Cerebral infarction and risk factors in acute type A aortic dissection with arch branch extension.

OBJECTIVE: Stanford type A aortic dissection (AAD) may affect the supra-aortic arteries, which are associated with acute ischemic stroke (AIS) or transient ischemic attack (TIA). This study aimed to investigate cerebral perfusion, the infarction incidence and risk factors in AAD patients. METHODS: A total of 156 consecutive AAD patients were enrolled and divided into two groups according to whether the aortic arch branches were involved: the affected group (n = 90) and the unaffected group (n = 66). Clinical, echocardiographic/carotid Doppler data and cerebral infarction morbidity were compared between the groups. Independent predictors of 30-day AAD mortality were identified through multivariable Cox regression, and perioperative risk factors were analyzed. RESULTS: In total, 57.7% of AAD patients had aortic arch branch involvement. Abnormal Doppler waveforms were more common in the affected group (p < 0.05). Regarding intracranial perfusion, the blood flow volumes (BFVs) of the bilateral internal carotid arteries (ICAs) and right vertebral artery (RVA) in the affected group were significantly reduced (p < 0.05). The incidence of cerebral infarction in the affected group was significantly higher than that in the unaffected group (35.6% vs. 19.7%, p = 0.031). Multivariable analysis revealed that age >45 years old, right internal carotid artery (RICA) involvement and reduced left ventricular ejection fraction (LVEF) were significant predictors of perioperative death. CONCLUSIONS: Aortic arch branch involvement is common in patients with AAD and is associated with reduced cerebral blood flow (especially on the right side) and a higher incidence of cerebral infarction. Age, extension of the RICA dissection and LVEF impairment are independent risk factors for AAD-related death.

Retrograde flow in aortic isthmus in normal and fetal heart disease by principal component analysis and computational fluid dynamics.

OBJECTIVES: Reverse flow Retrograde flow (RF) of blood in the aortic isthmus can be observed in different types of fetal heart disease (FHD), including abnormalities in heart structure and function. This study sought to investigate the relationship between RF and blood flow parameters, and develop a computational fluid dynamics (CFD) model to understand the mechanisms underlying this observation. MATERIAL AND METHODS: A total of 281 fetuses (gestational age [GA] 26.6±.3 weeks) with FHD and 2803 normal fetuses (GA: 26.1±.1 weeks) by fetal echocardiography collected from May 2016 to December 2018. Principal component analysis (PCA) was performed to find the relationship and the CFD model reconstructed from 3D/4D spatio-temporal image correlation (STIC) images to simulate hemodynamics. RESULTS: There was a significant difference in the percentages of RF between the study (80/201 (39%)) and control (29/2803 (1%)) groups (p < 0.05). The RF occur when the aorta flow rate (left heart) is reduced to 60% by CFD stimulation. Pearson correlation analysis showed significant correlations between flow rate and wall shear stress(WSS) (r = .883, p = 0.047) variables at the AI. CONCLUSION: Volumetric flow rate of AO or left heart was the main component of the cause of RF. The hemodynamics of the cardiovascular system have highly complex behavior hinge on the turbulent nature of circulating blood flow.

Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan, China: Prevalence, Risk Factors, and Outcome.

