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Abstract Background Chimeric Antigen Receptor (CAR) T cells are now standard of care (SOC) for some patients with B cell and plasma cell malignancies and could disrupt the therapeutic landscape of solid tumors. However, access to CAR-T cells is not adequate to meet clinical needs, in part due to high cost and long lead times for manufacturing clinical grade virus. Non-viral site directed CAR integration can be accomplished using CRISPR/Cas9 and double-stranded DNA (dsDNA) or single-stranded DNA (ssDNA) via homology-directed repair (HDR), however yields with this approach have been limiting for clinical application (dsDNA) or access to large yields sufficient to meet the manufacturing demands outside early phase clinical trials is limited (ssDNA). Methods We applied homology-independent targeted insertion (HITI) or HDR using CRISPR/Cas9 and nanoplasmid DNA to insert an anti-GD2 CAR into the T cell receptor alpha constant (TRAC) locus and compared both targeted insertion strategies in our system. Next, we optimized post-HITI CRISPR EnrichMENT (CEMENT) to seamlessly integrate it into a 14-day process and compared our knock-in with viral transduced anti-GD2 CAR-T cells. Finally, we explored the off-target genomic toxicity of our genomic engineering approach. Results Here, we show that site directed CAR integration utilizing nanoplasmid DNA delivered via HITI provides high cell yields and highly functional cells. CEMENT enriched CAR T cells to approximately 80% purity, resulting in therapeutically relevant dose ranges of 5.5 × 108–3.6 × 109 CAR + T cells. CRISPR knock-in CAR-T cells were functionally comparable with viral transduced anti-GD2 CAR-T cells and did not show any evidence of off-target genomic toxicity. Conclusions Our work provides a novel platform to perform guided CAR insertion into primary human T-cells using nanoplasmid DNA and holds the potential to increase access to CAR-T cell therapies.

Hybrid biotic abiotic devices can be used to interface electronics with biological systems for novel therapies or to increase device functionality beyond silicon. Many strategies exist to merge the electronic and biological worlds, one dominated by electrons and holes as charge carriers, the other by ions. In the biological world, lipid bilayers and ion channels are essential to compartmentalize the cell machinery and regulate ionic fluxes across the cell membrane. Here, we demonstrate a bioelectronic device in which a lipid bilayer supported on H+-conducting Pd/PdHx contacts contains carbon nanotubes porin (CNTP) channels. This bioelectronic device uses CNTPs to control of H+ flow across the lipid bilayer with a voltage applied to the Pd/PdHx contacts. Potential applications of these devices include local pH sensing and control.

Objective: To investigate if predictors of wound complications differed between patients undergoing excision and primary anastomosis urethroplasty (EPA) and augmented urethroplasty., Methods: The National Surgical Quality Improvement Program database from 2006 to 2018 was queried for male patients undergoing urethroplasty. Thirty-day wound complications were identified and categorized (superficial/deep/organ-space surgical site infections and dehiscence). Multivariable logistic regression was performed to determine risk factors associated with wound complications. Smoking history was defined as current smoker within the past year., Results: Urethroplasty was performed in 2251 males, with 25.46% (n = 573) using a flap or graft. There was no significant difference in wound complications for patients undergoing augmented urethroplasty (n = 17, 2.97%) or EPA (n = 45, 2.68%) (p = 0.9). The augmented group had a higher BMI, longer operative time, and longer length of stay. On multivariable logistic regression, risk factors associated with wound complications for patients undergoing EPA were diabetes (OR 2.56, p = 0.03) and smoking (OR 2.32, p = 0.02). However, these factors were not associated with wound complications in patients undergoing augmented urethroplasty., Conclusions: Smoking and diabetes were associated with increased wound complications for men undergoing EPA, but not in patients undergoing augmented urethroplasty. Patients with comorbidities associated with worse wound healing may be more likely to have a wound complication when undergoing EPA., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Heart failure is the leading cause of morbidity and mortality in adults with congenital heart disease. However, for many in this population, heart transplantation is not possible or requires longer wait times, necessitating prolonged circulatory support. The medium to long-term durable ventricular assist device therapy provides a possible solution. We analyzed outcomes of 9 patients with congenital heart disease and at least 3 years of durable mechanical support, all age 18 or older at the time of ventricular assist device implantation at our affiliated pediatric and adult hospitals. Palliated congenital anatomies varied and included biventricular physiologies as well as single ventricles with Fontan circulation. The median duration of support was 4.2 years, including 3 patients successfully bridged to transplant, averaging 2.1 years on the waitlist. Device-related complications were infrequent with HeartMate 3, a feasible and sustainable option for either bridge to transplant or destination strategies in adults with congenital heart disease., Competing Interests: Disclosure statement C.R.B. reports a financial relationship with Abbott; H.T. reports a relationship with Abbott; I.A. serves as a consultant and proctor for Berlin Heart, Inc., Medtronic Inc., Jarvik Inc., BiVACOR Inc., and Sony-Olympus Medical Solutions Inc.; A.C. reports financial relationships with Medtronic Inc. and Abbott. The remaining authors have no conflicts of interest to report., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: There is no FDA-approved left ventricular assist device (LVAD) for smaller children permitting routine hospital discharge. Smaller children supported with LVADs typically remain hospitalized for months awaiting heart transplant-a major burden for families and a challenge for hospitals. We describe the initial outcomes of the Jarvik 2015, a miniaturized implantable continuous flow LVAD, in the NHLBI-funded Pumps for Kids, Infants, and Neonates (PumpKIN) study, for bridge-to-heart transplant., Methods: Children weighing 8 to 30 kg with severe systolic heart failure and failing optimal medical therapy were recruited at 7 centers in the United States. Patients with severe right heart failure and single-ventricle congenital heart disease were excluded. The primary feasibility endpoint was survival to 30 days without severe stroke or non-operational device failure., Results: Of 7 children implanted, the median age was 2.2 (range 0.7, 7.1) years, median weight 10 (8.2 to 20.7) kilograms; 86% had dilated cardiomyopathy; 29% were INTERMACS profile 1. The median duration of Jarvik 2015 support was 149 (range 5 to 188) days where all 7 children survived including 5 to heart transplant, 1 to recovery, and 1 to conversion to a paracorporeal device. One patient experienced an ischemic stroke on day 53 of device support in the setting of myocardial recovery. One patient required ECMO support for intractable ventricular arrhythmias and was eventually transplanted from paracorporeal biventricular VAD support. The median pump speed was 1600 RPM with power ranging from 1-4 Watts. The median plasma free hemoglobin was 19, 30, 19 and 30 mg/dL at 7, 30, 90 and 180 days or time of explant, respectively. All patients reached the primary feasibility endpoint. Patient-reported outcomes with the device were favorable with respect to participation in a full range of activities. Due to financial issues with the manufacturer, the study was suspended after consent of the eighth patient., Conclusion: The Jarvik 2015 LVAD appears to hold important promise as an implantable continuous flow device for smaller children that may support hospital discharge. The FDA has approved the device to proceed to a 22-subject pivotal trial. Whether this device will survive to commercialization remains unclear because of the financial challenges faced by industry seeking to develop pediatric medical devices. (Supported by NIH/NHLBI HHS Contract N268201200001I, clinicaltrials.gov 02954497)., (Copyright © 2024 International Society for the Heart and Lung Transplantation. All rights reserved.)

