Evaluating the Effect of COVID-19 on Outpatient Opioid Utilization Among Health First Colorado Members and a National Non-Medicaid Cohort: An Interrupted Time Series Analysis.

Objective: COVID-19, coinciding with the opioid epidemic in the United States, has had significant impacts on health-care utilization. While mixed, early analyses signaled a potential resurgence in opioid use following the pandemic. The primary study objective was to assess the association of the COVID-19 pandemic with opioid utilization among Health First Colorado (Colorado's Medicaid Program) members and a non-Medicaid managed care cohort who did not have a diagnosis of cancer or sickle cell disease. Patients and Methods: Using an interrupted time series and segmented regression analysis, this population-level study assessed the association of the COVID-19 pandemic on prescribed utilization of long- and short-acting opioid analgesics among Health First Colorado members and a random sample of non-Medicaid managed care members. Pharmacy claims data for both cohorts were assessed between October 1, 2018, and September 30, 2021, with April 2020 identified as the interruption of interest. We evaluated the following monthly opioid use measures separately for short-acting and long-acting opioids: number of members filling an opioid, total fills, and total days supplied. Results: Short- and long-acting opioid utilization was significantly decreasing among Health First Colorado members in the 18 months prior to the start of COVID-19. After the onset of the pandemic, utilization stabilized and slopes were not significantly different from zero. Among the non-Medicaid managed care cohort, short- and long-acting opioid utilization significantly decreased in the 18 months leading up to the onset of the pandemic. After the onset of the pandemic, utilization of long-acting opioids stabilized, while utilization of short-acting opioids significantly increased. Conclusion: While we observed an increase in opioid utilization measures post-pandemic in the non-Medicaid managed care cohort, a similar increase was not observed in Health First Colorado members suggesting that thoughtful opioid policies put in place pre-pandemic may have been effective at controlling potential inappropriate opioid utilization.

Longitudinal Assessment of Multimorbidity Medication Patterns among Smokers in the COPDGene Cohort.

Background and objectives: Chronic obstructive pulmonary disease (COPD) is usually comorbid with other chronic diseases. We aimed to assess the multimorbidity medication patterns and explore if the patterns are similar for phase 1 (P1) and 5-year follow-up phase 2 (P2) in the COPDGene cohort. Materials and Methods: A total of 5564 out of 10,198 smokers from the COPDGene cohort who completed 2 visits, P1 and P2 visits, with complete medication use history were included in the study. We conducted latent class analysis (LCA) among the 27 categories of chronic disease medications, excluding COPD treatments and cancer medications at P1 and P2 separately. The best number of LCA classes was determined through both statistical fit and interpretation of the patterns. Results: We found four classes of medication patterns at both phases. LCA showed that both phases shared similar characteristics in their medication patterns: LC0: low medication; LC1: hypertension (HTN) or cardiovascular disease (CVD)+high cholesterol (Hychol) medication predominant; LC2: HTN/CVD+type 2 diabetes (T2D) +Hychol medication predominant; LC3: Hychol medication predominant. Conclusions: We found similar multimorbidity medication patterns among smokers at P1 and P2 in the COPDGene cohort, which provides an understanding of how multimorbidity medication clustered and how different chronic diseases combine in smokers.

Opportunities, barriers, and recommendations in down syndrome research.

BACKGROUND: Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. OBJECTIVE: The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. METHODS: NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. RESULTS: This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. CONCLUSIONS: This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy.

Validity of an Automated Algorithm to Identify Cirrhosis Using Electronic Health Records in Patients with Primary Biliary Cholangitis.

