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There is significant uncertainty in describing prognosis and a lack of reliable entry criteria for palliative care studies in children with advanced heart disease (AHD). This study evaluates the utility of the surprise question-"Would you be surprised if this child died within the next year?"-to predict one-year mortality in children with AHD and assess its utility as entry criteria for future trials. This is a prospective cohort study of physicians and nurses caring for children (1 month-19 years) with AHD hospitalized ≥ 7 days. AHD was defined as single ventricle physiology, pulmonary vein stenosis or pulmonary hypertension, or any cardiac diagnosis with signs of advanced disease. Primary physicians were asked the surprise question and medical record review was performed. Forty-nine physicians responded to the surprise question for 152 patients. Physicians responded "No, I would not be surprised if this patient died" for 54 (36%) patients, 20 (37%) of whom died within 1 year, predicting one-year mortality with 77% sensitivity, 73% specificity, 37% positive predictive value, and 94% negative predictive value. Patients who received a "No" response had an increased 1-year risk of death (hazard ratio 7.25, p 0.001). Physician years of experience, subspecialty, and self-rated competency were not associated with the accuracy of the surprise question. The surprise question offers promise as a bedside screening tool to identify children with AHD at high risk for mortality and help physicians identify patients who may benefit from palliative care and advance care planning discussions.

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.

Purpose: We sought to establish whether nucleated red blood cells (NRBCs) are predictive of disposition, morbidity, and mortality for pediatric patients presenting to the emergency department (ED).Methods: A single center retrospective cohort study examining all ED encounters from patientsResults: The prevalence of NRBCs was 8.9% (4,195/46,991 patient encounters). Patient with NRBCs were younger (median age 4.58 vs 8.23 years; PConclusions: Presence of NRBCs is an independent predictor for mortality, including in-hospital mortality, ICU admission, CPR, and readmission within 30 days for children presenting to the ED.

Pneumatosis intestinalis (PI) is a rare complication after thoracic organ transplantation. There are several theories for explaining the pathophysiology of this disease. In this paper, we highlight three cases of PI in a single pediatric center, one after lung transplantation and two after heart transplantation. Although the presentations differed, all cases improved with non-surgical therapies. There are not many articles in the pediatric literature about post-transplantation PI, and there are still many questions regarding the incidence, etiology, and treatment for this disease.

Cardiac disease results in significant morbidity and mortality in patients with muscular dystrophy (MD). Single centers have reported their ventricular assist device (VAD) experience in specific MDs and in limited numbers. This study sought to describe the outcomes associated with VAD therapy in an unselected population across multiple centers.We examined outcomes of patients with MD and dilated cardiomyopathy implanted with a VAD at Advanced Cardiac Therapies Improving Outcomes Network (ACTION) centers from 9/2012 to 9/2020.A total of 19 VADs were implanted in 18 patients across 12 sites. The majority of patients had dystrophinopathy (66%) and the median age at implant was 17.2 years (range 11.7-29.5). Eleven patients were non-ambulatory (61%) and 6 (33%) were on respiratory support pre-VAD. Five (28%) patients were implanted as a bridge to transplant, 4 of whom survived to transplant. Of 13 patients implanted as bridge to decision or destination therapy, 77% were alive at 1 year and 69% at 2 years. The overall frequencies of positive outcome (transplanted or alive on device) at 1 year and 2 years were 84% and 78%, respectively. Two patients suffered a stroke, 2 developed sepsis, 1 required tracheostomy, and 1 experienced severe right heart failure requiring right-sided VAD.This study demonstrates the potential utility of VAD therapies in patients with muscular dystrophy. Further research is needed to further improve outcomes and better determine which patients may benefit most from VAD therapy in terms of survival and quality of life.

We describe waiting times for pediatric heart transplant (HT) candidates after the 2016 revision to the US allocation policy. The OPTN database was queried for pediatric HT candidates listed between 7/2016 and 4/2019. Of the 1789 included candidates, 65% underwent HT, 14% died/deteriorated, 8% were removed for improvement, and 13% were still waiting at the end of follow-up. Most candidates were status 1A at HT (81%). Median wait times differ substantially by listing status, blood type, and recipient weight. The likelihood of HT was lower in candidates25 kg and in those with blood type O; The25 kg, blood type O subgroup experiences longer wait times and higher wait list mortality. For status 1A candidates, median wait times were 108 days (≤25 kg, blood type O), 80 days (≤25 kg, non-O), 47 days (25 kg, O), and 24 days (25 kg, non-O). We found that centers with more selective organ acceptance practices, based on a lower median Pediatric Heart Donor Assessment Tool (PH-DAT) score for completed transplants, experience longer status 1A wait times for their listed patients. These data can be used to counsel families and to select appropriate advanced heart failure therapies to support patients to transplant.