Background: Traditionally, low cardiac output has been considered the primary hemodynamic driver of renal function and injury. Adult data suggest that central venous pressure (CVP) is a more important factor., Objectives: The authors hypothesized that in children with cardiovascular disease, higher CVP predicts lower estimated glomerular filtration rate (eGFR) and worsening renal function (WRF)., Methods: We performed a single-center cohort study of patients aged 3 months to 21 years with biventricular circulation undergoing cardiac catheterization. Pearson's correlation and linear and Cox regression analyses were performed to determine associations with eGFR at the time of catheterization and WFR within 180 days after catheterization., Results: 312 patients had median age 7.9 years (IQR: 2.3 to 14.5 years), median eGFR 97 mL/min/1.73 m 2 (IQR: 81-118 mL/min/1.73 m 2 ), median CVP 7 mm Hg (IQR: 5-9 mm Hg), and median cardiac index 3.7 mL/min/m 2 (IQR: 2.9-4.6 mL/min/m 2 ). Nearly half (48%) were transplant recipients. In multivariable analysis, CVP was independently associated with eGFR (β = -2.65; 95% CI: -4.02, -1.28; P  < 0.001), as was being a transplant recipient (β = -10.20; 95% CI: -17.74, -2.65; P  = 0.008), while cardiac index was not. Fifty-one patients (16%) developed WRF. In a proportional hazards model adjusting for cardiac index, only higher CVP (HR: 1.10; 95% CI: 1.04-1.17; P  = 0.002) and greater contrast volume by weight (HR: 1.05; 95% CI: 1.01-1.10; P  = 0.021) predicted WRF. CVP ≥7 mm Hg likewise predicted WRF (HR: 2.57; 95% CI: 1.29-5.12; P  = 0.007)., Conclusions: Among children with a spectrum of cardiovascular disease, higher CVP is associated with lower eGFR and development of WRF, independent of cardiac index., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: PRDM16 plays a role in myocardial development through TGF-β (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human cardiomyopathy development is unclear. This study aims to determine the impact of PRDM16 loss-of-function variants on cardiomyopathy in humans., Methods: Individuals with PRDM16 variants were identified and consented. Induced pluripotent stem cell-derived cardiomyocytes were generated from a proband hosting a Q187X nonsense variant as an in vitro model and underwent proliferative and transcriptional analyses. CRISPR (clustered regularly interspaced short palindromic repeats)-mediated knock-in mouse model hosting the Prdm16 Q187X allele was generated and subjected to ECG, histological, and transcriptional analysis., Results: We report 2 probands with loss-of-function PRDM16 variants and pediatric left ventricular noncompaction cardiomyopathy. One proband hosts a PRDM16-Q187X variant with left ventricular noncompaction cardiomyopathy and demonstrated infant-onset heart failure, which was selected for further study. Induced pluripotent stem cell-derived cardiomyocytes prepared from the PRDM16-Q187X proband demonstrated a statistically significant impairment in myocyte proliferation and increased apoptosis associated with transcriptional dysregulation of genes implicated in cardiac maturation, including TGF-β-associated transcripts. Homozygous Prdm16 Q187X/Q187X mice demonstrated an underdeveloped compact myocardium and were embryonically lethal. Heterozygous Prdm16 Q187X/WT mice demonstrated significantly smaller ventricular dimensions, heightened fibrosis, and age-dependent loss of TGF-β expression. Mechanistic studies were undertaken in H9c2 cardiomyoblasts to show that PRDM16 binds TGFB3 promoter and represses its transcription., Conclusions: Novel loss-of-function PRDM16 variant impairs myocardial development resulting in noncompaction cardiomyopathy in humans and mice associated with altered TGF-β signaling., Competing Interests: Disclosures None.

