Karl G. Sylvester

All Publications

• Altered expression of the L-arginine/nitric oxide pathway in ovarian cancer: metabolic biomarkers and biological implications. BMC cancer Chen, L., Tang, Q., Zhang, K., Huang, Q., Ding, Y., Jin, B., Liu, S., Hwa, K., Chou, C. J., Zhang, Y., Thyparambil, S., Liao, W., Han, Z., Mortensen, R., Schilling, J., Li, Z., Heaton, R., Tian, L., Cohen, H. J., Sylvester, K. G., Arent, R. C., Zhao, X., McElhinney, D. B., Wu, Y., Bai, W., Ling, X. B. 2023; 23 (1): 844

  Abstract

  Ovarian cancer (OC) is a highly lethal gynecological malignancy. Extensive research has shown that OC cells undergo significant metabolic alterations during tumorigenesis. In this study, we aim to leverage these metabolic changes as potential biomarkers for assessing ovarian cancer.A functional module-based approach was utilized to identify key gene expression pathways that distinguish different stages of ovarian cancer (OC) within a tissue biopsy cohort. This cohort consisted of control samples (n = 79), stage I/II samples (n = 280), and stage III/IV samples (n = 1016). To further explore these altered molecular pathways, minimal spanning tree (MST) analysis was applied, leading to the formulation of metabolic biomarker hypotheses for OC liquid biopsy. To validate, a multiple reaction monitoring (MRM) based quantitative LCMS/MS method was developed. This method allowed for the precise quantification of targeted metabolite biomarkers using an OC blood cohort comprising control samples (n = 464), benign samples (n = 3), and OC samples (n = 13).Eleven functional modules were identified as significant differentiators (false discovery rate, FDR < 0.05) between normal and early-stage, or early-stage and late-stage ovarian cancer (OC) tumor tissues. MST analysis revealed that the metabolic L-arginine/nitric oxide (L-ARG/NO) pathway was reprogrammed, and the modules related to "DNA replication" and "DNA repair and recombination" served as anchor modules connecting the other nine modules. Based on this analysis, symmetric dimethylarginine (SDMA) and arginine were proposed as potential liquid biopsy biomarkers for OC assessment. Our quantitative LCMS/MS analysis on our OC blood cohort provided direct evidence supporting the use of the SDMA-to-arginine ratio as a liquid biopsy panel to distinguish between normal and OC samples, with an area under the ROC curve (AUC) of 98.3%.Our comprehensive analysis of tissue genomics and blood quantitative LC/MSMS metabolic data shed light on the metabolic reprogramming underlying OC pathophysiology. These findings offer new insights into the potential diagnostic utility of the SDMA-to-arginine ratio for OC assessment. Further validation studies using adequately powered OC cohorts are warranted to fully establish the clinical effectiveness of this diagnostic test.

  View details for DOI 10.1186/s12885-023-11192-8

  View details for PubMedID 37684587

  View details for PubMedCentralID 8192829

• Development of a Urine Metabolomics Biomarker-Based Prediction Model for Preeclampsia during Early Pregnancy. Metabolites Zhang, Y., Sylvester, K. G., Jin, B., Wong, R. J., Schilling, J., Chou, C. J., Han, Z., Luo, R. Y., Tian, L., Ladella, S., Mo, L., Maric, I., Blumenfeld, Y. J., Darmstadt, G. L., Shaw, G. M., Stevenson, D. K., Whitin, J. C., Cohen, H. J., McElhinney, D. B., Ling, X. B. 2023; 13 (6)

  Abstract

  Preeclampsia (PE) is a condition that poses a significant risk of maternal mortality and multiple organ failure during pregnancy. Early prediction of PE can enable timely surveillance and interventions, such as low-dose aspirin administration. In this study, conducted at Stanford Health Care, we examined a cohort of 60 pregnant women and collected 478 urine samples between gestational weeks 8 and 20 for comprehensive metabolomic profiling. By employing liquid chromatography mass spectrometry (LCMS/MS), we identified the structures of seven out of 26 metabolomics biomarkers detected. Utilizing the XGBoost algorithm, we developed a predictive model based on these seven metabolomics biomarkers to identify individuals at risk of developing PE. The performance of the model was evaluated using 10-fold cross-validation, yielding an area under the receiver operating characteristic curve of 0.856. Our findings suggest that measuring urinary metabolomics biomarkers offers a noninvasive approach to assess the risk of PE prior to its onset.