OBJECTIVE: To characterize viscoelastic testing profiles of children with multisystem inflammatory syndrome in children (MIS-C). METHODS: This single-center retrospective review included 30 patients diagnosed with MIS-C from March 1 to September 1, 2020. Thromboelastography (TEG) with platelet mapping was performed in 19 (63%) patients and compared to age- and sex-matched controls prior to cardiac surgery. Relationships between TEG parameters and inflammatory markers were assessed using correlation. RESULTS: Patients with MIS-C had abnormal TEG results compared to controls, including decreased kinetic (K) time (1.1 vs. 1.7 minutes, p

Objective: To characterize viscoelastic testing profiles of children with multisystem inflammatory syndrome in children (MIS-C). Methods: This single-center retrospective review included 30 patients diagnosed with MIS-C from January 1 to September 1, 2020. Thromboelastography (TEG) with platelet mapping was performed in 19 (63%) patients and compared to age- and gender- matched controls via Student’s t-test and Wilcoxon rank sum test. Pearson’s and Spearman correlation were used to assess relationships between TEG parameters and inflammatory markers. Results: Patients with MIS-C had abnormal TEG results compared to controls, including decreased K time (1.1 vs. 1.7 min, P

Purpose Pulmonary arterial catheters (PAC) provide real-time hemodynamic data that has been used to tailor ICU therapies, aid in surgical decision making in adults with ADHF and in predicting right-heart failure (RHF) in adults undergoing LVAD evaluation. Approximately 1/3 of patients develop RVF after LVAD insertion. Patients who required rescue RVAD have increased mortality when compared to planned BiVAD implantation. Right ventricular stroke work index (RVSWI) has been demonstrated to predict RHF in adults. Prediction of RHF and data on use of PAC in children are limited. Methods Pediatric patients with ADHF and biventricular circulation undergoing PAC placement at Boston Children's Hospital from 2013 through 2018 were included in this retrospective cohort study. Data were collected as part of an ongoing QI project. Variables predictive of RVF in adults undergoing LVAD implantation were compared between patients with and without RHF. Pedimacs definition of RHF was used for post-VAD patients: RV dysfunction requiring inotropic support at 14 days. Results Thirteen PAC were placed in 11 patients, aged 2 to 18 years old, with biventricular circulation and ADHF. Eight patients had DCM, 2 had CHD and one RCM. Nine PAC were placed to aid in pre-VAD decision making. One to assess awake hemodynamics for transplant candidacy, and one was placed at the time of OHT. Nine PAC were placed by catheterization and 4 in the OR. Mean duration of PAC monitoring was 3.7 days (0.4 to 9.3 days). RVSWI alone was able to significantly predict post-LVAD RVF. All patients free from RVF post-LVAD implantation were discharged home before OHT, at an average or 27 +/-4 days. No patients with RVF reached discharge before transplantation. There were 2 AEs possibly related to the presence of a PAC, including one episode of hemodynamically well-tolerated EAT and one episode of slow VT. Conclusion PAC use in pediatrics is feasible with low rates of adverse events. Low pre-implantation RVSWI was associated with RHF after LVAD implantation. All patients undergoing LVAD implantation with no RHF were discharged home while every patient with RHF remained hospitalized until RVAD implantation or OHT. Arrhythmias occurred in two patients PACs. Though both were hemodynamically stable lines were removed, illustrating the opportunity for managing staff in optimum use of PACs.

Objectives: To evaluate different refractive cutoffs for spectacle provision with regards to their impact on visual improvement and spectacle compliance. Design: Prospective study of visual improvement and spectacle compliance. Participants: South African school children aged 6–19 years receiving free spectacles in a programme supported by Helen Keller International. Methods: Refractive error, age, gender, urban versus rural residence, presenting and best-corrected vision were recorded for participants. Spectacle wear was observed directly at an unannounced follow-up examination 4–11 months after initial provision of spectacles. The association between five proposed refractive cutoff protocols and visual improvement and spectacle compliance were examined in separate multivariate models. Main outcomes: Refractive cutoffs for spectacle distribution which would effectively identify children with improved vision, and those more likely to comply with spectacle wear. Results: Among 8520 children screened, 810 (9.5%) received spectacles, of whom 636 (79%) were aged 10–14 years, 530 (65%) were girls, 324 (40%) had vision improvement ⩾3 lines, and 483 (60%) were examined 6.4±1.5 (range 4.6 to 10.9) months after spectacle dispensing. Among examined children, 149 (31%) were wearing or carrying their glasses. Children meeting cutoffs ⩽−0.75D of myopia, ⩾+1.00 D of hyperopia and ⩾+0.75 D of astigmatism had significantly greater improvement in vision than children failing to meet these criteria, when adjusting for age, gender and urban versus rural residence. None of the proposed refractive protocols discriminated between children wearing and not wearing spectacles. Presenting vision and improvement in vision were unassociated with subsequent spectacle wear, but girls (p⩽0.0006 for all models) were more likely to be wearing glasses than were boys. Conclusions: To the best of our knowledge, this is the first suggested refractive cutoff for glasses dispensing validated with respect to key programme outcomes. The lack of association between spectacle retention and either refractive error or vision may have been due to the relatively modest degree of refractive error in this African population.