Objective: We report the largest pediatric single-center experience with an Impella (Abiomed Inc) catheter-based axial pump support., Methods: We conducted a retrospective cohort study of all patients with acute decompensated heart failure or cardiogenic shock requiring catheter-based axial pump support between October 2014 and February 2022. The primary outcome per individual encounter (hospital admission) was defined as bridge-to-recovery, bridge-to-durable ventricular assist device support, bridge-to-cardiac transplantation, or death at 6 months after catheter-based axial pump explantation. Adverse events were defined according to the Pediatric Interagency Registry for Mechanical Circulatory Support criteria., Results: Our final study cohort included 37 encounters with 43 catheter-based axial pump implantations. A single catheter-based axial pump device was used for support in 33 encounters (89%), with 2 catheter-based axial pump devices used in 3 (8%) separate encounters and 3 catheter-based axial pump devices used in 1 (3%) encounter. The median [range] age, weight, and body surface area at implantation were 16.8 [6.9-42.8] years, 61.1 [23.1-123.8] kg, and 1.7 [0.8-2.5] m 2 , respectively. The predominant causes of circulatory failure were graft failure/rejection in 16 patients (43%), followed by cardiomyopathy in 7 patients (19%), arrhythmia refractory to medical therapies in 6 patients (16%), myocarditis/endocarditis in 4 patients (11%), and heart failure due to congenital heart disease in 4 patients (11%). Competing outcomes analysis showed a positive outcome with bridge-to-recovery in 58%, bridge-to-durable VAD support in 14%, and bridge-to-cardiac transplantation in 14% at 6 months. Fourteen percent of encounters resulted in death at 6 months., Conclusions: We demonstrate that catheter-based axial pump support in children results in excellent 1- and 6-month survival with an acceptable adverse event profile., (Copyright © 2022. Published by Elsevier Inc.)

Background: Ventricular assist device (VAD) support for failing Glenn circulation represents a unique challenge., Methods: We conducted a retrospective review of clinical outcomes in patients with VAD support for failing Glenn circulation between 2010 and 2020 at a tertiary pediatric institution., Results: Ten patients were included: INTERMACS profiles were 1 in 3 patients and 2 in 7 patients. The median age, weight, and body surface area were 3.2 years, 13.0 kg, and 0.5 m 2 , respectively. Seven patients (70%) were implanted with continuous-flow devices and 3 with para-corporeal devices. Nine patients (90%) received heart transplant, with a median support duration of 77 days. Four (67%) out of 6 patients supported with discharge-capable devices were managed as outpatients. Post-transplant survival was 100%, with a median (range) follow up duration of 3.5 (1.8-11.9) years. There were 3 neurologic complications in 3 patients (0.9 events per patient-year); 2 intraoperative events (fatal hypoxia and symptomatic embolic stroke) and 1 postoperative (asymptomatic subarachnoid hemorrhage). Pump thrombosis occurred in one patient (0.3 events per patient-year), requiring pump exchange at day 65. Five patients (50%) received concomitant Fontan completion (fenestrated in 1). The Fontan-upgraded patients (vs Glenn) tended to be larger (median (range): 15.9 (12.6-22.9) vs 9.1 (7.7-22.8) kg), older (4.7 (3.1-6.5) vs 1.1 (0.9-10.1) years) and had a higher PaO 2 /FiO 2 ratio (192 (52-336) vs 76 (59-78) mm Hg) on postoperative day 1., Conclusion: Our experience suggests the feasibility of durable VAD support for failing Glenn circulation. Concomitant Fontan completion may be considered in select patients to improve oxygen delivery., Competing Interests: Disclosure statement IA: Serves as a consultant/proctor for Berlin Heart, Inc., Abbot Inc., Abiomed, Inc., Medtronic, Inc., Jarvik Inc., BiVACOR Inc., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Although ventricular failure is a late finding in adults with AC, we hypothesize that this is a presenting symptom in pediatric heart failure patients who undergo HT and that their ventricular arrhythmia burden could differentiate AC from other cardiomyopathies., Methods: We performed a single-center retrospective cohort study reviewing 457 consecutive pediatric (≤18 years) HT recipients at our institution. Explanted hearts were examined to establish the primary diagnosis, based on pathologic findings. Demographic and clinical variables were compared between AC versus non-HCM cardiomyopathy cases., Results: Forty-five percent (n = 205/457) had non-HCM cardiomyopathies as the underlying primary diagnosis. Ten cases (10/205 = 4.9%) were diagnosed with AC. All 10 had biventricular disease. In 8/10 patients (80%), AC diagnosis was unrecognized pre-HT. Compared with non-AC cardiomyopathies, the AC group was older at diagnosis (9.3 years vs. 4.3 years, p = .012) and transplant (11.1 years vs. 6.5 years, p = .010), had more ventricular arrhythmias (80.0% vs 32.8%, p = .003), and required more anti-arrhythmic use (80.0% vs 32.3%, p = .001). Genetic testing yielded causative pathogenic variants in all tested individuals (n = 5/5, 100%)., Conclusion: AC is often an unrecognized cardiomyopathy pretransplant in children who undergo HT. Pediatric non-HCM phenotypes with heart failure who have a significant ventricular arrhythmia burden should be investigated for AC., (© 2022 Wiley Periodicals LLC.)

