suggests that in some children with PAH, syncope may simply reflect acute pulmonary vasoconstriction to an adverse stimulus. Larger prospective studies are warranted to further assess syncope as a marker for a vasoreactive phenotype with implications for treatment and long-term outcomes., Competing Interests: Conflict of interest: Columbia University has received research support from Actelion, Bayer, Janssen and United Therapeutics for U.S. Krishnan and E.B. Rosenzweig to perform clinical trials. E.B. Rosenzweig has consulted for Bayer and receives grant funding from the National Institutes of Health. No conflicts of interest exist for A.N. Linder, J. Hsia or S.V. Krishnan., (Copyright ©The authors 2022.)

Background: Congenital diaphragmatic hernia (CDH) accounts for 8% of all major congenital anomalies. Neonates who are small for gestational age (SGA) generally have a poorer prognosis. We sought to identify risk factors and variables associated with outcomes in neonates with CDH who are SGA in comparison to neonates who are appropriate for gestational age (AGA)., Methods: We used the multicenter Diaphragmatic Hernia Research & Exploration Advancing Molecular Science (DHREAMS) study to include neonates enrolled from 2005 to 2019. Chi-squared or Fisher's exact tests were used to compare categorical variables and t tests or Wilcoxon rank sum for continuous variables. Cox model analyzed time to event outcomes and logistic regression analyzed binary outcomes., Results: 589 neonates were examined. Ninety were SGA (15.3%). SGA patients were more likely to be female (p = 0.003), have a left sided CDH (p = 0.05), have additional congenital anomalies and be diagnosed with a genetic syndrome (p < 0.001). On initial single-variable analysis, SGA correlated with higher frequency of death prior to discharge (p < 0.001) and supplemental oxygen requirement at 28 days (p = 0.005). Twice as many SGA patients died before repair (12.2% vs 6.4%, p = 0.04). Using unadjusted Cox model, the risk of death prior to discharge among SGA patients was 1.57 times the risk for AGA patients (p = 0.029). There was no correlation between SGA and need for ECMO, pulmonary hypertensive medication at discharge or oxygen at discharge. After adjusting for confounding variables, SGA no longer correlated with mortality prior to discharge or incidence of unrepaired defects but remained significant for oxygen requirement at 28 days (p = 0.03)., Conclusion: Infants with CDH who are SGA have worse survival and poorer lung function than AGA infants. However, the outcome of SGA neonates is impacted by other factors including gestational age, genetic syndromes, and particularly congenital anomalies that contribute heavily to their poorer prognosis., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Extracorporeal Membrane Oxygenation (ECMO) is offered to patients with congenital diaphragmatic hernia (CDH) who are in severe respiratory and cardiac failure. We aim to describe the types of complications among these patients and their impact on survival., Methods: A single-center, retrospective review of CDH patients cannulated onto ECMO between January 2005 and November 2020 was conducted. ECMO complications, as categorized by the Extracorporeal Life Support Organization (ELSO), were correlated with survival status. Descriptive statistics were used to compare observed complications between survivors and non-survivors., Results: In our cohort of CDH neonates, 21% (54/258) were supported with ECMO, of whom, 61% (33/54) survived. Survivors and non-survivors were similar in baseline characteristics except for birthweight z-score (p = 0.043). Seventy percent of CDH neonates experienced complications during their ECMO run, with the most common categories being metabolic (48.1%) and mechanical (38.9%), followed by hemorrhage (22.2%), neurological (18.5%), renal (11.1%), pulmonary (7.4%), and cardiovascular (7.4%). The median number of complications per patient was higher in the non-survivor group  (2 (IQR: 1-4) vs 1 (IQR: 0-2), p = 0.043). In addition, mechanical (57.1% vs 27.3%, p = 0.045) and renal (28.6% vs 0%, p = 0.002) complications were more common among non-survivors compared to survivors., Conclusion: Complications occur frequently among ECMO-treated newborns with CDH, some of which have serious long-term consequences. Survivors had higher birth weight z-scores, shorter ECMO runs, and fewer complications per patient. Mechanical and renal complications were independently associated with mortality, emphasizing the utility of more focused strategies to target fluid balance and renal protection and to prevent circuit and cannula complications., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022. Published by Elsevier Inc.)