BACKGROUND: Biopsy remains the gold standard for determining fibrosis stage in patients with primary biliary cholangitis (PBC), but it is unavailable for most patients. We used data from the 11 US health systems in the FibrOtic Liver Disease Consortium to explore a combination of biochemical markers and electronic health record (EHR)-based diagnosis/procedure codes (DPCs) to identify the presence of cirrhosis in PBC patients. METHODS: Histological fibrosis staging data were obtained from liver biopsies. Variables considered for the model included demographics (age, gender, race, ethnicity), total bilirubin, alkaline phosphatase, albumin, aspartate aminotransferase (AST) to platelet ratio index (APRI), Fibrosis 4 (FIB4) index, AST to alanine aminotransferase (ALT) ratio, and >100 DPCs associated with cirrhosis/decompensated cirrhosis, categorized into ten clusters. Using least absolute shrinkage and selection operator regression (LASSO), we derived and validated cutoffs for identifying cirrhosis. RESULTS: Among 4328 PBC patients, 1350 (32%) had biopsy data; 121 (9%) were staged F4 (cirrhosis). DPC clusters (including codes related to cirrhosis and hepatocellular carcinoma diagnoses/procedures), Hispanic ethnicity, ALP, AST/ALT ratio, and total bilirubin were retained in the final model (AUROC=0.86 and 0.83 on learning and testing data, respectively); this model with two cutoffs divided patients into three categories (no cirrhosis, indeterminate, and cirrhosis) with specificities of 81.8% (for no cirrhosis) and 80.3% (for cirrhosis). A model excluding DPCs retained ALP, AST/ALT ratio, total bilirubin, Hispanic ethnicity, and gender (AUROC=0.81 and 0.78 on learning and testing data, respectively). CONCLUSION: An algorithm using laboratory results and DPCs can categorize a majority of PBC patients as cirrhotic or noncirrhotic with high accuracy (with a small remaining group of patients' cirrhosis status indeterminate). In the absence of biopsy data, this EHR-based model can be used to identify cirrhosis in cohorts of PBC patients for research and/or clinical follow-up.

Associations between childhood cancer treatment and tooth agenesis.

AIM: The aim of this study was to determine the prevalence of dental developmental disturbances in long-term survivors of childhood malignancies in New Zealand children. This study reports associations with potential risk factors to inform oncologists and dentists of the likelihood of dental abnormalities. METHODS: The study population was children aged 14-16 years old who were diagnosed with cancer prior to 10 years of age. A total of 156 children were eligible, of which 59 participated in this study. The indices used in this study were Holtta's Defect Index (HDI), and Oral Health Impact Profile-14 (OHIP-14). RESULTS: The prevalence of agenesis was 15.3%, microdontia 6.8% and root abnormalities 32.2%. Cyclophosphamide equivalent doses above 8,000mg/m2, stem cell therapy (SCT), and head and neck radiation therapy (HNRT) were associated with a higher mean number of teeth missing due to agenesis. SCT and HNRT were associated with a higher total HDI. A binary logistic regression was carried out to determine the odds of agenesis and found that HNRT was the main contributing factor (OR=7.7, p-value=0.04). The linear regression model found that dactinomycin and agenesis correlated with the largest mean OHIP-14. CONCLUSION: This study found that childhood cancer survivors in New Zealand had a high prevalence of developmental dental abnormalities and it identified potential risk factors related to their cancer treatment. Inequitable access to oral rehabilitation for this patient group argues for a mechanism for consistent improved access to publicly funded dental care across district health boards in New Zealand.

Cerebral protection strategies in aortic arch surgery: A network meta-analysis.

OBJECTIVE: Cerebral protection for aortic arch surgery has been widely studied, but comparisons of all the available strategies have rarely been performed. We performed direct and indirect comparisons of antegrade cerebral perfusion, retrograde cerebral perfusion, and deep hypothermic circulatory arrest in a network meta-analysis. METHODS: After a systematic literature search, studies comparing any combination of antegrade cerebral perfusion, retrograde cerebral perfusion, and deep hypothermic circulatory arrest were included, and a frequentist network meta-analysis was performed using the generic inverse variance method. The primary outcomes were postoperative stroke and operative mortality. Secondary outcomes were postoperative transient neurologic deficits, myocardial infarction, respiratory complications, and renal failure. RESULTS: A total of 68 studies were included with a total of 26,968 patients. Compared with deep hypothermic circulatory arrest, both antegrade cerebral perfusion and retrograde cerebral perfusion were associated with significantly lower postoperative stroke and operative mortality rates: antegrade cerebral perfusion (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.51-0.75; and OR, 0.63, 95% CI, 0.51-0.76, respectively) and retrograde cerebral perfusion (OR, 0.66; 95% CI, 0.54-0.82; and OR, 0.57; 95% CI, 0.45-0.71, respectively). Antegrade cerebral perfusion and retrograde cerebral perfusion were associated with similar incidence of primary outcomes. No difference among the 3 techniques was found in secondary outcomes. At meta-regression, circulatory arrest duration correlated with the neuroprotective effect of antegrade cerebral perfusion and retrograde cerebral perfusion compared with deep hypothermic circulatory arrest. Unilateral or bilateral antegrade cerebral perfusion and arrest temperature did not influence the results. CONCLUSIONS: Antegrade cerebral perfusion and retrograde cerebral perfusion are associated with better postoperative outcomes compared with deep hypothermic circulatory arrest, and the relative benefit increases with the duration of the circulatory arrest. No differences between antegrade cerebral perfusion and retrograde cerebral perfusion were found for all the explored outcomes.

