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Bright debris discs can contain large amounts of CO gas. This gas was thought to be a protoplanetary remnant until it was recently shown that it could be released in collisions of volatile-rich solids. As CO is released, interstellar UV radiation photodissociates CO producing CI, which can shield CO allowing a large CO mass to accumulate. However, this picture was challenged because CI is inefficient at shielding if CO and CI are vertically mixed. Here, we study for the first time the vertical evolution of gas to determine how vertical mixing affects the efficiency of shielding by CI. We present a 1D model that accounts for gas release, photodissociation, ionisation, viscous evolution, and vertical mixing due to turbulent diffusion. We find that if the gas surface density is high and the vertical diffusion weak ($\alpha_{\rm v}/\alpha[H/r]^2$) CI and CO become well mixed, shortening the CO lifetime. Moreover, diffusion could also limit the amount of dust settling. High-resolution ALMA observations could resolve the vertical distribution of CO and CI, and thus constrain vertical mixing and the efficiency of CI shielding. We also find that the CO and CI scale heights may not be good probes of the mean molecular weight, and thus composition, of the gas. Finally, we show that if mixing is strong the CO lifetime might not be long enough for CO to spread interior to the planetesimal belt where gas is produced., Comment: Accepted for publication in MNRAS (18 pages, 14 figures)

Background: The World Health Organization acknowledges quality of life (QOL) as subjectively perceived overall well-being by the individual and recognizes it as an essential construct for overall health and wellness. The purpose of this study was to examine the association of infant, environmental, and parental factors with the QOL of mothers of infants at four months post-hospital discharge from cardiac surgery. Methods: Secondary analysis of prospectively collected data from the REACH randomized clinical trial of telehealth home monitoring. The sample included mothers (n = 148) of infants with congenital heart disease who provided data at four months post-discharge. Ten imputations were generated using fully conditional specification methods to address missing data and were combined. All analyses were performed on the imputed data. Mothers’ QOL was the main outcome of the analysis, as measured by the Ulm Quality of Life Inventory for Parents. Predictors on QOL were identified based on the World Health Organization QOL framework which recognizes the multidimensional domains influencing QOL that include personal factors, environmental factors, and physical factors related to disease and functioning. Results: The treatment and control groups did not differ on any study variable, thus data were collapsed and analyzed together. Final multivariable model found that the combination of dyadic adjustment, social support, parenting stress, and post-traumatic stress symptoms explained approximately three-quarters of the variance in QOL scores. Conclusions: QOL for mothers of infants with congenital heart disease is largely influenced by psychosocial factors. Future research targeted toward improving maternal QOL should include psychosocial interventions that address social networks and stress.

Stellar binaries represent a substantial fraction of stellar systems, especially among young stellar objects. Accordingly, binaries play an important role in setting the architecture of a large number of protoplanetary discs. Binaries in coplanar and polar orientations with respect to the circumbinary disc are stable configurations and could induce non-axisymmetric structures in the dust and gas distributions. In this work, we suggest that the structures shown in the central region of the protoplanetary disc HD 169142 are produced by the presence of an inner stellar binary and a circumbinary (P-type) planet. We find that a companion with a mass-ratio of 0.1, semi-major axis of 9.9 au, eccentricity of 0.2, and inclination of 90{\deg}, together with a 2 Jupiter Mass coplanar planet on a circular orbit at 45 au reproduce the structures at the innermost ring observed at 1.3 mm and the shape of spiral features in scattered light observations. The model predicts changes in the disc's dust structure, and star's astrometric parameters, which would allow testing its veracity by monitoring this system over the next 20 years., Comment: 11 pages, 7 figures, accepted for publication in MNRAS