Purpose of Review: While there have now been a variety of large reviews on adult pericarditis, this detailed review specifically focuses on the epidemiology, clinical presentation, diagnosis, and management of pediatric pericarditis. We have tried to highlight most pediatric studies conducted on this topic, with special inclusion of important adult studies that have shaped our understanding of and management for acute and recurrent pericarditis., Recent Findings: We find that the etiology of pediatric pericarditis differs from adult patients with pericarditis and has evolved over the years. Also, with the current COVID-19 pandemic, it is important for pediatric clinicians to be aware of pericardial involvement both due to the infection and from vaccination. Oftentimes, pericarditis maybe the only cardiac involvement in children with COVID-19, and so caregivers should maintain a high index of suspicion when they encounter children with pericarditis.  Large-scale contemporary epidemiological data regarding incidence and prevalence of both acute and recurrent pericarditis is lacking in pediatrics, and future studies should focus on highlighting this important research gap. Most of the current management strategies for pediatric pericarditis are from experiences gathered from adult data. Pediatric multicenter trials are warranted to understand the best management strategy for those with acute and recurrent pericarditis., Case Vignette: A 6-year-old child with a past history of pericarditis almost 2 months ago comes in with a 2-day history of chest pain and fever. Per mother, he stopped his steroids about 2 weeks ago, and for the last 2 days has had a temperature of 102F and has been complaining of sharp mid-sternal chest pain that gets worse when he lies down and is relieved when he sits up and leans forward. On examination, he is tachycardic (heart rate 160 bpm), with normal blood pressure for age. He appears to be in pain (5/10), and on auscultation has a pericardial friction rub. His lab studies are notable for elevated white blood cell count and inflammatory markers (CRP and ESR). His electrocardiogram reveals sinus tachycardia and diffuse ST-elevation in all precordial leads. His echocardiogram demonstrates normal biventricular function and a trace pericardial effusion. His cardiac MRI confirms recurrent pericarditis. He is started on indomethacin and colchicine. He has complete resolution of his symptoms by day 3 of admission and is discharged with close follow-up., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Serum chloride plays an important role in fluid homeostasis and is associated with impaired diuretic responsiveness and mortality in adults with heart failure (HF). We sought to characterize the relationship of serum chloride and diuretic efficiency (DE) and to determine its prognostic importance in children hospitalized with acute decompensated HF (ADHF). We studied DE, defined as net fluid output/kg+constant per mg of loop diuretic/kg, in 200 children hospitalized with ADHF. Median serum chloride at admission was 102 mmol/L (interquartile range 99 to 105 mmol/L), and hypochloremia (chloride ≤96 mmol/L) was present in 16% of the population at admission. Serum chloride correlated with serum sodium (r = 0.66; p < 0.001) and bicarbonate (r = -0.39; p < 0.001). In the adjusted analysis, lower chloride was associated with reduced DE (p < 0.001). Serum sodium was associated with DE on the unadjusted analysis; however, the association was eliminated when added to the model with chloride (p = 0.442). Lower chloride was also associated with features of inadequate decongestion during hospitalization: a positive fluid balance (p = 0.003), greater cumulative loop diuretic dose per weight (p = 0.001), addition of a thiazide diuretic during hospitalization (p < 0.001), less weight loss (p = 0.025), and longer length of stay (p = 0.003). Chloride concentration was independently associated with death or transplant 1 year after admission (hazard ratio 0.94; p < 0.001). As a dichotomous variable, hypochloremia was independently associated with reduced DE (p < 0.001) and decreased 1-year transplant-free survival (hazard ratio 2.3, p < 0.001). Lower serum chloride at hospital admission is strongly and independently associated with impaired DE and reduced transplant-free survival in children hospitalized with ADHF., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cardiac disease has emerged as a leading cause of mortality in Duchenne muscular dystrophy in the current era. This survey sought to identify the diagnostic and therapeutic approach to DMD among pediatric cardiologists in Advanced Cardiac Therapies Improving Outcomes Network. Pediatric cardiology providers within ACTION (a multi-center pediatric heart failure learning network) were surveyed regarding their approaches to cardiac care in DMD. Thirty-one providers from 23 centers responded. Cardiac MRI and Holter monitoring are routinely obtained, but the frequency of use and indications for ordering these tests varied widely. Angiotensin converting enzyme inhibitor and aldosterone antagonist are generally initiated prior to onset of systolic dysfunction, while the indications for initiating beta-blocker therapy vary more widely. Seventeen (55%) providers report their center has placed an implantable cardioverter defibrillator in at least 1 DMD patient, while 11 providers (35%) would not place an ICD for primary prevention in a DMD patient. Twenty-three providers (74%) would consider placement of a ventricular assist device (VAD) as destination therapy (n = 23, 74%) and three providers (10%) would consider a VAD only as bridge to transplant. Five providers (16%) would not consider VAD at their institution. Cardiac diagnostic and therapeutic approaches vary among ACTION centers, with notable variation present regarding the use of advanced therapies (ICD and VAD). The network is currently working to harmonize medical practices and optimize clinical care in an era of rapidly evolving outcomes and cardiac/skeletal muscle therapies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy and can predispose individuals to sudden death. Most pediatric HCM patients host a known pathogenic variant in a sarcomeric gene. With the increase in exome sequencing (ES) in clinical settings, incidental variants in HCM-associated genes are being identified more frequently. Diagnostic interpretation of incidental variants is crucial to enhance clinical patient management. We sought to use amino acid-level signal-to-noise (S:N) analysis to establish pathogenic hotspots in sarcomeric HCM-associated genes as well as to refine the 2015 American College of Medical Genetics (ACMG) criteria to predict incidental variant pathogenicity. Methods and Results: Incidental variants in HCM genes (MYBPC3, MYH7, MYL2, MYL3, ACTC1, TPM1, TNNT2, TNNI3, and TNNC1) were obtained from a clinical ES referral database (Baylor Genetics) and compared to rare population variants (gnomAD) and variants from HCM literature cohort studies. A subset of the ES cohort was clinically evaluated at Texas Children’s Hospital. We compared the frequency of ES and HCM variants at specific amino acid locations in coding regions to rare variants (MAF < 0.0001) in gnomAD. S:N ratios were calculated at the gene- and amino acid-level to identify pathogenic hotspots. ES cohort variants were re-classified using ACMG criteria with S:N analysis as a correlate for PM1 criteria, which reduced the burden of variants of uncertain significance. In the clinical validation cohort, the majority of probands with cardiomyopathy or family history hosted likely pathogenic or pathogenic variants. Conclusions: Incidental variants in HCM-associated genes were common among clinical ES referrals, although the majority were not disease-associated. Leveraging amino acid-level S:N as a clinical tool may improve the diagnostic discriminatory ability of ACMG criteria by identifying pathogenic hotspots.