Histopathology-guided mass spectrometry differentiates benign nevi from malignant melanoma.

PURPOSE: Distinguishing benign nevi from malignant melanoma using current histopathological criteria may be very challenging and is one the most difficult areas in dermatopathology. The goal of this study was to identify proteomic differences, which would more reliably differentiate between benign and malignant melanocytic lesions. METHODS: We performed histolpathology - guided mass spectrometry (HGMS) profiling analysis on formalin-fixed, paraffin embedded tissue samples to identify differences at the proteomic level between different types of benign nevi and melanomas. A total of 756 cases, of which 357 cases of melanoma and 399 benign nevi, were included in the study. The specimens originated from both biopsies (376 samples) and tissue microarray (TMA) cores (380 samples). After obtaining mass spectra from each sample, classification models were built using a training set of biopsy specimens from 111 nevi and 100 melanomas. The classification algorithm developed on the training data set was validated on an independent set of 288 nevi and 257 melanomas from both biopsies and TMA cores. RESULTS: In the melanoma cohort, 239/257 (93%) cases classified correctly in the validation set, 3/257 (1.2%) classified incorrectly, and 15/257 (5.8%) classified as indeterminate. In the cohort of nevi, 282/288 (98%) cases classified correctly, 1/288 (0.3%) classified incorrectly, and 5/288 (1.7%) were indeterminate. HGMS showed a sensitivity of 98.76% and specificity of 99.65% in determining benign vs malignant. CONCLUSION: HGMS proteomic analysis is an objective and reliable test with minimal tissue requirements, which can be a helpful ancillary test in the diagnosis of challenging melanocytic lesions.

Repair of Sinus Venosus Defect and Anomalous Pulmonary Veins Associated With Vein of Galen Malformation.

Sinus venosus defect (SVD) is a deficiency in the sinus venosus portion of the atrium, often associated with partial anomalous pulmonary venous connections. In patients with vein of Galen malformation (VGAM), SVD provides a unique challenge with respect to embolization treatment. In our case, the child had percutaneous device closure of the SVD prior to VGAM embolization. Nine years later, he required surgical removal of the SVD device and Warden procedure due to progressive right-sided cardiac enlargement.

The Effect of Left Cardiac Sympathetic Denervation on Exercise in Patients With Long QT Syndrome.

OBJECTIVES: This study evaluated the effect of left cardiac sympathetic denervation (LCSD) on heart rate, cardiac contractility, and cardiopulmonary fitness in human subjects. BACKGROUND: The primary treatment for long QT syndrome (LQTS) is beta-blocker (BB) therapy, but some patients experience breakthrough cardiac events or intolerable side effects. LCSD provides a significant antifibrillatory, protective effect in LQTS. However, the effect of LCSD on cardiopulmonary fitness in humans has not been previously described. METHODS: A retrospective analysis of patients with LQTS and LCSD (2006 to 2017) who had both pre- and post-LCSD exercise stress tests (N = 55; 39 females; mean age at LCSD 22 ± 12 years; mean follow-up 5.1 ± 2.5 years; 36 patients with LQT1; 15 patients with LQT2). Forty patients (73%) were receiving BBs pre-LCSD. RESULTS: Mean peak heart rate before LCSD was 143 ± 23 beats/min, mean peak oxygen consumption (VO2) was 32 ± 10 ml/kg/min, and mean peak respiratory exchange ratio was 1.14 ± 0.12. There was no difference in peak heart rate, peak VO2, peak QTc, or respiratory exchange ratio pre- and post-LCSD. To evaluate the isolated effect of LCSD, the study performed a subset analysis of patients with LCSD monotherapy (n = 10) or no change in BB dose (n = 12). Patient-matched pre- and post-LCSD exercise testing showed no difference in heart rate, VO2, or left ventricular function following LCSD. CONCLUSIONS: LCSD provides increased protection from an LQTS-triggered event without negatively affecting peak heart rate, cardiopulmonary fitness, or cardiac contractility, as assessed by both treadmill exercise stress testing and echocardiography.