BACKGROUND: To investigate deep vein thrombosis (DVT) in hospitalized patients with coronavirus disease 2019 (COVID-19), we performed a single institutional study to evaluate its prevalence, risk factors, prognosis, and potential thromboprophylaxis strategies in a large referral and treatment center. METHODS: We studied a total of 143 patients with COVID-19 from January 29, 2020 to February 29, 2020. Demographic and clinical data, laboratory data, including ultrasound scans of the lower extremities, and outcome variables were obtained, and comparisons were made between groups with and without DVT. RESULTS: Of the 143 patients hospitalized with COVID-19 (age 63±14 years, 74 [51.7%] men), 66 patients developed lower extremity DVT (46.1%: 23 [34.8%] with proximal DVT and 43 [65.2%] with distal DVT). Compared with patients who did not have DVT, patients with DVT were older and had a lower oxygenation index, a higher rate of cardiac injury, and worse prognosis, including an increased proportion of deaths (23 [34.8%] versus 9 [11.7%]; P=0.001) and a decreased proportion of patients discharged (32 [48.5%] versus 60 [77.9%]; P<0.001). Multivariant analysis showed an association only between CURB-65 (confusion status, urea, respiratory rate, and blood pressure) score 3 to 5 (odds ratio, 6.122; P=0.031), Padua prediction score ≥4 (odds ratio, 4.016; P=0.04), D-dimer >1.0 µg/mL (odds ratio, 5.818; P<0.014), and DVT in this cohort, respectively. The combination of a CURB-65 score 3 to 5, a Padua prediction score ≥4, and D-dimer >1.0 µg/mL has a sensitivity of 88.52% and a specificity of 61.43% for screening for DVT. In the subgroup of patients with a Padua prediction score ≥4 and whose ultrasound scans were performed >72 hours after admission, DVT was present in 18 (34.0%) patients in the subgroup receiving venous thromboembolism prophylaxis versus 35 (66.0%) patients in the nonprophylaxis group (P=0.010). CONCLUSIONS: The prevalence of DVT is high and is associated with adverse outcomes in hospitalized patients with COVID-19. Prophylaxis for venous thromboembolism may be protective in patients with a Padua protection score ≥4 after admission. Our data seem to suggest that COVID-19 is probably an additional risk factor for DVT in hospitalized patients.

Prenatal diagnosis of caudal regression with heterotaxy syndrome: "A mermaid with a broken heart".

Caudal regression syndrome (CRS) is a rare congenital malformation with varying degrees of early gestational developmental failure. It is characterized by agenesis of the sacrum and lumbar spine, with lower limb neurological deficit and accompanying deformities of the pelvis, lower extremities, genitourinary, and gastrointestinal systems. We report a case of CRS associated with rare complex congenital heart defect, that is, heterotaxy syndrome, diagnosed prenatally.

Comparison of prenatal ultrasound and postmortem findings in fetuses with common pulmonary vein atresia.

BACKGROUND: The previous literature on common pulmonary vein atresia (CPVA) mainly consists of neonatal case reports. There is a lack of research on the prenatal diagnosis of CPVA. METHODS: We conducted a retrospective study of all fetuses with CPVA confirmed by autopsy between August 2010 and May 2018. Prenatal echocardiographic features, autopsy findings, and genetic test results were analyzed. We compared fetal CPVA with total anomalous pulmonary venous return (TAPVR) and neonatal CPVA. RESULTS: During the study period, fetal echocardiography was performed on 31 617 fetuses. Six cases of CPVA were identified by autopsies, including 1 case performed with a cardiovascular cast. All 6 cases (100%) had asplenia syndrome (AS) and bilateral superior vena cava (BSVC). In 1 case (16.7%), the prenatal ultrasound results were in complete agreement with the postmortem findings. Four cases (66.7%) were misdiagnosed as TAPVR by prenatal echocardiography. For the remaining case (16.7%), no pulmonary venous anomalies were detected on prenatal echocardiography. No aneuploidy was identified in any of the cases. There were no statistically significant differences among the proportions of associated complex anomalies and AS between the fetal CPVA and TAPVR groups. The proportion of associated complex anomalies and AS in the fetal CPVA group was higher than that in the neonatal group (P < 0.05). CONCLUSIONS: Prenatal diagnosis of fetal CPVA is difficult and challenging even for experts. Our study showed that fetal CPVA is often combined with AS, complex cardiac malformations, and BSVC. These findings may help in the diagnosis of fetal CPVA.

Isolated premature restriction or closure of foramen ovale in fetuses: Echocardiographic characteristics and outcome.

BACKGROUND: Premature restriction or closure of foramen ovale (FO) in otherwise structurally normal hearts may be associated with right ventricular dilation, tricuspid regurgitation, pericardial effusion, heart failure, even poor perinatal outcomes. Data about these rare conditions are lacking. METHODS: We retrospectively reviewed the echocardiographic records of 9704 fetuses seen from 2010 to 2014 in Beijing Anzhen Hospital, a regional and national referral center, to ascertain the presence of restriction or closure of FO. We collected the fetal echocardiography and perinatal outcome data for this group of fetuses with restriction or closure of FO. RESULTS: In this large, single-institution cohort (n = 9704), 6707 fetuses seen between 23 and 37 weeks of gestation had normal heart structures; of these, 60 (0.89%) had restrictive FO (rFO) and 5 (0.07%) had closure of FO (cFO). Fetal echocardiographic images showed right atrial dilation in 48 (73.84%), right ventricular dilation in 38 (58.46%), tricuspid regurgitation in 19 (29.23%), and pericardial effusion in 10 (15.38%). Also in this group, 50 (83.3%) with rFO and 4 (80.0%) with cFO had follow-up data. No prenatal deaths occurred in either the rFO or the cFO group, but the neonatal mortality included 1 in the rFO group and 2 in the cFO group. CONCLUSION: Premature rFO/cFO are rare in fetuses with otherwise structurally normal hearts. The fetal echocardiographic characteristics include right atrial and ventricular dilated, tricuspid regurgitation, and pericardial effusion. Most fetuses had a good outcome, although there was an association between rFO, especially cFO, with neonatal morality and complications (prematurity, maternal preeclampsia and placental abruption, hydrops fetalis, and necrotizing enterocolitis with perforation).