Despite increasing utilization of continuous-flow pediatric ventricular assist devices (VAD) in children, data on exercise testing and cardiac rehabilitation (CR) are unknown. We described variation in CR practices and identified barriers to exercise testing and CR. A survey was performed through the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) representing pediatric VAD centers across North America. Descriptive statistics were performed. A multidisciplinary cohort of 52 respondents from 28 pediatric VAD centers responded. Although 38% reported performing exercise testing, most (65%) used 6 minute walk tests rather than formal cycle or treadmill exercise testing. While all respondents refer to physical therapy during the initial inpatient stay for VAD placement, only 52% refer to a CR program. When performed, CR was performed at an ACTION center (84%), a local specialized center (21%), or a home-based CR program (26%). Commonly cited barriers to either CR or exercise testing were inadequate resources, inadequate implementation logistics knowledge, concerns about safety, inability of patients to travel to a CR facility, and concern about utility of exercise testing or CR. Over 90% of centers were interested in implementing a standardized pediatric VAD CR program. Utilization of exercise testing and CR after VAD placement is variable. Despite perceived barriers, most pediatric VAD centers are interested in implementing a standardized CR program for recipients. In response to this interest, we plan to implement a standardized CR protocol to all ACTION pediatric VAD centers in an effort to improve pretransplant waitlist rehabilitation and post-transplant outcomes., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

Discharging children on ventricular assist device (VAD) support offers advantages for quality of life. We sought to describe discharge and readmission frequency in children on VAD support. All VAD-implanted patients aged 10-21 years at Advanced Cardiac Therapies Improving Outcomes Network (ACTION) centers were identified from the Pediatric Health Information System database (2009-2018). Discharge frequency on VAD was calculated. Patients discharged on VAD were compared with those not discharged. Freedom from readmission was assessed using the Kaplan-Meier method. A total of 298 VAD-implanted patients from 25 centers were identified, of which 163 (54.7%) were discharged. Discharges increased over time (36.9% [2009-2012] vs. 59.7% [2013-2018], p = 0.001). Of 144 discharged patients with follow-up, 96 (66.7%) were readmitted for reasons other than transplantation. Heart failure was the most common reason for readmission (27.7%), followed by infection (25.8%) and hematologic concerns (16.8%). In-hospital mortality on readmission was uncommon (1.8%) and the median length of stay was 6 days (interquartile range 2-19 days). Discharge of children on VAD support has increased over time, although variability exists across centers. Readmissions are common with diverse indications; however, the risk of mortality is low. Further interventions, including collaboration in ACTION, are critical to increasing discharges and optimizing outpatient management., Competing Interests: Disclosure: Dr. Zafar is a consultant for SynCardia and has received travel and accommodation funding from Abbott specifically for ACTION meetings. Dr. Lorts is a consultant for Abbott, Berlin Heart, and SynCardia, Inc. Dr. Conway has an unrestricted educational grant from Abbott. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2020.)