Innovative 2-Step Management Strategy Utilizing EXIT Procedure for a Fetus With Hypoplastic Left Heart Syndrome and Intact Atrial Septum.

Hypoplastic left heart syndrome (HLHS) with intact atrial septum (HLHS-IAS) carries a high risk of mortality and affects about 6% of all patients with HLHS. Fetal interventions, postnatal transcatheter interventions, and postnatal surgical resection have all been used, but the mortality risk continues to be high in this subgroup of patients. We describe a novel, sequential approach to manage HLHS-IAS and progressive fetal hydrops. A 28-year-old, gravida 4 para 2 mother was referred to Mayo Clinic for fetal HLHS. Fetal echocardiography at 28 weeks of gestation demonstrated HLHS-IAS with progressive fetal hydrops. The atrial septum was thick and muscular with no interatrial communication. Ultrasound-guided fetal atrial septostomy was performed with successful creation of a small atrial communication. However, fetal echocardiogram at 33 weeks of gestation showed recurrence of a pleural effusion and restriction of the atrial septum. We proceeded with an Ex uteroIntrapartum Treatment (EXIT) delivery and open atrial septectomy. This was performed successfully, and the infant was stabilized in the intensive care unit. The infant required venoarterial extracorporeal membrane oxygenator support on day of life 1. The patient later developed hemorrhagic complications, leading to his demise on day of life 9. This is the first reported case of an EXIT procedure and open atrial septectomy performed without cardiopulmonary bypass for an open-heart operation and provides a promising alternative strategy for the management of HLHS-IAS in select cases.

Opioid Prescribing in Rural Family Practices: A Qualitative Study.

BACKGROUND: Rural Tennessee, especially rural East Tennessee has seen a dramatic increase in rates of controlled drug prescriptions and controlled drug overdose deaths in recent years. However, little is known about the individual decisions to prescribe or continue prescriptions with relation to addiction concerns. OBJECTIVES: The purpose of this study was to learn more about what factors lead to physicians' prescribing control drugs for non-cancer pain through the use of focus groups. METHODS: A qualitative study, using focus groups, in five family medicine clinics in East Tennessee and Southwest Virginia. The investigators used a semi-structured interview guide designed to facilitate group discussions about prescription drug abuse and misuse. RESULTS: There were four main themes identified by the focus groups: (1) prescribers' changing prescribing patterns over time; (2) factors that influence controlled drug prescribing; (3) use and barriers to using state prescription drug monitoring programs (PDMPs); (4) prescribing controlled drugs to women of childbearing age. Each theme had several subthemes. CONCLUSIONS: The balance between treating the patient's symptoms and causing potential harm is a challenge. The patient's pain cannot be ignored, but the potential harm of opioid therapy is not taken lightly. As the public health concern of prescription drug abuse in rural Appalachia continues to spread, prescribers are aware of their connection to the problem, and ultimately the solution.

Phenotype of Children with QT Prolongation Identified Using an Institution-Wide QT Alert System.