Introduction: From fetal echocardiography to fetal cardiology: A journey of over half a century.

In this Special Issue of the Journal, 8 review articles that represent the new developments and applications of fetal echocardiography and fetal cardiology for diagnosis, prognosis, and treatment of fetal cardiovascular disease are included. The goal was to provide an updated review of the evidence for the current and emerging use of fetal echocardiography and cardiac magnetic resonance, improved diagnosis of challenging congenital heart disease, new tools for evaluation of fetal systolic and diastolic function, better prognosis and risk stratification of newborns with congenital heart diseases, and new and promising therapies for fetuses with cardiovascular disease.

Prenatal diagnosis of total anomalous pulmonary venous connection by 2D and 3D fetal echocardiography.

OBJECTIVE: Prenatal diagnosis of total anomalous pulmonary venous connection (TAPVC) by fetal echocardiography (FE) remains a challenge. We sought to ascertain the diagnostic accuracy of 2D and 3D spatiotemporal image correlation (STIC) FE and the potential incremental value of 3D STIC FE for prenatal diagnosis and assessment of TAPVC. METHODS: This study was conducted retrospectively in a single tertiary referral center. The study population consisted of 74 TAPVC from 17 063 fetuses by FE from August 2010 to April 2016. The 3D volume acquisition was also performed by STIC. RESULTS: A total of 17 063 fetal echocardiograms in our institution were queried and 74 (0.4%) were identified with TAPVC. In the TAPVC group, 11 had postnatal echocardiographic study, 25 had autopsies, 36 declined autopsy and 2 lost for follow-up. The sensitivity of FE for diagnosis of TAPVC was 97.14%, specificity 99.98%, respectively. In our cohort, 31 fetuses were evaluated by both 2D and 3D STIC and were confirmed by postnatal echocardiography or autopsies. TAPVC was diagnosed in all 31 patients (100%) by both 2D FE and 3D STIC. Furthermore, the classification of subtypes of TAPVC and accurate diagnosis of the drainage pathway was correct in 26 (83.9%) and 24 (77.4%) cases by 2D FE, respectively; but in 31 (100%) and 31 (100%) cases by 3D STIC. CONCLUSION: 2D and 3D STIC FE provide accurate diagnosis of TAPVC with excellent sensitivity and specificity. 3D STIC FE has incremental value in further evaluation of classification of TAPVC types and drainage pathways.

Modeling of coarctation of aorta in human fetuses using 3D/4D fetal echocardiography and computational fluid dynamics.

OBJECTIVES: We sought to develop a hemodynamic model of aortic and ductal arches using computational fluid dynamics (CFD) and 3D/4D spatio-temporal image correlation (STIC) fetal echocardiography and to investigate the hemodynamics of coarctation of aorta (CoA) in human fetuses using this approach. METHODS: We obtained 3D/4D STIC fetal echocardiographic images of the aortic and ductal arches (DA) in five normal fetuses. Based on these images, we simulated the hemodynamics in the two arches using CFD. Subsequently, we reduced the dimensions of aortic isthmus from 100% to 85%, 70%, 55%, 40%, and 25% of the original dimension digitally. Numerical simulation was repeated in each condition, and flow profile, velocity, pressure, and wall shear stress (WSS) were compared with those of the baseline normal aortic and ductal arches. RESULTS: With the progressive narrowing in the aortic isthmus, there were alterations in the flow profile, velocity, pressure, and WSS. The downstream vortexes disappeared, and the double helix profile became single helix. When the aortic isthmus reduced by 55% in dimension, there was an exponential increase in velocity and WSS and decrease in pressure. CONCLUSIONS: The aortic and ductal arch geometry and flow lead to the alterations in flow profile, velocity, pressure, and WSS in the aortic isthmus in normal and CoA models, which are conductive of ductal issue migration into these areas. A 55% reduction in the dimension of aortic isthmus is associated with exponential change in velocity, pressure, and WSS, a probable threshold for hemodynamically significant CoA.