Lung cancer maintains a relatively small survival rate (~19%) over a 5-year period and up to 80–85% of all lung cancer diagnoses are Non-Small Cell Lung Cancer (NSCLC). To determine whether metformin reduces non-small cell lung cancer (NSCLC) LL/2 cell growth, cells were grown in vitro and treated with metformin for 48 h. qPCR was used to assess genes related to cell cycle regulation and pro-apoptotic markers, namely Cyclin D, CDK4, p27, p21, and HES1. Treatment with 10 mM metformin significantly reduced HES1 expression (p = 0.011). Furthermore, 10 mM metformin treatment significantly decreased REDD1 (p = 0.0082) and increased p-mTOR Ser2448 (p = 0.003) protein expression. Control cells showed significant reductions in phosphorylated p53 protein expression (p = 0.0367), whereas metformin treated cells exhibited reduced total p53 protein expression (p = 0.0078). There were no significant reductions in AMPK, PKB/AKT, or STAT3. In addition, NSCLC cells were treated for 48 h. with 10 mM metformin, 4 µM gamma-secretase inhibitor (GSI), or the combination of metformin (10 mM) and GSI (4 µM) to determine the contribution of respective signaling pathways. Metformin treatment significantly reduced total nucleus expression of the proliferation maker Ki-67 with an above 65% reduction in Ki-67 expression between control and metformin-treated cells (p = 0.0021). GSI (4 µM) treatment significantly reduced Ki-67 expression by ~20% over 48 h (p = 0.0028). Combination treatment (10 mM metformin and 4 µM GSI) significantly reduced Ki-67 expression by more than 50% over 48 h (p = 0.0245). As such, direct administration of metformin (10 mM for 48 h) proved to be an effective pharmaceutical agent in reducing the proliferation of cultured non-small cell cancer cells. These intriguing in vitro results, therefore, support the further study of metformin in appropriate in vivo models as an anti-oncogenic agent and/or an adjunctive therapy.

Muscular flaps may represent a valid treatment option for prosthetic infection after knee arthroplasty.We present the results of 20 consecutive patients treated with the use of medial gastrocnemius flap for the management of different types of injuries or integumentary defects after total knee arthroplasty. Tissue necrosis or dehiscence occurred within 1 and 2 months after arthroplasty. The mean follow-up was 23.4 (12-60) months. Clinical outcome was evaluated according to the infection control rate and post-operative Knee Society Score (KSS).Prosthesis salvage and complete restoration of skin coverage were achieved in all patients. Functional assessment was performed using the KSS score. The final knee KSS score was classified as excellent (score: 80-100) in 0 patients, good (score: 70-79) in 17 patients, fair (score: 60-69) in 2 patients, and poor (score: 60) in 1 patient. Residual Extension Deficit: 0-20°; Very Satisfactory in 17 patients. 30-70° Satisfactory in 2 patients, 80-90° Unsatisfactory in 1 patient. Patients who successfully underwent flap treatment experienced a much greater increase in both components of the KSS score.The results highlight the effectiveness of medial gastrocnemius muscular flap for the treatment of prosthetic knee infection, in terms of function, limb salvage, cost-effectiveness and post-surgery quality of life. Further larger studies may consolidate these findings.

Proximal periprosthetic femoral fractures (PPFFs) are gradually increasing and surgical management is often associated with high risk of complications, due to elderly population and associated comorbidities.We retrospectively assessed 39 patients at least at 2-years follow-up. We identified two study groups, similar for demographic data. Group A included patients surgically treated without involving prosthetic implants, whereas Group B included patients in which an implant revision was performed.Data were recorded from January 2017 to February 2020, and 39 patients were included: 30 females (76.9%) and 9 males (23.1%), with a confirmed diagnosis of periprosthetic fracture of the proximal femur. 23 (58.9%) patients were treated with Open Reduction and Internal Fixation (ORIF), 12 (30.7%) with revision surgery and 4 (10.3%) were treated by modular megaprosthesis.The treatment options considered in the study, revision arthroplasty and internal fixation had shown no significant differences as a matter of clinical outcomes and postoperative complications.