  View details for DOI 10.3390/metabo13060715

  View details for PubMedID 37367874

• Fecal Keratin 8 Is a Noninvasive and Specific Marker for Intestinal Injury in Necrotizing Enterocolitis. Journal of immunology research Wang, K., Tao, G., Sun, Z., Wei, J., Liu, J., Taylor, J., Gibson, M., Mostaghimi, M., Good, M., Sylvester, K. G. 2023; 2023: 5356646

  Abstract

  Specific biomarkers of intestinal injury associated with necrotizing enterocolitis (NEC) are needed to diagnose and monitor intestinal mucosal injury and recovery. This study aims to develop and test a modified enzyme-linked immunosorbent assay (ELISA) protocol to detect the total keratin 8 (K8) in the stool of newborns with NEC and investigate the clinical value of fecal K8 as a marker of intestinal injury specifically associated with NEC. We collected fecal samples from five newborns with NEC and five gestational age-matched premature neonates without NEC at the Lucile Packard Children's Hospital Stanford and Washington University School of Medicine, respectively. Fecal K8 levels were measured using a modified ELISA protocol and Western blot, and fecal calprotectin was measured using a commercial ELISA kit. Clinical data, including gestational age, birth weight, Bell stage for NEC, feeding strategies, total white blood cell (WBC) count, and other pertinent clinical variables, were collected and analyzed. Fecal K8 levels were significantly higher in the pre-NEC group (1-2 days before diagnosis of NEC) and NEC group than those in the non-NEC group (p = 0.013, p = 0.041). Moreover, fecal K8 was relatively higher at the onset of NEC and declined after the resolution of the disease (p = 0.019). Results with similar trends to fecal K8 were also seen in fecal calprotectin (p = 0.046), but not seen in total WBC count (p = 0.182). In conclusion, a modified ELISA protocol for the total K8 protein was successfully developed for the detection of fecal K8 in the clinical setting of premature newborns with NEC. Fecal K8 is noted to be significantly increased in premature newborns with NEC and may, therefore, serve as a noninvasive and specific marker for intestinal epithelial injury associated with NEC.

  View details for DOI 10.1155/2023/5356646

  View details for PubMedID 36959922

  View details for PubMedCentralID PMC10030213

• Data-driven longitudinal characterization of neonatal health and morbidity. Science translational medicine De Francesco, D., Reiss, J. D., Roger, J., Tang, A. S., Chang, A. L., Becker, M., Phongpreecha, T., Espinosa, C., Morin, S., Berson, E., Thuraiappah, M., Le, B. L., Ravindra, N. G., Payrovnaziri, S. N., Mataraso, S., Kim, Y., Xue, L., Rosenstein, M. G., Oskotsky, T., Marić, I., Gaudilliere, B., Carvalho, B., Bateman, B. T., Angst, M. S., Prince, L. S., Blumenfeld, Y. J., Benitz, W. E., Fuerch, J. H., Shaw, G. M., Sylvester, K. G., Stevenson, D. K., Sirota, M., Aghaeepour, N. 2023; 15 (683): eadc9854

  Abstract

  Although prematurity is the single largest cause of death in children under 5 years of age, the current definition of prematurity, based on gestational age, lacks the precision needed for guiding care decisions. Here, we propose a longitudinal risk assessment for adverse neonatal outcomes in newborns based on a deep learning model that uses electronic health records (EHRs) to predict a wide range of outcomes over a period starting shortly before conception and ending months after birth. By linking the EHRs of the Lucile Packard Children's Hospital and the Stanford Healthcare Adult Hospital, we developed a cohort of 22,104 mother-newborn dyads delivered between 2014 and 2018. Maternal and newborn EHRs were extracted and used to train a multi-input multitask deep learning model, featuring a long short-term memory neural network, to predict 24 different neonatal outcomes. An additional cohort of 10,250 mother-newborn dyads delivered at the same Stanford Hospitals from 2019 to September 2020 was used to validate the model. Areas under the receiver operating characteristic curve at delivery exceeded 0.9 for 10 of the 24 neonatal outcomes considered and were between 0.8 and 0.9 for 7 additional outcomes. Moreover, comprehensive association analysis identified multiple known associations between various maternal and neonatal features and specific neonatal outcomes. This study used linked EHRs from more than 30,000 mother-newborn dyads and would serve as a resource for the investigation and prediction of neonatal outcomes. An interactive website is available for independent investigators to leverage this unique dataset: https://maternal-child-health-associations.shinyapps.io/shiny_app/.