Rationale: Hemodynamic assessments direct care among children with pulmonary hypertension, yet the use of cardiac catheterization is highly variable, which could impact patient care and research. Objectives: We analyzed hemodynamic findings from right heart catheterization (RHC) and left heart catheterization and acute vasodilator testing (AVT) and the safety of catheterization in children with World Symposium on Pulmonary Hypertension (WSPH) group 1 and 3 subtypes in a large multicenter North American cohort. Methods: Of 1,475 children enrolled in the Pediatric Pulmonary Hypertension Network Registry (2014-2020), there were 1,383 group 1 and 3 patients, of whom 671 (48.5%) underwent RHC at diagnosis and were included for analysis. Results: Compared with those without diagnostic RHC, these children were older, less likely to be an infant or preterm, more often female, treated with targeted pulmonary hypertension medications at diagnosis, and had advanced World Health Organization functional class. Catheterization was performed without a difference in complication rates between WSPH groups. Pulmonary capillary wedge pressure was well correlated with left ventricular end-diastolic pressure and left atrial pressures. Results of AVT using three different methods were comparable; positive AVT results were observed in 8.0-11.8% of subjects, did not differ between WSPH groups 1 and 3, and were not associated with freedom from the composite endpoint of lung transplantation or death during follow-up. Conclusions: In a large pediatric pulmonary hypertension cohort, diagnostic RHC with or without left heart catheterization in WSPH group 1 and 3 patients was performed safely at experienced pediatric pulmonary hypertension centers. Hemodynamic differences were noted between group 1 and 3 subjects. Higher mean pulmonary arterial pressure and mean pulmonary arterial pressure/mean systemic arterial pressure ratio were associated with a higher risk of death/transplantation. Findings suggest overall safety and potential value of RHC as a standard diagnostic approach to guide pulmonary hypertension management in children.

Background/purpose: As survival rates for patients with congenital diaphragmatic hernia (CDH) increase, long-term sequelae become increasingly prevalent. We present the outcomes of patients who underwent CDH repair at our institution and discuss standardization of follow-up care in our long-term multidisciplinary follow-up clinic., Methods: A retrospective review of patients followed in multidisciplinary clinic after CDH repair at our institution from January 1, 2005 to December 1, 2020., Results: A total of 193 patients met inclusion criteria, 73 females (37.8%) and 120 males (62.2%). Left-sided defects were most common (75.7%), followed by right-sided defects (20.7%). Median age at repair was 4 days (IQR 3-6) and 59.6% of all defects required patch repair. Median length of stay was 29 days (IQR 16.8-50.0). Median length of follow up was 49 months (IQR 17.8-95.3) with 25 patients followed for more than 12 years. Long-term outcomes included gastroesophageal reflux disease (42.0%), diaphragmatic hernia recurrence (10.9%), asthma (23.6%), neurodevelopmental delay (28.6%), attention deficit hyperactivity disorder (7.3%), autism (1.6%), chest wall deformity (15.5%), scoliosis (11.4%), and inguinal hernia (6.7%)., Conclusion: As survival of patients with CDH improves, long-term care must be continuously studied and fine-tuned to ensure appropriate surveillance and optimization of long-term outcomes., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To describe the safety and tolerability of treatment with ambrisentan and tadalafil in pediatric pulmonary hypertension (PH)., Study Design: This retrospective observational two-center study included subjects (≤18 years of