$\kappa$CrB is a ${\sim}2.5\,$Gyr old K1 sub-giant star, with an eccentric exo-Jupiter at ${\sim}2.8\,$au and a debris disc at tens of au. We present ALMA Band 6 ($1.3\,$mm) and HST scattered light ($0.6\,\mu$m) images, demonstrating $\kappa$CrB's broad debris disc, covering an extent $50{-}180\,$au in the millimetre (peaking at $110\,$au), and $51{-}280\,$au in scattered light (peaking at $73\,$au). By modelling the millimetre emission, we estimate the dust mass as ${\sim}0.016\,M{\oplus}$, and constrain lower-limit planetesimal sizes as $D_{\rm{max}}{>}1\,$km and the planetesimal belt mass as $M_{\rm{disc}}{>}1\,M_{\oplus}$. We constrain the properties of an outer body causing a linear trend in 17 years of radial velocity data to have a semi-major axis $8{-}66\,$au and a mass $(0.4{-}120)\,M_{\rm{Jup}}$. There is a large inner cavity seen in the millimetre emission, which we show is consistent with carving by such an outer massive companion with a string of lower mass planets. Our scattered light modelling shows that the dust must have a high anisotropic scattering factor ($g{\sim}0.8{-}0.9$) but an inclination ($i{\sim}30{-}40\,$degrees) that is inferred to be significantly lower than the $i{\sim}61\,$degrees millimetre inclination. The origin of such a discrepancy is unclear, but could be caused by a misalignment in the micron and millimetre sized dust. We place an upper limit on the CO gas mass of $M_{\rm{CO}}{, Comment: Accepted for publication in MNRAS. 21 pages, 14 figures

Hypothesis: We hypothesized that a single regimen of no or limited diuretics post-discharge after pediatric cardiac surgery for patients with two ventricles is not inferior to prolonged diuretics for prevention of readmission for pleural effusion. Material and Methods: A prospective, one-armed, safety non-inferiority trial with historical controls was performed at a single center, quaternary, children’s hospital. Inclusion criteria were children aged 3 months to 18 years after pediatric cardiac surgery resulting in a two- ventricle repair between 7/2020 and 7/2021. Eligible patients were compared with patients from a five-year historical period (selected using a database search). The intervention was that “regular risk” patients received no diuretics and pre-specified “high risk” patients received five days of twice per day furosemide at discharge. Results: 61 subjects received the intervention. None were readmitted for pleural effusions, though 1 subject was treated for a symptomatic pleural effusion with outpatient furosemide. The study was halted after an interim analysis demonstrated that 4 subjects were readmitted with pericardial effusion during the study period versus 2 during the historical control (2.9% versus 0.2%, p = 0.003). Conclusions: We found no evidence that limited post-discharge diuretics results in an increase in readmissions for pleural effusions. This conclusion is limited as not enough subjects were enrolled to definitively show that this strategy is not inferior to the historical practice. There was a small, but statistically significant, increase in readmissions for pericardial effusions after implementation of this study protocol.

Truncus arteriosus is a congenital heart defect with high resource use, cost, and mortality. Value assessment (outcome relative to cost) can improve quality of care and decrease cost. This study hypothesized that truncus arteriosus repair at a high-volume center would result in better outcomes at lower cost (higher value) compared with a low-volume center.This study retrospectively analyzed a multicenter cohort of neonates undergoing truncus arteriosus repair (2004 to 2015) by using the Pediatric Health Information Systems database. Multivariate quantile, logistic, and negative binomial regression models were used to evaluate total hospital cost, in-hospital mortality, ventilation days, intensive care unit length of stay (LOS), hospital LOS, and days of inotropic agent use by center volume (high-volume3/year) and age at repair while adjusting for sex, ethnicity, race, genetic abnormality, prematurity, low birth weight, concurrent interrupted arch repair, and truncal valve repair.Of 1024 neonates with truncus arteriosus, 495 (48%) were treated at high-volume centers. Costs at the 75th percentile were lower at high-volume vs low-volume centers by $28,456 (P = .02) at all ages at repair. Patients at high-volume centers had lower median postoperative ventilation days (5 days vs 6 days; P.001), intensive care unit LOS (13 days vs 19 days; P.001), hospital LOS (23 days vs 28 days; P = .02), and inotropic agent use (3 days vs 4 days; P = .004). In-hospital mortality did not differ by center volume.In neonates undergoing truncus arteriosus repair, costs are lower and outcomes are better at high-volume centers, thus resulting in higher value at all ages of repair. Value-based interventions should be considered to improve outcomes and decrease cost in truncus arteriosus care.