QT prolongation is an independent risk factor for cardiovascular mortality in adults. However, there is little information available on pediatric patients with QT prolongation and their outcomes. Herein, we evaluated the prevalence of QT prolongation in pediatric patients identified by an institution-wide QT alert system, and the spectrum of their phenotype. Patients with documented QT prolongation on an ECG obtained between November 2010 and June 2011 were included. There were 1303 pediatric ECGs, and 68 children had electrographically isolated QT prolongation. Comprehensive review of medical records was performed with particular attention to QT-prolonging clinical, laboratory, and medication data, which were summarized into a pro-QTc score. Overall, 68 (5 %) pediatric patients had isolated QT prolongation. The mean age of this pediatric cohort was 9 ± 6 years, and the average QTc was 494 ± 42 ms. All children had 1 or more QT-prolonging risk factor(s), most commonly QT-prolonging medications. One patient was identified with congenital long QT syndrome (LQTS), which was not previously diagnosed. In one-year follow-up, only one pediatric death (non-cardiac) occurred (1.5 %). Potentially QT-offending/pro-arrhythmic medications were changed in 80 % of pediatric patients after the physician received the QT alert. Children with QT prolongation had very low mortality and minimal polypharmacy. Still, medications and other modifiable conditions were the most common causes of QT prolongation. Children with a prolonged QTc should be evaluated for modifiable QT-prolonging factors. However, if no risk factors are present or the QTc does not attenuate after risk factor modification/removal, the child should be evaluated for congenital LQTS.

Induction of apoptosis in human myeloid leukemia cells by remote exposure of resistive barrier cold plasma.

Cold atmospheric plasma (CAP), an ambient temperature ionized gas, is gaining extensive interest as a promising addition to anti-tumor therapy primarily due to the ability to generate and control delivery of electrons, ions, excited molecules, UV photons, and reactive species such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) to a specific site. The heterogeneous composition of CAP offers the opportunity to mediate several signaling pathways that regulate tumor cells. Consequently, the array of CAP generated products has limited the identification of the mechanisms of action on tumor cells. The aim of this work is to assess the cell death response of human myeloid leukemia cells by remote exposure to CAP generated RNS by utilizing a novel resistive barrier discharge system that primarily produces RNS. The effect of variable treatments of CAP generated RNS was tested in THP-1 cell (human monocytic leukemia cell line), a model for hematological malignancy. The number of viable cells was evaluated with erythrosine-B staining, while apoptosis and necrosis was assessed by endonuclease cleavage observed by agarose gel electrophoresis and detection of cells with the exclusionary dye propidium iodide and fluorescently labeled annexin-V by flow cytometry and fluorescent microscopy. Our observations indicate that treatment dosage levels of 45 s of exposure to CAP emitted RNS-induced apoptotic cell death and for higher dosage conditions of ≥50 s of exposure to CAP induced necrosis. Overall the results suggest that CAP emitted RNS play a significant role in the anti-tumor potential of CAP.

Cone reconstruction in children with Ebstein anomaly: the Mayo Clinic experience.

OBJECTIVE: Valve repair for pediatric patients with Ebstein anomaly has historically yielded varied results. The cone reconstruction (CR) first described by Da Silva has revolutionized the surgical approach to these patients. This study reports our recent experience with CR in children and young adults with Ebstein anomaly. DESIGN: Electronic medical records were reviewed for all patients < 21 years old who had surgery to repair Ebstein anomaly at Mayo Clinic Rochester between June 2007 and December 2012. Clinical data including preoperative demographics, intraoperative procedures, and postoperative outcomes were recorded. RESULTS: Eighty-four patients initially had a cone reconstruction (54% male, mean age 10.1 ± 5.9 years). Indications for operation included cardiomegaly (42%), cyanosis (19%), and heart failure (19%). The preoperative echocardiogram demonstrated severe tricuspid regurgitation in 91% of patients. There was one early death and 3 early CR breakdowns requiring reoperation (2 re-repair, 1 tricuspid replacement). Eighty-two patients (98%) had successful CR at the time of hospital discharge. Patient age, gender, cardiopulmonary bypass time, and aortic cross-clamp time were not associated with early CR failure. Use of a partial or eccentric annuloplasty ring correlated with successful initial CR (P = .01). There have been no early CR breakdowns since 2010. Follow-up information was available for 77 patients (longest follow-up 6.5 years; mean 0.8 ± 0.2 years). The most recent postoperative echocardiogram demonstrated mild or no tricuspid regurgitation in 83%. Tricuspid stenosis (mean gradient > 5 mm Hg) was present in 6 patients. There was one late death (motor vehicle accident) and one late re-repair of the tricuspid valve 4 years after initial operation. CONCLUSIONS: CR in children and young adults with Ebstein anomaly can be performed with low early mortality and excellent durability at short-term follow-up. CR represents an important surgical option for young patients. It is applicable to patients with a broad range of anatomic variability and precludes valve replacement in the vast majority. CR should be considered prior to the deleterious effects of chronic right ventricular volume overload and the development of systolic dysfunction, which hamper long-term prognosis. Therefore, early referral for surgical evaluation is recommended.