age) with PH receiving combination therapy with ambrisentan and tadalafil. Before initiating this therapy, many patients were on other therapies for PH. At baseline, patients either received no therapy or monotherapy with a phosphodiesterase 5 inhibitor (PDE5i) or endothelin receptor antagonist (ERA) (Group A), switched from a different PDE5i and ERA (Group B), or were on prostanoid therapy with or without a PDE5i and/or ERA (Group C and D). Demographics, symptoms, and adverse effects were collected. Pre- and postvalues for exercise capacity, hemodynamics, and biomarkers were compared., Results: There were 43 subjects (26 F, 17 M) ages 4-17.5 years (median 9.3) with World Symposium of PH group 1, 3, and 5. Significant improvements were seen in change scores at follow-up in the entire sample and Group A for 6-min walk distance: +37.0 (6.5-71.0) [p = 0.022], mean pulmonary artery pressure: -6.0 (-14.0 to -3.5) [p = .002], pulmonary vascular resistance: -1.7 (-6.2 to -1.0) [p = .003], NT-proBNP -32.9 (-148.9 to -6.7) [p = .025]. WHO functional class improved in 39.5% and was unchanged in 53.5%; PH risk scores improved in 16%; were unchanged in 56%; and declined in 14%. Three patients discontinued therapy (two headaches, one peripheral edema). Seven patients were hospitalized for worsening disease (2/7 had a Potts shunt placed, 2/7 had an atrial septostomy). There were no deaths or lung transplantation., Conclusions: Combination therapy with ambrisentan and tadalafil was well-tolerated, with an acceptable safety profile in a select group of children. This therapy was associated with improved exercise capacity and hemodynamics in children who were treatment naïve or on monotherapy with a PH medication before the initiation of ambrisentan and tadalafil. Based on these early data, further study of combination therapy in pediatric PH is warranted., (© 2021 Wiley Periodicals LLC.)

Rationale: There are currently no data supporting specific dosing and weaning strategies for parenteral prostanoid therapy in children with pulmonary arterial hypertension (PAH). Objectives: To describe the clinical practice of intravenous (IV) or subcutaneous (SC) prostanoid therapy in pediatric PAH and identify dosing strategies associated with favorable outcome. Methods: From an international multicenter cohort of 275 children with PAH, 98 patients who received IV/SC prostanoid therapy were retrospectively analyzed. Results: IV/SC prostanoids were given as monotherapy (20%) or combined with other PAH-targeted drugs as dual (46%) or triple therapy (34%). The median time-averaged dose was 37 ng/kg/min, ranging 2-136 ng/kg/min. During follow-up, IV/SC prostanoids were discontinued and transitioned to oral or inhaled PAH-targeted therapies in 29 patients. Time-dependent receiver operating characteristic analyses showed specific hemodynamic criteria at discontinuation of IV/SC prostanoids (mean pulmonary arterial pressure < 35 mm Hg and/or pulmonary vascular resistance index < 4.4 Wood units [WU]⋅m 2 ) identified children with favorable long-term outcome after IV/SC prostanoid discontinuation, compared with patients who do not meet those criteria ( P  = 0.027). In the children who continued IV/SC prostanoids until the end of follow-up, higher dose (>25 ng/kg/min), early start after diagnosis, and combination with other PAH-targeted drugs were associated with better transplant-free survival. Conclusions: Early initiation of IV/SC prostanoids, higher doses of IV/SC prostanoids, and combination with additional PAH-targeted therapy were associated with favorable outcome. Transition from IV/SC prostanoid therapy to oral or inhaled therapies is safe in the long term in selected children, identified by reaching hemodynamic criteria for durable IV/SC prostanoid discontinuation while on IV/SC prostanoid therapy.