Background: TTN , the largest gene in the human body, encodes TTN (titin), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN , particularly truncating variants (TTNtvs), have been implicated in the pathogenicity of cardiomyopathy. Despite this link, there is also a high burden of TTNtvs in the ostensibly healthy general population. This complicates the diagnostic interpretation of incidentally identified TTNtvs, which are of increasing abundance given expanding clinical exome sequencing., Methods: Incidentally identified TTNtvs were obtained from a large referral database of clinical exome sequencing (Baylor Genetics) and compared with rare population variants from genome aggregation database and cardiomyopathy-associated variants from cohort studies in the literature. A subset of TTNtv-positive children evaluated for cardiomyopathy at Texas Children's Hospital was retrospectively reviewed for clinical features of cardiomyopathy. Amino acid-level signal-to-noise analysis was performed., Results: Pathological hotspots were identified within the A-band and N-terminal I-band that closely correlated with regions of high percent-spliced in of exons. Incidental TTNtvs and population TTNtvs did not localize to these regions. Variants were reclassified based on current American College of Medical Genetics and Genomics criteria with incorporation of signal-to-noise analysis among Texas Children's Hospital cases. Those reclassified as likely pathogenic or pathogenic were more likely to have evidence of cardiomyopathy on echocardiography than those reclassified as variants of unknown significance., Conclusions: Incidentally found TTNtvs are common among clinical exome sequencing referrals. Pathological hotspots within the A-band of TTN may be informative in determining variant pathogenicity when incorporated into current American College of Medical Genetics and Genomics guidelines.

Durable ventricular assist devices (VADs) have significantly improved survival to transplantation among children with advanced stages of heart failure. The fundamental goals of VAD therapy include decreasing mortality, minimizing adverse events, and improving quality of life. As the pediatric VAD experience has evolved with reduced device related complications and improved survival, VAD therapy is being considered not only as a bridge to transplantation (BTT) but also as a bridge to decision (BTD) and as destination therapy (DT). Data regarding pediatric DT VAD are limited to anecdotal or case reports of children being supported for long periods with VADs and by default being classified as DT VAD. This article reviews current trends in the use of DT VAD and adverse events in children vs adults on VAD, and provides a framework for patient selection with the use of a multidisciplinary approach including palliative care. The general approach to determining DT VAD candidacy should include: 1) a reasonable success that the patient will survive the peri- and postoperative state; and 2) a high likelihood that the patient will be able to be discharged out of hospital and have adequate caregiver support. Patients with muscular dystrophy and failing Fontan physiology are examples of pediatric populations for whom DT VAD may be considered and which require unique considerations., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Loop diuretics are considered first-line therapy for congestion in children with heart failure, although some patients remain volume overloaded during treatment. We sought to characterize loop diuretic responsiveness (DR) in children hospitalized with acute decompensated failure and to determine whether a decreased response was associated with worse outcomes., Methods and Results: DR was calculated for 108 consecutive children ˂21 years of age who were hospitalized with acute decompensated heart failure. DR was defined as net fluid (mL) output per 1 mg of furosemide equivalents during the first 72 hours of treatment with a loop diuretic. The primary outcome was the composite end point of inpatient death or use of mechanical circulatory support. The median DR was 6.0 mL/mg (interquartile range -2.4 to 15.7 mL/mg). Thirty-two percent of patients remained in a positive fluid balance after 72 hours of treatment with a loop diuretic. Death or use of mechanical circulatory support occurred in 29 patients (27%). Low DR was associated with the composite end point, even after adjusting for net urine output and loop diuretic dose indexed to weight (odds ratio 5.3; P = .003). Patients with low DR also experienced longer length of hospital stay than patients with greater DR (median 33 days vs 11 days; P = .002)., Conclusion: In children hospitalized with acute decompensated heart failure, early diminished loop DR during decongestion therapy is common and portends a poor prognosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Predictors of right ventricle (RV) dysfunction after continuous-flow left ventricular assist device (CF-LVAD) implantation in children are not well described. We explored the association of preimplantation Pulmonary Artery Pulsatility index (PAPi) and other hemodynamic parameters as predictors of prolonged postoperative inotropes/pulmonary vasodilator use after CF-LVAD implantation., Design: Retrospective chart review., Setting: Single tertiary care pediatric referral center., Patients: Patients who underwent CF-LVAD implantation from January 2012 to October 2017., Interventions: Preimplantation invasive hemodynamic parameters were analyzed to evaluate the association with post-CF-LVAD need for prolonged (>72 hours) use of inotropes/pulmonary vasodilators., Measurements and Main Results: Preimplantation cardiac catheterization data was available for 12 of 44 patients who underwent CF-LVAD implant during the study period. Median (IQR) age and BSA of the cohort were 15.3 years (10.2, 18) and 1.74 m 2 (0.98, 2.03). Group 1 (n = 6) included patients with need for prolonged inotropes/pulmonary vasodilator use after CF-LVAD implantation and Group 2 (n = 6) included those without. Baseline demographic parameters, cardiopulmonary bypass time, and markers of RV afterload (pulmonary vascular resistance, PA compliance and elastance) were similar among the two groups. PAPi was significantly lower in group 1 compared to group 2 (0.96 vs 3.6, respectively; P = .004). Post-LVAD stay in the intensive care unit was longer for patients in group 1 (46 vs 23 days, P = .52). Brain natriuretic peptide was significantly higher at 3 months after implantation in group 1; P = .01., Conclusions: The need for inotropes/pulmonary vasodilators in the postoperative period can be predicted by the preimplantation intrinsic RV contractile reserve as assessed by PAPi rather than the markers of RV afterload. Further investigation and correlation with clinical outcomes is needed., (© 2019 Wiley Periodicals, Inc.)