Pluripotent embryonic stem cells (ESCs) undergo self-renewal until stimulated to differentiate along specific lineage pathways. Many of the transcriptional networks that drive reprogramming of a self-renewing ESC to a differentiating cell have been identified. However, fundamental questions remain unanswered about the epigenetic programs that control these changes in gene expression. Here we report that the histone ubiquitin hydrolase ubiquitin-specific protease 22 (USP22) is a critical epigenetic modifier that controls this transition from self-renewal to differentiation. USP22 is induced as ESCs differentiate and is necessary for differentiation into all three germ layers. We further report that USP22 is a transcriptional repressor of the locus encoding the core pluripotency factor sex-determining region Y-box 2 (SOX2) in ESCs, and this repression is required for efficient differentiation. USP22 occupies the Sox2 promoter and hydrolyzes monoubiquitin from ubiquitylated histone H2B and blocks transcription of the Sox2 locus. Our study reveals an epigenetic mechanism that represses the core pluripotency transcriptional network in ESCs, allowing ESCs to transition from a state of self-renewal into lineage-specific differentiation programs. Background: Ubiquitin-specific protease 22 (USP22) is a deubiquitylating enzyme with established biological functions in cancer cells. Results: USP22 drives differentiation of embryonic stem cells (ESCs) and represses sex-determining region Y-box 2 (SOX2) transcription. Conclusion: USP22 is induced during ESC differentiation to repress SOX2 transcription. Significance: Understanding the epigenetic programs that control changes in gene expression during the transition from self-renewal to differentiation.

Direct conversion of fibroblasts to induced cardiomyocytes (iCMs) has great potential for regenerative medicine. Recent publications have reported significant progress, but the evaluation of reprogramming has relied upon non-functional measures such as flow cytometry for cardiomyocyte markers or GFP expression driven by a cardiomyocyte-specific promoter. The issue is one of practicality: the most stringent measures – electrophysiology to detect cell excitation and the presence of spontaneously contracting myocytes – are not readily quantifiable in the large numbers of cells screened in reprogramming experiments. However, excitation and contraction are linked by a third functional characteristic of cardiomyocytes: the rhythmic oscillation of intracellular calcium levels. We set out to optimize direct conversion of fibroblasts to iCMs with a quantifiable calcium reporter to rapidly assess functional transdifferentiation. We constructed a reporter system in which the calcium indicator GCaMP is driven by the cardiomyocyte-specific Troponin T promoter. Using calcium activity as our primary outcome measure, we compared several published combinations of transcription factors along with novel combinations in mouse embryonic fibroblasts. The most effective combination consisted of Hand2, Nkx2.5, Gata4, Mef2c, and Tbx5 (HNGMT). This combination is >50-fold more efficient than GMT alone and produces iCMs with cardiomyocyte marker expression, robust calcium oscillation, and spontaneous beating that persist for weeks following inactivation of reprogramming factors. HNGMT is also significantly more effective than previously published factor combinations for the transdifferentiation of adult mouse cardiac fibroblasts to iCMs. Quantification of calcium function is a convenient and effective means for the identification and evaluation of cardiomyocytes generated by direct reprogramming. Using this stringent outcome measure, we conclude that HNGMT produces iCMs more efficiently than previously published methods.

PURPOSE. To study the prevalence and determinants of compliance with spectacle wear among school-age children in Oaxaca, Mexico, who were provided spectacles free of charge. METHODS. A cohort of 493 children aged 5 to 18 years chosen by random cluster sampling from primary and secondary schools in Oaxaca, Mexico, all of whom had received free spectacles through a local program, underwent unannounced, direct examination to determine compliance with spectacle wear within 18 months after initial provision of spectacles. Potential determinants of spectacle wear including age, gender, urban versus rural residence, presenting visual acuity, refractive error, and time since dispensing of the spectacles were examined in univariate and multivariate regression models. Children not currently wearing their spectacles were asked to select the reason from a list of possibilities, and reasons for noncompliance were analyzed within different demographic groups. RESULTS. Among this sample of children with a mean age of 10.4 2.6 years, the majority (74.5%) of whom were myopic (spherical equivalent [SE] 0.50 D), 13.4% (66/493) were wearing their spectacles at the time of examination. An additional 34% (169/493) had the spectacles with them but were not wearing them. In regression models, the odds of spectacle wear were significantly higher among younger (OR 1.19 per year of age; 95% CI, 1.05‐1.33) rural (OR 10.6; 95% CI, 5.3‐21.0) children and those with myopia 1.25 D (OR 3.97; 95% CI, 1.98‐7.94). The oldest children and children in urban‐suburban areas were significantly more likely to list concerns about the appearance of the glasses or about being teased than were younger, rurally resident children. CONCLUSIONS. Compliance with spectacle wear may be very low, even when spectacles are provided free of charge, particularly among older, urban children, who have been shown in many populations to have the highest prevalence of myopia. As screening programs for refractive error become increasingly common throughout the world, new strategies are needed to improve compliance if program resources are to be maximized. (Invest Ophthalmol Vis Sci. 2006;47:925‐928)