The Neurodevelopmental and Psychological Outcomes Working Group of the Cardiac Neurodevelopmental Outcome Collaborative was formed in 2018 through support from an R13 grant from the National Heart, Lung, and Blood Institute with the goals of identifying knowledge gaps regarding the neurodevelopmental and psychological outcomes of individuals with CHD and investigations needed to advance science, policy, clinical care, and patient/family outcomes. Accurate characterisation of neurodevelopmental and psychological outcomes in children with CHD will drive improvements in patient and family outcomes through targeted intervention. Decades of research have produced a generalised perspective about neurodevelopmental and psychological outcomes in this heterogeneous population. Future investigations need to shift towards improving methods, measurement, and analyses of outcomes to better inform early identification, prevention, and intervention. Improved definition of underlying developmental, neuropsychological, and social-emotional constructs is needed, with an emphasis on symptom networks and dimensions. Identification of clinically meaningful outcomes that are most important to key stakeholders, including patients, families, schools and providers, is essential, specifically how and which neurodevelopmental differences across the developmental trajectory impact stakeholders. A better understanding of the discontinuity and patterns of neurodevelopment across the lifespan is critical as well, with some areas being more impactful at some ages than others. Finally, the field needs to account for the impact of race/ethnicity, socio-economic status, cultural and linguistic diversity on our measurement, interpretation of data, and approach to intervention and how to improve generalisability to the larger worldwide population of patients and families living with CHD.

In 2018, the Neurodevelopmental and Psychosocial Interventions Working Group of the Cardiac Neurodevelopmental Outcome Collaborative convened through support from an R13 grant from the National Heart, Lung, and Blood Institute to survey the state of neurodevelopmental and psychosocial intervention research in congenital heart disease and to propose a slate of critical questions and investigations required to improve outcomes for this growing population of survivors and their families. Prior research, although limited, suggests that individualized developmental care interventions delivered early in life are beneficial for improving a range of outcomes including feeding, motor and cognitive development, and physiological regulation. Interventions to address self-regulatory, cognitive, and social-emotional challenges have shown promise in other medical populations yet their applicability and effectiveness for use in individuals with congenital heart disease have not been examined. To move this field of research forward, we must strive to better understand the impact of neurodevelopmental and psychosocial intervention within the congenital heart disease population including adapting existing interventions for individuals with congenital heart disease. We must examine the ways in which dedicated cardiac neurodevelopmental follow-up programs bolster resilience and support children and families through the myriad transitions inherent to the experience of living with congenital heart disease. And we must ensure that interventions are person-/family-centered, inclusive of individuals from diverse cultural backgrounds as well as those with genetic/medical comorbidities, and proactive in their efforts to include individuals who are at highest risk but who may be traditionally less likely to participate in intervention trials.

OBJECTIVES We leveraged decomposition analysis, commonly used in labor economics, to understand determinants of cost differences related to location of admission in children undergoing neonatal congenital heart surgery. DESIGN A retrospective cohort study. SETTING Pediatric Health Information Systems database. PATIENTS Neonates (

There are currently limited accurate national estimates for pediatric heart failure (HF).This study aims to describe the current burden of primary and comorbid pediatric HF in the United States.International Classification of Diseases, Clinical Modification codes were used to identify HF cases and comorbidities from the Kids' Inpatient Database, National Inpatient Sample, National Emergency Department (ED) Sample, and National Vital Statistics System for 2012 and 2016. To describe HF events, all visits/events among pediatric and adult subjects were included in the analysis. HF events were classified into 1 of 3 groups: 1) no HF; 2) primary HF; or 3) comorbid HF. We compared patients with and without HF and calculated unique event rates with age and sex standardization.Congenital heart disease, conduction disorders/arrhythmias, and cardiomyopathy were responsible for the majority of pediatric HF-related ED visits and hospitalizations. Compared to 2012, in 2016, there was an increase in comorbid HF ED visits (rate ratio: 1.93; P 0.001) and primary HF hospitalizations (rate ratio: 1.14; P = 0.002). Pediatric HF burden was lower compared to adult HF; however, deaths in the ED and in-hospital were significantly more likely in children presenting with HF than adults.The burden of pediatric HF continues to increase. Compared to adults with HF presenting to the ED and in-hospital, outcomes are inferior and per patient resource use is higher for children hospitalized with HF. National initiatives to understand risk factors for morbidity and mortality in pediatric HF and continued surveillance and mitigation of preventable risk factors may attenuate this uptrend.