Pulmonary hypoplasia in fetuses with congenital conotruncal defects.

OBJECTIVES: We sought to investigate pulmonary hypoplasia (PH) and associated risk factors in fetuses with congenital conotruncal defect (CTD). METHODS: A total of 75 fetuses with CTD (gestational age (GA): 22-32 weeks) and 150 normal GA-matched fetuses as the control group were studied. We measured diameters of aorta (Ao); main, left, and right pulmonary artery (PA); and their Z-scores by fetal echocardiography (FE). We also measured the lung area, lung area/chest area ratio (LCR), lung-to-head circumference ratio (LHR), right lung area/head circumference2 (quantitative lung index, QLI), and Z-scores. RESULTS: The PA, left pulmonary artery (LPA), RPA, and their Z-scores and the lung area measurements (except for QLI) were significantly smaller in the CTD group, compared with the normal control group. Subgroup analysis showed the following: (1) CTD with right ventricular outflow tract obstruction (RVOTO) had smaller main and branch PA dimensions and small lung areas in contrast to CTD without RVOTO. (2) CTD with pulmonary atresia had smaller LPA and RPA dimensions but no difference in lung areas. (3) In the common types of CTD, lung area variables were mostly smaller in double outlet right ventricle (DORV) and tetralogy of Fallot (TOF), but there was no difference in transposition of the great arteries (TGA). CONCLUSIONS: CTD is associated with hypoplastic main and branch pulmonary arteries as well as PH. Risk factors for PH included defect types (DORV and TOF but not TGA) and RVOTO. It is plausible that pulmonary blood flow, rather than the type of CTD, RVOTO, or pulmonary artery dimensions, plays a key role in PH.

Cerebrovascular hemodynamics in fetuses with congenital heart disease.

BACKGROUND AND OBJECTIVE: It is hypothesized that diminished cerebral vascular resistance or the "brain sparing effect" is associated with fetuses with complex congenital heart defects (CHD) and may affect their neurodevelopmental outcome. An alternative explanation is that it is related to the location, cardiac output, pressure, and resistance in left heart obstructive CHDs. We sought to determine the effects of various left and right heart obstructive defects on the cerebral and placental hemodynamics and to evaluate the utility of these variables for the assessment and prognosis of CHDs. METHODS: A total of 290 fetal echocardiograms were reviewed, including 91 fetuses with CHD and 199 normal ones. The CHD fetuses were divided into four groups, that is, left-sided obstructive lesions (LSOL), hypoplastic left heart syndrome (HLHS), right-sided obstructive lesions (RSOL), and hypoplastic right heart syndrome (HRHS). The pulsatility index of middle cerebral artery (MCA-PI) and umbilical artery (UA-PI) were measured by pulse-wave Doppler, and their Z scores were also derived. Cerebroplacental ratio (CPR) was calculated as: CPR=MCA-PI/UA-PI. RESULTS: There was no significant difference in MCA-PI between the 4 CHD and normal control groups (P>.05). However, MCA-PI and Z score decreased in aortic stenosis but not in interrupted aortic arch or coarctation subgroups, whereas they increased in pulmonary atresia but not pulmonary stenosis or tetralogy of Fallot subgroups compared with normal group (P<.05). There was no significant difference in CPR between any study group or subgroup and normal control group. CONCLUSIONS: Our study suggests MCA-PI is lower in aortic stenosis and high in pulmonary atresia but not significantly different in other LSOL, HLHS, RSOL, and HRHS. MCA-PI regulation in CHD is probably more associated with left and right outflow obstruction, location of the obstruction, and hemodynamics rather than "brain sparing effect" or preferential shunting of blood to the fetal brain, heart, and adrenals in the stressed fetus (eg, IUGR). CPR may not be a sensitive measure for the effect of CHDs and their severity on cerebral and placental circulation.