Regulated cellular exposure to non-thermal plasma allows preferentially directed apoptosis in acute monocytic leukemia cells.

This research investigated the modulation of cell death through exposure of non-thermal resistive barrier based indirect air plasma on monocytic leukemia cancer cells (THP-1). Specifically, we explored cell death through apoptosis and necrosis, since generally apoptotic cell death has a limited inflammatory response as compared to necrosis. We have demonstrated a preference for apoptosis in plasma treated THP-1 cells, under specific plasma characteristics and dosage levels, using fluorescent dyes conjugated with annexin V followed by identification of the cells through fluorescent microscopy and flowcytometry diagnostics. At much higher plasma dosages, the necrotic morphologies in the THP-1 cells were observed. The presented outcomes in the death morphologies of plasma treated THP-1 cells signify the need for further investigation on the cellular mechanisms induced by the indirect plasma exposure. The results obtained from this research indicate the significant potential for the use of our portable non-thermal resistive barrier based indirect plasma treatment method as an inexpensive and less invasive method for treating leukemia and other cancerous lesions.

Factors associated with strabismus in spina bifida myelomeningocele.

PURPOSE: Higher prevalence of strabismus in individuals with spina bifida myelomeningocele (SBM) has previously been attributed to hydrocephalus; however, SBM is associated with many other complications. This study investigates the relation between strabismus and other factors in SBM. METHODS: Children aged 3 to 18 years with SBM (n = 112) received an eye examination including assessment of ocular alignment by cover or Hirschberg test. Gestational age, respiratory distress at birth, birth weight, maternal age at birth, number of shunt revisions, and spinal lesion level were also obtained. The relation between these factors and strabismus was analyzed. RESULTS: Forty-two participants had strabismus. Maternal age (P = .4) and respiratory distress (P = .6) were not significantly related to strabismus. Lower birth weight was suggestive of a relation with strabismus (logistic regression, P = .05) and younger gestational age was related to strabismus (logistic regression, P = .01). Participants who had at least one shunt revision were more likely to have strabismus (Fisher's exact test, P = .038). Spinal lesion level was significantly related to strabismus with increased likelihood of strabismus for spinal lesions closer to the brain (Wald chi-square, 1,100 = 4.29, P = .038). CONCLUSION: These findings indicate that several factors are associated with strabismus in SBM. Some of these factors (lower birth weight and younger gestational age) are associated with strabismus in the general population, whereas the association of strabismus and level of spinal lesion may be unique to SBM and may be related to the more severe brain dysmorphology associated with upper level spinal lesions.

FoxO1 is required in endothelial but not myocardial cell lineages during cardiovascular development.

BACKGROUND: The forkhead transcription factor FoxO1 is involved in cell cycle regulation during cardiovascular development. Systemic loss of FoxO1 results in lethality at embryonic day 10.5 with severe cardiovascular defects; however, the cell-type-specific requirements for FoxO1 in cardiovascular development are unknown. Here we examine the role of FoxO1 using a conditional loss of function approach. RESULTS: Loss of FoxO1 in differentiated cardiac myocytes has no apparent effect on cardiovascular development. In contrast, endothelial-specific FoxO1 deficiency in Tie2Cre;FoxO1(fl/fl) embryos results in lethality at E10.5, which recapitulates the FoxO1-null phenotype. Tie2Cre;FoxO1(fl/fl) embryos have an intact differentiated endothelium, but display defective remodeling of vasculature. Additional effects on heart development include reduced myocardial trabeculation, which is likely secondary to the endothelial abnormalities, and hypoplasia of endocardial cushions. CONCLUSIONS: The phenotype of Tie2Cre;FoxO1(fl/fl) mutant embryos demonstrates that FoxO1 is required specifically in endothelial cells to regulate formation of the heart and vasculature during development.