Critical theory

Cardiac magnetic resonance (CMR) provides tissue characterization and structural and functional data. CMR has high sensitivity and specificity for myocarditis in adults and children. The relationship between pediatric CMR use, cost, and clinical outcome has not been studied.This work aims to describe temporal trends in CMR imaging for pediatric myocarditis and examine associations between CMR use, hospital cost, and outcomes.A retrospective cohort study of all inpatients 21 years of age with a diagnosis of myocarditis reported to the Pediatric Health Information System (2004-2019) was performed. Trends in CMR use were examined. A propensity-matched subcohort using center and patient level variables was used to assess whether outcomes differed by CMR use.A total of 4,195 children with myocarditis from 47 hospitals were identified. The median age was 11.5 years (IQR: 1.5-16.0 years) and 2,617 (62%) were male. CMR was used in 23% and mortality occurred in 6%. CMR use during hospitalization increased from 2% in 2004 to 37% in 2019 (odds ratio [OR]: 1.19 [95% CI: 1.17-1.21]). After propensity score matching, CMR use was associated with higher median cost (+$5,340 [95% CI: +$1,739 to +$9,936]) and similar median length of stay (0 days [95% CI: -1 to +1 days]). Using quantile regression, CMR was associated with lower 90th percentile cost (-$77,200 [95% CI: -$127,373 to -$31,339]). More children receiving CMR were discharged alive in the first 30 days after admission (OR: 1.89 days [95% CI: 1.28-2.29]). Within the propensity matched cohort, 10 of 790 CMR recipients died compared to 42 of 790 in the non-CMR group.CMR use in children with myocarditis has increased over the past 15 years. CMR use is associated with higher cost of hospitalization and similar length of stay for most children but lower cost among the sickest children. CMR use in specific patients may improve clinical outcomes at a lower cost.

Introduction: Safety of vigorous exercise for individuals with appropriately-treated HCM remains debated. Physical activity practices in this population have not been described. The objective of this report is to describe physical activity pattern in HCM patients. Long term follow up which is ongoing will determine safety of vigorous exercise. Methods: The NIH-funded LIVE-HCM study prospectively enrolled individuals age 8-60 years with clinically overt HCM or patients with a positive genetic test for sarcomeric HCM. Participants (or parents, for children) answered surveys describing activity patterns. Vigorous exercise was defined as > 6 METS for > 60 hours per year. Clinical and demographic data were derived from medical record review. Results: Among 1798 participants, 745 (41%) reported exercising vigorously, including 296 competitive athletes, with 59 at high-school or college varsity level, 770 (43%) were exercising at moderate, and 283 (16%) at low levels. Of those working, 6% described jobs more active than walking, including 16 in protective services, and 11 in sports/coaching. Clinical/demographic data including imaging characteristics and treatments, are shown in Table, and were mostly similar amongst the exercise-groups. Conclusions: Many patients with HCM are engaged in vigorous exercise including competitive athletics. Prospective follow-up of this cohort is ongoing. Comparison of arrhythmic outcomes outcomes in vigorous exercisers vs moderate/low level exercisers will help determine the safety of exercise in HCM patients.