Fetal echocardiographic characteristics of fused heart in thoracopagus conjoined twins.

Conjoined twins (CT) are rare with possible serious malformations in which soft tissue, bone, or some organs are joined in utero. The extent of cardiac fusion and intracardiac anatomy of CT determine the viability, natural history, and outcome of potential surgical intervention. Early prenatal diagnosis and assessment may provide a window of opportunity to counsel the family for their informed decision on the pregnancy and to plan for prenatal and perinatal care. In this report, we describe a case of thoracopagus twins diagnosed by fetal echocardiography at 23-week gestation. The 2 hearts fused at the atrial and ventricular levels. The outcome and review of literature on fetal echocardiographic characteristics of this malformation are discussed.

Pediatric Cardio-Oncology: Screening, Risk Stratification, and Prevention of Cardiotoxicity Associated with Anthracyclines.

Anthracyclines have significantly improved the survival of children with malignant tumors, but the associated cardiotoxicity, an effect now under the purview of pediatric cardio-oncology, due to its cumulative and irreversible effects on the heart, limits their clinical application. A systematic screening and risk stratification approach provides the opportunity for early identification and intervention to mitigate, reverse, or prevent myocardial injury, remodeling, and dysfunction associated with anthracyclines. This review summarizes the risk factors, surveillance indexes, and preventive strategies of anthracycline-related cardiotoxicity to improve the safety and efficacy of anthracyclines.

A Membrane-Targeting Aggregation-Induced Emission Probe for Monitoring Lipid Droplet Dynamics in Ischemia/Reperfusion-Induced Cardiomyocyte Ferroptosis.

Myocardial ischemia/reperfusion injury (MIRI) is the leading cause of irreversible myocardial damage. A pivotal pathogenic factor is ischemia/reperfusion (I/R)-induced cardiomyocyte ferroptosis, marked by iron overload and lipid peroxidation. However, the impact of lipid droplet (LD) changes on I/R-induced cardiomyocyte ferroptosis is unclear. In this study, an aggregation-induced emission probe, TPABTBP is developed that is used for imaging dynamic changes in LD during myocardial I/R-induced ferroptosis. TPABTBP exhibits excellent LD-specificity, superior capability for monitoring lipophagy, and remarkable photostability. Molecular dynamics (MD) simulation and super-resolution fluorescence imaging demonstrate that the TPABTBP is specifically localized to the phospholipid monolayer membrane of LDs. Imaging LDs in cardiomyocytes and myocardial tissue in model mice with MIRI reveals that the LD accumulation level increase in the early reperfusion stage (0-9 h) but decrease in the late reperfusion stage (>24 h) via lipophagy. The inhibition of LD breakdown significantly reduces the lipid peroxidation level in cardiomyocytes. Furthermore, it is demonstrated that chloroquine (CQ), an FDA-approved autophagy modulator, can inhibit ferroptosis, thereby attenuating MIRI in mice. This study describes the dynamic changes in LD during myocardial ischemia injury and suggests a potential therapeutic target for early MIRI intervention.

Pediatric echocardiography: new developments and applications.

In this Special Issue of the Journal, 6 review articles that represent the new developments and applications of echocardiography for diagnosis and assessment of congenital heart disease from fetus to adult are included. The goal is to provide an updated review of the evidence for the current and potential use of some of the new methodologies, i.e. fetal echocardiography, tissue Doppler imaging, strain imaging by speckle tracking imaging, ventricular synchrony, quantification using real time three-dimensional (3D) echocardiography, and 3D echocardiography for adults with congenital heart disease. We hope this effort will provide an impetus for more investigation and ultimately clinical application of these new methodologies to improve the care of those with congenital and acquired heart diseases in the pediatric population and beyond.

Real time three-dimensional echocardiography for quantification of ventricular volumes, mass, and function in children with congenital and acquired heart diseases.