The objective of this study is to report a benign mesenchymal neoplasm, cellular angiofibroma. We describe a 34-year-old male with a 4-month history of a painless right inguinal mass. CT scan of the abdomen and pelvis showed a 6.6 cm, oval-shaped mass without any distinguishing radiographical features. Surgical excision of the mass was performed. Tissue was extracted for immunohistochemical analysis, which stained positive for CD34 and Desmin, confirming cellular angiofibroma of the spermatic cord. Thus, this report highlights the importance of a challenging diagnostic case for providers due to the narrow range of imaging modalities and therefore limited treatment options., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: With expanding use of clinical whole exome sequencing (WES), genetic variants of uncertain significance are increasingly identified. As pathologic mutations in genes associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) carry a risk of sudden death, determining the diagnostic relevance of incidentally identified variants associated with these genes is critical., Methods: WES variants from a large, predominantly pediatric cohort (N = 7,066 probands) were obtained for nine ARVC-associated genes (Baylor Miraca). For comparison, a control cohort was derived from the gnomAD database and an ARVC case cohort (N = 1,379 probands) was established from ARVC cases in the literature. Topologic mapping was performed and signal-to-noise analysis was conducted normalizing WES, or case variants, against control variant frequencies. Retrospective chart review was performed of WES cases evaluated clinically (Texas Children's Hospital)., Results: Incidentally identified variants occurred in 14% of WES referrals and localized to genes which were rare among ARVC cases yet similar to controls. Amino acid-level signal-to-noise analysis of cases demonstrated "pathologic hotspots" localizing to critical domains of PKP2 and DSG2 while WES variants did not. PKP2 ARM7 and ARM8 domains and DSG2 N-terminal cadherin-repeat domains demonstrated high pathogenicity while normalized WES variant frequency was low. Review of clinical data available on WES referrals demonstrated none with evidence of ARVC among variant-positive individuals., Conclusions: Incidentally identified variants are common among pediatric WES testing with gene frequencies similar to "background" variants. Incidentally identified variants are unlikely to be pathologic., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Background: Our institutional policy is to continue centrifugal-flow ventricular assist device support for 3 months or more without activation on the transplant wait-list for physical recovery and assessment of possible myocardial recovery. We evaluated our single-institutional outcomes with centrifugal-flow ventricular assist device support in children., Methods: Prospectively collected outcomes data in consecutive patients aged 18 years or less with centrifugal-flow ventricular assist device support were reviewed., Results: There were 40 implantations in 39 patients (28 with cardiomyopathy, 11 with congenital heart disease, including 3 with univentricular physiology). The median support was 8 months (range, 1-79), with 13 patients (33%) supported for 12 months or more and a cumulative duration of 41 patient-years. The median age and weight at implantation were 11 (4-18) years and 35 (14-98) kg, respectively. The median body surface area was 1.1 (0.7-2.2) m 2 , with 16 patients (40%) having a body surface area less than 1.0 m 2 . Thirty-four patients (85%) had Interagency Registry for Mechanically Assisted Circulatory Support 1 or 2. Children with congenital heart disease were significantly smaller (P < .01) and had more prior cardiac interventions (P < .01) than those with cardiomyopathy. There were 2 early mortalities (5%) in children with cardiomyopathy. Of the 38 patients with successful implantations, 36 (95%) were discharged home and managed as outpatients. Overall adverse event rates were 5.1 (bleeding), 0.8 (device malfunction), 6.1 (infection), 3.9 (neurologic dysfunction), and 1.0 (renal dysfunction) (per 100 patient-month). In the 21 patients with cardiomyopathy supported for 3 months or more, 5 (24%) experienced normalization of left ventricular function; 4 underwent successful explantation, and 1 remains on support., Conclusions: This study demonstrates favorable outcomes of centrifugal-flow ventricular assist device support in children, including those with congenital heart disease, with an increased incidence of cardiac recovery., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: Elevated central venous pressure (CVP) has deleterious effects on several organ systems in patients with Fontan circulation. However, the relationship between CVP and estimated glomerular filtration rate (eGFR) has not been assessed in patients with Fontan circulation., Methods: Patients with Fontan circulation whose hemodynamics were assessed by catheterization between 1987 and 2015 and had a serum creatinine measured within 72 hours prior to the procedure were included for analysis. Patients with primary kidney disease were excluded. Renal function was calculated by "bedside Schwartz" equation in children (< 18 years) and Modification of Diet in Renal Disease equation in adults. Renal dysfunction (RD) was defined by eGFR < 90mL/min/1.73m 2 . Fontan patients with and without RD were compared based on demographics, co-morbidities, medication use, echocardiographic findings, hemodynamics assessed at time of catheterization, and laboratory testing values., Results: Sixty-seven patients with Fontan circulation met inclusion criteria and 15 patients (22%) had RD; eGFR (mL/min/1.73m 2 ) was 60-89in 13 (87%), 45-59in 1 (7%), and 30-45in 1 (7%). Compared to patients with eGFR equal to or greater than 90, patients with RD had higher CVP (18.0 [15.0-21.0] mm Hg vs 13.5 [12.3-16.0] mm Hg (P = 0.001), lower pulmonary blood flow 2.2 [1.9-2.6] L/min/m 2 vs 2.8 [2.3-3.7] L/min/m 2 , higher ventricular end-diastolic pressure 10.5 [7.0-17.3] mm Hg vs 8.0 [6.0-10.0] mm Hg (P = 0.050), were more likely to have worse atrioventricular valve regurgitation (P = 0.02) and were more likely to be African American (P = 0.009)., Conclusions: In this study population, renal dysfunction in patients with Fontan circulation is associated with increased CVP and factors that affect CVP. African Americans with Fontan circulation may be at particular risk for renal dysfunction. Continued investigation of the effects of venous congestion on kidneys and other factors associated with renal dysfunction in patients with Fontan circulation is warranted., (© 2018 Wiley Periodicals, Inc.)