Background and Objectives:Little data exist on provider perspectives about counselling and shared decision-making for complex CHD, ways to support and improve the process, and barriers to effective communication. The goal of this qualitative study was to determine providers’ perspectives regarding factors that are integral to shared decision-making with parents faced with complex CHD in their fetus or newborn; and barriers and facilitators to engaging in effective shared decision-making.Methods:We conducted semi-structured interviews with providers from different areas of practice who care for fetuses and/or children with CHD. Providers were recruited from four geographically diverse centres. Interviews were recorded, transcribed, and analysed for key themes using an open coding process with a grounded theory approach.Results:Interviews were conducted with 31 providers; paediatric cardiologists (n = 7) were the largest group represented, followed by nurses (n = 6) and palliative care providers (n = 5). Key barriers to communication with parents that providers identified included variability among providers themselves, factors that influenced parental comprehension or understanding, discrepant expectations, circumstantial barriers, and trust/relationship with providers. When discussing informational needs of parents, providers focused on comprehensive short- and long-term outcomes, quality of life, and breadth and depth that aligned with parental goals and needs. In discussing resources to support shared decision-making, providers emphasised the need for comprehensive, up-to-date information that was accessible to parents of varying situations and backgrounds.Conclusions:Provider perspectives on decision-making with families with CHD highlighted key communication issues, informational priorities, and components of decision support that can enhance shared decision-making.

Non-small-cell lung cancer (NSCLC) makes up 80–85% of lung cancer diagnoses. Lung cancer patients undergo surgical procedures, chemotherapy, and/or radiation. Chemotherapy and radiation can induce deleterious systemic side effects, particularly within skeletal muscle. To determine whether metformin reduces NSCLC tumor burden while maintaining skeletal muscle health, C57BL/6J mice were injected with Lewis lung cancer (LL/2), containing a bioluminescent reporter for in vivo tracking, into the left lung. Control and metformin (250 mg/kg) groups received treatments twice weekly. Skeletal muscle was analyzed for changes in genes and proteins related to inflammation, muscle mass, and metabolism. The LL/2 model effectively mimics lung cancer growth and tumor burden. The in vivo data indicate that metformin as administered was not associated with significant improvement in tumor burden in this immunocompetent NSCLC model. Additionally, metformin was not associated with significant changes in key tumor cell division and inflammation markers, or improved skeletal muscle health. Metformin treatment, while exhibiting anti-neoplastic characteristics in many cancers, appears not to be an appropriate monotherapy for NSCLC tumor growth in vivo. Future studies should pursue co-treatment modalities, with metformin as a potentially supportive drug rather than a monotherapy to mitigate cancer progression.

The autoregulation of cerebral blood flow protects against brain injury from transient fluctuations in arterial blood pressure. Impaired autoregulation may contribute to hypoperfusion injury in neonates and infants. Monitoring cerebral autoregulation in neonatal cardiac surgery as a guide for arterial blood pressure management may reduce neurodevelopmental morbidity. Cerebral autoregulation monitoring has been validated in animal models and in an adult trial autoregulation monitoring during bypass improved postoperative delirium scores. The nuances of pediatric cardiac disease and congenital heart surgery make simply applying adult trial findings to this unique population inappropriate. Therefore, dedicated pediatric clinical trials of cerebral autoregulation monitoring are indicated.

The congenital heart care community faces a myriad of public health issues that act as barriers toward optimum patient outcomes. In this article, we attempt to define advocacy and policy initiatives meant to spotlight and potentially address these challenges. Issues are organized into the following 3 key facets of our community: patient population, health care delivery, and workforce. We discuss the social determinants of health and health care disparities that affect patients in the community that require the attention of policy makers. Furthermore, we highlight the many needs of the growing adults with congenital heart disease and those with comorbidities, highlighting concerns regarding the inequities in access to cardiac care and the need for multidisciplinary care. We also recognize the problems of transparency in outcomes reporting and the promising application of telehealth. Finally, we highlight the training of providers, measures of productivity, diversity in the workforce, and the importance of patient–family centered organizations in advocating for patients. Although all of these issues remain relevant to many subspecialties in medicine, this article attempts to illustrate the unique needs of this population and highlight ways in which to work together to address important opportunities for change in the cardiac care community and beyond. This article provides a framework for policy and advocacy efforts for the next decade.

To outline key elements in providing compassionate end-of-life care for pediatric patients with end-stage heart failure on mechanical circulatory support (MCS) such as extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs). Approximately one in five pediatric patients with end-stage heart failure die on VAD support, with higher mortality associated with patients supported on ECMO. While it is considered ethically and legally permissible to withdraw MCS, pediatric-specific guidelines regarding indications and end-of-life management on MCS are lacking. A multidisciplinary approach with early consultation of the palliative care team is essential for all patients being considered for MCS. Guiding families through end-of-life care on MCS requires frequent and honest communication by engaging in shared decision-making regarding prognosis and potential clinical pathways, advanced care and preparedness planning, and identifying and meeting patients’/families’ goals of care.