Pediatric pulmonary hypertension (PH) is a rare disease with historically very high morbidity and mortality. In the past 20 years, there has been a growing recognition that pediatric PH, although having similarities to adult PH, is a unique entity with its own particular pathogeneses, presentation, and management. With better understanding and earlier diagnosis of pediatric PH, and as more medications have become available, survival of children with PH has also significantly improved. This article reviews the various forms of PH in childhood, with a focus on both established and investigational therapies that are available for children with PH., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Pulmonary vein stenosis (PVS) is an emerging cause of pulmonary hypertension in preterm infants. It is an often lethal condition with poor long.term prognosis and high mortality. Previous work suggests an association between necrotizing enterocolitis (NEC) and PVS, supporting a possible role for inflammatory processes due to gastrointestinal (GI) pathology as an associated risk factor for PVS., Study Description: We performed a matched case-control study where infants with PVS were matched for gestational age with infants without PVS. Hospital records were reviewed for prior history of NEC or other gut pathology., Results: Twenty-four PVS patients were matched with 68 controls; 63% of patients (15/24) had prior GI pathology as opposed to 19% (13/68) of controls. The GI pathology group had a significantly higher growth restriction and C-reactive protein. The mean gradient across the pulmonary veins was higher in the gut pathology group versus controls, as was mortality (29% vs. 9%)., Conclusions: The previously described association between PVS and intestinal pathology was further strengthened by this study. The presence of GI pathology should lead to early surveillance and intervention for PVS., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Annals of Pediatric Cardiology.)

Competing Interests: Conflict of interest: S.H. Abman has nothing to disclose. Conflict of interest: M.P. Mullen reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study; personal fees from Actelion, outside the submitted work. Conflict of interest: L.A. Sleeper reports grants from the National Heart, Lung, and Blood Institute (subcontract from University of Colorado), during the conduct of the study. Conflict of interest: E.D. Austin has nothing to disclose. Conflict of interest: E.B. Rosenzweig reports grants from the National Institutes of Health, during the conduct of the study. Conflict of interest: J.P. Kinsella has nothing to disclose. Conflict of interest: The University of Colorado contracts with Actelion, Bayer, Gilead and United Therapeutics for D. Ivy to be a consultant and preform clinical research trials. Conflict of interest: R.K. Hopper has nothing to disclose. Conflict of interest: J.U. Raj has nothing to disclose. Conflict of interest: J. Fineman has nothing to disclose. Conflict of interest: R.L. Keller reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study. Conflict of interest: A. Bates has nothing to disclose. Conflict of interest: U.S. Krishnan has nothing to disclose. Conflict of interest: C.M. Avitabile has nothing to disclose. Conflict of interest: A. Davidson has nothing to disclose. Conflict of interest: M.D. Natter reports grants from the National Heart, Lung, and Blood Institute, during the conduct of the study. Conflict of interest: K.D. Mandl reports no specific conflicts, however in the interest of full disclosure, reports personal fees from Merck, and philanthropy from Eli Lily to his lab, during the conduct of the study.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: In spring 2020, a novel hyperinflammatory process associated with severe acute respiratory syndrome coronavirus 2 multisystem inflammatory syndrome in children (MIS-C) was described. The long-term impact remains unknown. We report longitudinal outcomes from a New York interdisciplinary follow-up program., Methods: All children <21 years of age, admitted to NewYork-Presbyterian with MIS-C in 2020, were included. Children were followed at 1 to 4 weeks, 1 to 4 months, and 4 to 9 months postdischarge., Results: In total, 45 children were admitted with MIS-C. The median time to last follow-up was 5.8 months (interquartile range 1.3-6.7). Of those admitted, 76% required intensive care and 64% required vasopressors and/or inotropes. On admission, patients exhibited significant nonspecific inflammation, generalized lymphopenia, and thrombocytopenia. Soluble interleukin (IL) IL-2R, IL-6, IL-10, IL-17, IL-18, and C-X-C Motif Chemokine Ligand 9 were elevated. A total of 80% ( n = 36) had at least mild and 44% ( n = 20) had moderate-severe echocardiographic abnormalities including coronary abnormalities (9% had a z score of 2-2.5; 7% had a z score > 2.5). Whereas most inflammatory markers normalized by 1 to 4 weeks, 32% ( n = 11 of 34) exhibited persistent lymphocytosis, with increased double-negative T cells in 96% of assessed patients ( n = 23 of 24). By 1 to 4 weeks, only 18% ( n = 7 of 39) had mild echocardiographic findings; all had normal coronaries. At 1 to 4 months, the proportion of double-negative T cells remained elevated in 92% (median 9%). At 4 to 9 months, only 1 child had persistent mild dysfunction. One had mild mitral and/or tricuspid regurgitation., Conclusions: Although the majority