The field of paediatric ventricular assist device (VAD) support is growing rapidly. Among paediatric patients, those with complex congenital heart disease represent a challenging population for VAD support. This report describes a patient with a remote history of an arterial switch operation for d-transposition of the great arteries who developed ischaemic cardiomyopathy necessitating centrifugal-flow VAD support as a bridge to cardiac transplantation. Because of the unique anatomy and the complicated vascular situation, implantation of the centrifugal-flow VAD and subsequent explantation for cardiac transplantation required modifications to the standard surgical approach. The details of surgical pitfalls encountered are described.

Graft rejection is the most common factor that limits graft survival after transplantation. During infancy, the humoral immune system is partially suppressed and humoral rejection of a cardiac allograft has not been reported in the absence of risk factors such as prior transplantation, blood transfusions, ventricular assist devices, and elevation of panel reactive antibodies. We present a case of an infant with dilated cardiomyopathy who developed multiple episodes of acute humoral rejection after heart transplantation in the absence of risk factors., (© 2018 Wiley Periodicals, Inc.)

Chemotherapy-induced cardiotoxicity in adults and children is a topic with a growing interest in the cardiology literature. The ability to detect cardiac dysfunction in a timely manner is essential in order to begin adequate treatment and prevent further deterioration. This article aims to provide a review on the myocardial injury process, chemotherapeutic agents that lead to cardiotoxicity, the definition of cardiotoxicity, and the methods of timely detection and treatment., (© 2017 Wiley Periodicals, Inc.)

Purpose: Female urethral reconstruction can be used successfully to treat a heterogeneous group of urethral disorders through an expanding number of unique approaches. Understanding the diverse etiologies of female urethral stricture and loss is essential in evaluating and diagnosing patients. Although there is an appreciable body of literature addressing female urethral reconstruction individually, there is a paucity of resources that approach this issue holistically. We discuss the relevant female urethral anatomy, pathophysiology, diagnosis and evaluation of female urethral disorders, and current reconstructive techniques, as well as published outcomes data and potential future directions for female urethral reconstruction., Materials and Methods: We reviewed articles published in English and indexed in the PubMed®, Embase® and Google Scholar™ databases, and consulted textbooks. Key search terms used were female, urethra, urethral reconstruction, urethroplasty, pathology, stricture, vaginal flap, bladder flap, graft, dilation, pubovaginal sling, catheterization, imaging, tissue engineering and bioscaffold. We created a synopsis of relevant articles, including original research studies and reviews., Results: Urethral tissue loss and strictures are caused by traumatic injuries, iatrogenic injuries and, rarely, infections and malignancies. A comprehensive patient history and physical examination are critical for diagnosis. Flexible cystoscopy, voiding cystourethrography and endovaginal magnetic resonance imaging can help to determine the surgical method of repair. Minimally invasive approaches to female urethral reconstruction are associated with poor outcomes. Definitive treatment options for repair of female urethral stricture include vaginal flap/wall urethroplasty, graft urethroplasty and distal urethrectomy with advancement meatoplasty. Repair techniques for urethral loss include primary closure, vaginal flap/wall urethroplasty and bladder flap urethroplasty. Vaginal flap approaches with well vascularized grafts and buccal mucosal grafts have high success rates. Tissue engineered grafts are being investigated as a novel treatment modality., Conclusions: Female urethral reconstruction is complex, and one must carefully evaluate patients afflicted with urethral disorders. Urethral stricture and urethral loss have different etiologies. Variations of a standard approach might best address the condition of an individual patient. Long-term outcomes data are not available for contemporary techniques of female urethral reconstruction. The highest success rates have been reported with vaginal flap and buccal mucosal graft urethroplasty. Further studies focusing on newer reconstruction techniques and long-term outcomes are warranted., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Urinary incontinence in women has a high prevalence and causes significant morbidity. Given that urinary incontinence is not generally a progressive disease, conservative therapies play an integral part in the management of these patients. We conducted a nonsystematic review of the literature to identify high-quality studies that evaluated the different components of conservative management of stress urinary incontinence, including behavioral therapy, bladder training, pelvic floor muscle training, lifestyle changes, mechanical devices, vaginal cones, and electrical stimulation. Urinary incontinence can have a severe impact on our healthcare system and patients' quality of life. There are currently a wide variety of treatment options for these patients, ranging from conservative treatment to surgical treatment. Although further research is required in the area of conservative therapies, nonsurgical treatments are effective and are preferred by some patients.

The inflammatory myofibroblastic tumor (IMT) is a rare benign tumor, known by several names and found in several locations throughout the body, including the lungs and genitourinary system (mostly the bladder). We report a case of a paratesticular IMT in a 17-year-old boy. Although the initial clinical diagnosis was rhabdomyosarcoma, the histopathologic examination revealed it to be an IMT. The preoperative diagnosis of a scrotal mass should differentiate between benign and malignant tumors. A definitive diagnosis of a scrotal mass should be established by surgical exploration and resection. It is important to counsel patients with scrotal masses regarding the possibility of orchiectomy, even in the case of a benign tumor such as IMT., (Copyright © 2011 Elsevier Inc. All rights reserved.)