Recent years have seen an exponential increase in the variety of healthcare data captured across numerous sources. However, mechanisms to leverage these data sources to support scientific investigation have remained limited. In 2013 the Pediatric Heart Network (PHN), funded by the National Heart, Lung, and Blood Institute, developed the Integrated CARdiac Data and Outcomes (iCARD) Collaborative with the goals of leveraging available data sources to aid in efficiently planning and conducting PHN studies; supporting integration of PHN data with other sources to foster novel research otherwise not possible; and mentoring young investigators in these areas. This review describes lessons learned through the development of iCARD, initial efforts and scientific output, challenges, and future directions. This information can aid in the use and optimisation of data integration methodologies across other research networks and organisations.

Mental disorders are the predominant chronic diseases of youth, with substantial life span morbidity and mortality. A wealth of evidence demonstrates that the neurodevelopmental roots of common mental health problems are present in early childhood. Unfortunately, this has not been translated to systematic strategies for improving population-level mental health at this most malleable neurodevelopmental period. We lay out a translational Mental Health, Earlier road map as a key future direction for prevention of mental disorder. This paradigm shift aims to reduce population attributable risk of mental disorder emanating from early life, by preventing, attenuating, or delaying onset/course of chronic psychopathology via the promotion of self-regulation in early childhood within large-scale health care delivery systems. The Earlier Pillar rests on a "science of when to worry" that (a) optimizes clinical assessment methods for characterizing probabilistic clinical risk beginning in infancy via deliberate incorporation of neurodevelopmental heterogeneity, and (b) universal primary-care-based screening targeting patterns of dysregulated irritability as a robust transdiagnostic marker of vulnerability to life span mental health problems. The core of the Healthier Pillar is provision of low-intensity selective intervention promoting self-regulation for young children with developmentally atypical patterns of irritability within an implementation science framework in pediatric primary care to ensure highest population impact and sustainability. These Mental Health, Earlier strategies hold much promise for transforming clinical outlooks and ensuring young children's mental health and well-being in a manner that reverberates throughout the life span.

Neurodevelopmental and psychosocial impairments negatively impact health-related quality of life for survivors with CHD and complicate the transition to independent adulthood. Risk for neurodevelopmental and psychosocial impairments is influenced by a complex interplay among genetic, foetal, surgical, perioperative, family, and social factors, requiring a multi-pronged approach to neuroprotection and intervention. To ensure future research can ultimately reduce the burden of CHD for individuals, families, and society, the most pressing issues in cardiac neurodevelopment requiring scientific investigation must be identified.Through funding from an R13 Grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health of the United States of America, the Cardiac Neurodevelopmental Outcome Collaborative convened a two-day meeting of international experts in cardiac neurodevelopmental and psychosocial research, clinical care, and health disparities, including patient and family stakeholders, to define the cardiac neurodevelopmental and psychosocial outcomes research agenda for the next decade. Seven multidisciplinary working groups were formed to address key domains crucial to the advancement of cardiac neurodevelopmental and psychosocial outcomes research: 1) Foetal Brain Development and Neuroprotection, 2) Surgical/Perioperative Neuroprotection and Neurodevelopment, 3) Characterization of Neurodevelopmental and Psychological Outcomes, 4) Neurodevelopmental and Psychosocial Intervention, 5) Parent Mental Health and Family Functioning, 6) Neurodevelopmental Education, Outreach and Advocacy, and 7) Health Disparities and Neurodevelopmental Outcomes. Working groups identified significant gaps in knowledge and critical questions that must be answered to further knowledge, policy, care, and outcomes. The development of a research agenda in cardiac neurodevelopmental and psychosocial outcomes is critical for informing collaborative initiatives and allocation of funding for research to scientific inquiries of highest value to key stakeholders.