of children with MIS-C present critically ill, most inflammatory and cardiac manifestations in our cohort resolved rapidly., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Purpose: To investigate students' experience (over time) with meta-reflection writing exercises, called Signature Reflections. These exercises were used to strengthen reflective capacity, as part of a 4-year reflective writing portfolio curriculum that builds on a recognized strategy for reflection (narrative medicine) and employs longitudinal faculty-mentors., Method: In 2018, the authors conducted 5 focus groups with 18 third-year students from the Columbia University Vagelos College of Physicians and Surgeons class of 2019 to examine students' experience with Signature Reflections. Using an iterative, thematic approach, they developed codes to reflect common patterns in the transcripts, distilled conceptually similar codes, and assembled the code categories into themes., Results: Three core themes (safe space, narrative experience, mirror of self) and 1 overarching theme (moving through time) were identified. Students frequently experienced relief at having a safe reflective space that promoted grappling with their fears or vulnerabilities and highlighted contextual factors (e.g., trusted faculty-mentors, protected time) that fostered a safe space for reflection and exploration. They often emphasized the value of tangible documentation of their medical school journey (narrative experience) and reported using Signature Reflections to examine their emerging identity (mirror of self). Overlapping with the core themes was a deep appreciation for the temporal perspective facilitated by the Signature Reflections (moving through time)., Conclusions: A longitudinal narrative medicine-based portfolio curriculum with pauses for meta-reflection allowed students, with faculty support, to observe their trajectory through medical school, explore fears and vulnerabilities, and narrate their own growth. Findings suggest that narrative medicine curricula should be required and sufficiently longitudinal to facilitate opportunities to practice the skill of writing for insight, foster relationships with faculty, and strengthen students' temporal perspectives of their development., (Copyright © 2020 by the Association of American Medical Colleges.)

Background and Objectives: Next generation sequencing (NGS) has promising applications in transfusion medicine. Exome sequencing (ES) is increasingly used in the clinical setting, and blood group interpretation is an additional value that could be extracted from existing data sets. We provide the first release of an open-source software tailored for this purpose and describe its validation with three blood group systems., Materials and Methods: The DTM-Tools algorithm was designed and used to analyse 1018 ES NGS files from the ClinSeq ® cohort. Predictions were correlated with serology for 5 antigens in a subset of 108 blood samples. Discrepancies were investigated with alternative phenotyping and genotyping methods, including a long-read NGS platform., Results: Of 116 genomic variants queried, those corresponding to 18 known KEL, FY and JK alleles were identified in this cohort. 596 additional exonic variants were identified KEL, ACKR1 and SLC14A1, including 58 predicted frameshifts. Software predictions were validated by serology in 108 participants; one case in the FY blood group and three cases in the JK blood group were discrepant. Investigation revealed that these discrepancies resulted from (1) clerical error, (2) serologic failure to detect weak antigenic expression and (3) a frameshift variant absent in blood group databases., Conclusion: DTM-Tools can be employed for rapid Kell, Duffy and Kidd blood group antigen prediction from existing ES data sets; for discrepancies detected in the validation data set, software predictions proved accurate. DTM-Tools is open-source and in continuous development., (© 2020 International Society of Blood Transfusion.)

Purpose: Congenital diaphragmatic hernia (CDH) is associated with significant mortality and long-term morbidity in some but not all individuals. We hypothesize monogenic factors that cause CDH are likely to have pleiotropic effects and be associated with worse clinical outcomes., Methods: We enrolled and prospectively followed 647 newborns with CDH and performed genomic sequencing on 462 trios to identify de novo variants. We grouped cases into those with and without likely damaging (LD) variants and systematically assessed CDH clinical outcomes between the genetic groups., Results: Complex cases with additional congenital anomalies had higher mortality than isolated cases (P = 8 × 10 -6 ). Isolated cases with LD variants had similar mortality to complex cases and much higher mortality than isolated cases without LD (P = 3 × 10 -3 ). The trend was similar with pulmonary hypertension at 1 month. Cases with LD variants had an estimated 12-17 points lower scores on neurodevelopmental assessments at 2 years compared with cases without LD variants, and this difference is similar in isolated and complex cases., Conclusion: We found that the LD genetic variants are associated with higher mortality, worse pulmonary hypertension, and worse neurodevelopment outcomes compared with non-LD variants. Our results have important implications for prognosis, potential intervention and long-term follow up for children with CDH.