Quantitative measurement of left ventricular (LV) volumes, mass, and function is one of the most common and important indications for echocardiography. These measurements are among the most powerful tools for diagnosis and prognosis of congenital and acquired heart diseases and for assessment of medical, percutaneous, and surgical interventions. Awareness is also growing of the importance of right ventricular (RV) volume, mass, and function in many cardiopulmonary diseases. Furthermore, there are challenges and opportunities to measure the volume, mass, and function of complex chambers such as the left atrium, right atrium, and the univentricular heart. As echocardiography continues to be the imaging modality of choice for these measurements, the strengths and limitations of M-mode, two-dimensional (2D), and recently three-dimensional (3D) echocardiographic (3DE) methodologies for accurate and reproducible measurement of these indices have been extensively investigated for congenital and acquired heart diseases. Evidence suggests that 3DE provides improved accuracy and reproducibility over 2D methods for measurement of LV volume and function calculation in adults and in children. Data have accumulated on the utility of 3DE for measuring chamber volumes and function for the RV and for the single ventricle, which may become more widely used in clinical and research arenas in the future. Finally, new advanced modes of analysis such as 3D strain and synchrony analysis by 3DE are promising methodologies that warrant further investigation.

Advances in fetal echocardiography: early imaging, three/four dimensional imaging, and role of fetal echocardiography in guiding early postnatal management of congenital heart disease.

In this article, we review a number of topics that we believe reflect new and exciting aspects of fetal echocardiography. These new advances include early fetal cardiovascular imaging around 14 weeks, the utility of three/four dimensional imaging technology for the fetus, and finally the utility of fetal echocardiography for antenatal and perinatal care of congenital heart diseases to improve and optimize outcome. Finally, we briefly discussed future directions in fetal cardiac intervention.

Cardiac structural and functional remodeling in the fetuses associated with maternal hypothyroidism during pregnancy.

OBJECTIVES: We sought to investigate the effect of maternal hypothyroidism during pregnancy on fetal cardiac structural and functional remodeling using fetal echocardiography. METHODS: A total of 59 pregnant women with history of hypothyroidism were prospectively enrolled as the study group, and 74 normal fetuses as the control group. Fetal echocardiography was performed on each subject. Demographic, clinical, and fetal echocardiographic variables were measured, including left ventricular (LV) and right ventricular (RV) free wall and ventricular septal thickness, fractional shortening (FS), stroke volume (SV), cardiac output (CO), combined cardiac output (CCO), cardiac index (CI), combined cardiac index (CCI), aortic and pulmonary artery velocity, ductus venosus (DV) and pulmonary vein (PV) spectral Doppler, and Tei index. RESULTS: The incidence of echogenic intracardiac foci (EIF) was higher in the study group than that in the control group (18.6% vs. 6.8%, p = .036). The thickness of LV free wall and interventricular septum was reduced, the pulmonary velocities and CCI, RV FS, CO, and CI were lower, the S, D, S/A, and pulsatility index (PI) of DV were higher, and LV Tei index was higher in the study group compared with the control group. There was no significant difference in other variables between the two groups. CONCLUSIONS: There is cardiac remodeling, and systolic, diastolic functional alterations in fetuses with maternal hypothyroidism. Further investigation is warranted to develop strategies to optimize the outcome of these fetuses.

Real time three-dimensional echocardiography for evaluation of congenital heart defects: state of the art.

Real time three-dimensional echocardiography (RT3DE) has been increasingly used in the diagnosis and assessment of congenital heart disease. A growing body of literature suggests that this new technology can be used as an integrated approach to assess the morphology of simple and complex congenital heart defects, flow abnormality, and left, right, and single ventricular function both qualitatively and quantitatively. This review summarizes the available evidence for the use of RT3DE in each of these areas. Future technology refinement in RT3DE and development of practice guidelines will increase the utilization of this new technology as a valuable tool to compliment 2D echocardiography/Doppler in clinical care and research to improve the care and outcome of congenital heart disease.

Collaborative Approach to Reach Everyone with Familial Hypercholesterolemia: CARE-FH Protocol.

The Collaborative Approach to Reach Everyone with Familial Hypercholesterolemia (CARE-FH) study aims to improve diagnostic evaluation rates for FH at Geisinger, an integrated health delivery system. This clinical trial relies upon implementation science to transition the initial evaluation for FH into primary care, attempting to identify individuals prior to the onset of atherosclerotic cardiovascular disease events. The protocol for the CARE-FH study of this paper is available online. The first phase of the project focuses on trial design, including the development of implementation strategies to deploy evidence-based guidelines. The second phase will study the intervention, rolled out regionally to internal medicine, community medicine, and pediatric care clinicians using a stepped-wedge design, and analyzing data on diagnostic evaluation rates, and implementation, service, and health outcomes.