Diagnosis of CHD substantially affects parent mental health and family functioning, thereby influencing child neurodevelopmental and psychosocial outcomes. Recognition of the need to proactively support parent mental health and family functioning following cardiac diagnosis to promote psychosocial adaptation has increased substantially over recent years. However, significant gaps in knowledge remain and families continue to report critical unmet psychosocial needs. TheParent Mental Health and Family Functioning Working Groupof the Cardiac Neurodevelopmental Outcome Collaborative was formed in 2018 through support from an R13 grant from the National Heart, Lung, and Blood Institute to identify significant knowledge gaps related to parent mental health and family functioning, as well as critical questions that must be answered to further knowledge, policy, care, and outcomes. Conceptually driven investigations are needed to identify parent mental health and family functioning factors with the strongest influence on child outcomes, to obtain a deeper understanding of the biomarkers associated with these factors, and to better understand how parent mental health and family functioning influence child outcomes over time. Investigations are also needed to develop, test, and implement sustainable models of mental health screening and assessment, as well as effective interventions to optimise parent mental health and family functioning to promote psychosocial adaptation. The critical questions and investigations outlined in this paper provide a roadmap for future research to close gaps in knowledge, improve care, and promote positive outcomes for families of children with CHD.

It has been demonstrated that inhibiting Notch signaling through γ-secretase inhibitor (GSI) treatment increases myogenesis, AKT/mTOR signaling, and muscle protein synthesis (MPS) in C2C12 myotubes. The purpose of this study was to determine if GSI-mediated effects on myogenesis and MPS are dependent on AKT/mTOR signaling. C2C12 cells were assessed for indices of myotube formation, anabolic signaling, and MPS following GSI treatment in combination with rapamycin and API-1, inhibitors of mTOR and AKT, respectively. GSI treatment increased several indices of myotube fusion and MPS in C2C12 myotubes. GSI-mediated effects on myotube formation and fusion were completely negated by treatment with rapamycin and API-1. Meanwhile, GSI treatment was able to rescue MPS in C2C12 myotubes exposed to rapamycin or rapamycin combined with API-1. Examination of protein expression revealed that GSI treatment was able to rescue pGSK3β Ser9 despite AKT inhibition by API-1. These findings demonstrate that GSI treatment is able to rescue MPS independent of AKT/mTOR signaling, possibly via GSK3β modulation.

Introduction: Racial/ethnic differences in CVH beginning at age 8 have been identified and linked with the development of cardiometabolic disease in adulthood; however, there is scarce research on CVH in very childhood. Our objective was to use a large, diverse pediatric EHR consortium to identify racial/ethnic patterns of clinical CVH from ages 2-12 years. Methods: We used ambulatory visit data spanning 2010-2018 from children aged 2-12 years within CAPriCORN - an EHR repository that combines medical records throughout the city of Chicago. The 4 clinical CVH metrics - BMI, blood pressure, cholesterol, and glucose - were categorized as ideal or non-ideal using available values of weight, height, blood pressure, laboratory readings, and ICD diagnosis codes. Multiple measurements within a given integer age were averaged by individual. Frequency of ideal and non-ideal status for each CVH metric was plotted by age in years and stratified by race/ethnicity (Figure). Results: There were 162,621 children included (47% female) with a median of 2 visits during follow-up. The race/ethnicity distribution was 4% Asian/Pacific Islander (API), 26% non-Hispanic Black (NHB), 44% non-Hispanic white (NHW), 18% Hispanic, and 8% other/unknown. Sustained decrease in ideal BMI occurred across race/ethnicity groups; however, proportion in ideal was consistently lower for NHB and Hispanic children. Ideal BP appeared to increase across childhood with few racial differences. Ideal cholesterol levels were constant across childhood, but the proportion of NHW children in ideal was lower than NHB and Hispanic children. Almost all individuals had ideal glucose levels throughout early childhood. Conclusions: Early childhood declines in CVH appeared to be driven by changes in ideal BMI. Racial/ethnic differences in ideal BMI and cholesterol were present by age 2 and were mostly sustained through age 12. Selection bias may account for some of these findings; consistent monitoring in early childhood is needed to better understand observed differences.