Pulmonary hypertension (PH) is common in premature infants with bronchopulmonary dysplasia (BPD) and is associated with significant mortality. Despite expert consensus suggesting the use of targeted therapies such as phosphodiesterase inhibitors, endothelin receptor antagonists, and prostanoids, there is little data on safety and outcomes in infants with BPD-associated PH (BPD-PH) treated with these medications. We sought to describe the pharmacologic management of BPD-PH and to report outcomes at our institution. Premature infants with BPD-PH born between 2005 and 2016 were included. Follow-up data were obtained through January 2020. A total of 101 patients (61 male, 40 female) were included. Of these, 99 (98.0%) patients were treated with sildenafil, 13 (12.9%) with bosentan, 35 (34.7%) with inhaled iloprost, 12 (11.9%) with intravenous epoprostenol, and nine (8.9%) with subcutaneous treprostinil. A total of 33 (32.7%) patients died during the study period and 10 (9.9%) were secondary to severe to pulmonary hypertension. Of the surviving patients, 57 (83.8%) had follow-up data at a median of 5.1 (range 0.38-12.65) years and 44 (77.2%) were weaned off PH medications at a median 2.0 (range 0-8) years. Mortality for BPD-PH remains high mostly due to co-morbid conditions. However, for those patients that survive to discharge, PH therapies can frequently be discontinued in the first few years of life.

To investigate whether transcatheter device closure of patent ductus arteriosus (PDA) is safe in children with pulmonary artery hypertension, we retrospectively analyzed our experience with 33 patients who underwent the procedure from January 2000 through August 2015. Pulmonary artery hypertension was defined as a pulmonary vascular resistance index (PVRI) >3 WU · m2. All 33 children (median age, 14.5 mo; median weight, 8.1 kg) underwent successful closure device implantation and were followed up for a median of 17.2 months (interquartile range [IQR], 1.0-63.4 mo). During catheterization, the median PVRI was 4.1 WU · m2 (IQR, 3.6-5.3 WU · m2), and the median mean pulmonary artery pressure was 38.0 mmHg (IQR, 25.5-46.0 mmHg). Premature birth was associated with pulmonary vasodilator therapy at time of PDA closure ( P=0.001) but not with baseline PVRI (P=0.986). Three patients (9.1%) had device-related complications (one immediate embolization and 2 malpositions). Two of these complications involved embolization coils. Baseline pulmonary vasodilator therapy before closure was significantly associated with intensive care unit admission after closure (10/12 [83.3%] with baseline therapy vs 3/21 [14.3%] without; P <0.001). Of 11 patients receiving pulmonary vasodilators before closure and having a device in place long-term, 8 (72.7%) were weaned after closure (median, 24.0 mo [IQR, 11.0-25.0 mo]). We conclude that transcatheter PDA closure can be performed safely in many children with pulmonary artery hypertension and improve symptoms, particularly in patients born prematurely. Risk factors for adverse outcomes are multifactorial, including coil use and disease severity. Multicenter studies in larger patient populations are warranted., (© 2020 by the Texas Heart® Institute, Houston.)

Objective: To investigate racial and ethnic differences in pulmonary hypertension subtypes and survival differences in a pediatric population., Study Design: This was a retrospective analysis of a cohort of patients with pulmonary hypertension (aged ≤18 years) enrolled in the Pediatric Pulmonary Hypertension Network registry between 2014 and 2018, comprising patients at eight Pediatric Centers throughout North America (n = 1417)., Results: Among children diagnosed after the neonatal period, pulmonary arterial hypertension was more prevalent among Asians (OR, 1.83; 95% CI, 1.21-2.79; P = .0045), lung disease-associated pulmonary hypertension among blacks (OR, 2.09; 95% CI, 1.48-2.95; P < .0001), idiopathic pulmonary arterial hypertension among whites (OR, 1.58; 95% CI, 1.06-2.41; P = .0289), and pulmonary veno-occlusive disease among Hispanics (OR, 6.11; 95% CI, 1.34-31.3; P = .0184). Among neonates, persistent pulmonary hypertension of the newborn (OR, 4.07; 95% CI, 1.54-10.0; P = .0029) and bronchopulmonary dysplasia (OR, 8.11; 95% CI, 3.28-19.8; P < .0001) were more prevalent among blacks, and congenital diaphragmatic hernia was more prevalent among whites (OR, 2.29; 95% CI, 1.25-4.18; P = .0070). An increased mortality risk was observed among blacks (HR, 1.99; 95% CI, 1.03-3.84; P = .0396), driven primarily by the heightened mortality risk among those with lung disease-associated pulmonary hypertension (HR, 2.84; 95% CI, 1.15-7.04; P = .0241)., Conclusions: We found significant racial variability in the prevalence of pulmonary hypertension subtypes and survival outcomes among children with pulmonary hypertension. Given the substantial burden of this disease, further studies to validate phenotypic differences and to understand the underlying causes of survival disparities between racial and ethnic groups are warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To assess the demographics, treatment algorithm, and outcomes in a large cohort of children treated with sildenafil., Study Design: A retrospective cohort study of children with pulmonary hypertension (PH) treated with sildenafil at a single institution between 2004 and 2015. Baseline and follow-up data collected by chart review., Results: There were 269 children included in this study: 47 with idiopathic pulmonary arterial hypertension, 53 with congenital heart disease, 135 with bronchopulmonary dysplasia, 24 with congenital diaphragmatic hernia, and 7 with other causes. Sildenafil was initial monotherapy in 84.8% and add-on therapy in 15.2%. Median follow-up time was 3.1 years (2  weeks-12.4 years). On follow-up, 99 (37%) remained on sildenafil or transitioned to tadalafil, 93 (35%) stopped sildenafil for improvement in PH, 54 (20%) died, and 20 (7%) were lost to follow-up. PH was most likely to improve in those with bronchopulmonary dysplasia, allowing for the discontinuation of sildenafil in 45%. Eighteen deaths were related to PH and 36 from other systemic causes. Two patients stopped sildenafil owing to airway spasm with desaturation. Overall survival was significantly lower in World Health Organization group 3 PH (bronchopulmonary dysplasia and congenital diaphragmatic hernia) vs group 1 (idiopathic pulmonary arterial hypertension and congenital heart disease), P = .02., Conclusions: In this retrospective experience in children with mainly World Health Organization groups 1 and 3 PH, low-dose sildenafil was well-tolerated, safe, and had an acceptable side effect profile. Although patients with group 3 PH have high mortality, survivors have a high likelihood of PH improving., (Published by Elsevier Inc.)

Portopulmonary hypertension (PoPH) is defined by the combination of portal hypertension and precapillary pulmonary arterial hypertension (PAH). Very little is known about this process in pediatric patients but prognosis is generally poor. We review our institutional experience and report on five patients with pediatric PoPH. The median age of PoPH diagnosis was six years and PAH was 14 years. PAH diagnosis was made by echocardiogram in all patients, four of whom also had cardiac catheterization. The median mean pulmonary artery pressure (mPAP) was 48.5 mmHg (interquartile range [IQR] = 46-60) with a median pulmonary vascular resistance index (PVRi) of 9 WU*M 2 (IQR = 8-22). All were acute pulmonary vasodilator testing non-responsive. All patients received targeted therapies. Three of five patients (60%) died despite an evidence-based approach to care. Of those who died, timing from the PoPH diagnosis to death ranged from three days to three years. Based upon our limited experience, PoPH is a disorder with significant mortality in childhood and challenges in treatment. Future research, focused on screening and early targeted treatment strategies, may alter the current dismal prognosis for these children.