  View details for DOI 10.1126/scitranslmed.adc9854

  View details for PubMedID 36791208

• Early prediction and longitudinal modeling of preeclampsia from multiomics. Patterns (New York, N.Y.) Maric, I., Contrepois, K., Moufarrej, M. N., Stelzer, I. A., Feyaerts, D., Han, X., Tang, A., Stanley, N., Wong, R. J., Traber, G. M., Ellenberger, M., Chang, A. L., Fallahzadeh, R., Nassar, H., Becker, M., Xenochristou, M., Espinosa, C., De Francesco, D., Ghaemi, M. S., Costello, E. K., Culos, A., Ling, X. B., Sylvester, K. G., Darmstadt, G. L., Winn, V. D., Shaw, G. M., Relman, D. A., Quake, S. R., Angst, M. S., Snyder, M. P., Stevenson, D. K., Gaudilliere, B., Aghaeepour, N. 2022; 3 (12): 100655

  Abstract

  Preeclampsia is a complex disease of pregnancy whose physiopathology remains unclear. We developed machine-learning models for early prediction of preeclampsia (first 16weeks of pregnancy) and over gestation by analyzing six omics datasets from a longitudinal cohort of pregnant women. For early pregnancy, a prediction model using nine urine metabolites had the highest accuracy and was validated on an independent cohort (area under the receiver-operating characteristic curve [AUC]= 0.88, 95% confidence interval [CI] [0.76, 0.99] cross-validated; AUC= 0.83, 95% CI [0.62,1] validated). Univariate analysis demonstrated statistical significance of identified metabolites. An integrated multiomics model further improved accuracy (AUC= 0.94). Several biological pathways were identified including tryptophan, caffeine, and arachidonic acid metabolisms. Integration with immune cytometry data suggested novel associations between immune and proteomic dynamics. While further validation in a larger population is necessary, these encouraging results can serve as a basis for a simple, early diagnostic test for preeclampsia.

  View details for DOI 10.1016/j.patter.2022.100655

  View details for PubMedID 36569558

• Butyrate induces development-dependent necrotizing enterocolitis-like intestinal epithelial injury via necroptosis. Pediatric research Wang, K., Tao, G., Salimi-Jazi, F., Lin, P., Sun, Z., Liu, B., Sinclair, T., Mostaghimi, M., Dunn, J., Sylvester, K. G. 2022

  Abstract

  BACKGROUND: The accumulation of short-chain fatty acids (SCFAs) from bacterial fermentation may adversely affect the under-developed gut as observed in premature newborns at risk for necrotizing enterocolitis (NEC). This study explores the mechanism by which specific SCFA fermentation products may injure the premature newborn intestine mucosa leading to NEC-like intestinal cell injury.METHODS: Intraluminal injections of sodium butyrate were administered to 14- and 28-day-old mice, whose small intestine and stool were harvested for analysis. Human intestinal epithelial stem cells (hIESCs) and differentiated enterocytes from preterm and term infants were treated with sodium butyrate at varying concentrations. Necrosulfonamide (NSA) and necrostatin-1 (Nec-1) were used to determine the protective effects of necroptosis inhibitors on butyrate-induced cell injury.RESULTS: The more severe intestinal epithelial injury was observed in younger mice upon exposure to butyrate (p=0.02). Enterocytes from preterm newborns demonstrated a significant increase in sensitivity to butyrate-induced cell injury compared to term newborn enterocytes (p=0.068, hIESCs; p=0.038, differentiated cells). NSA and Nec-1 significantly inhibited the cell death induced by butyrate.CONCLUSIONS: Butyrate induces developmental stage-dependent intestinal injury that resembles NEC. A primary mechanism of cell injury in NEC is necroptosis. Necroptosis inhibition may represent a potential preventive or therapeutic strategy for NEC.IMPACT: Butyrate induces developmental stage-dependent intestinal injury that resembles NEC. A primary mechanism of cell injury caused by butyrate in NEC is necroptosis. Necroptosis inhibitors proved effective at significantly ameliorating the enteral toxicity of butyrate and thereby suggest a novel mechanism and approach to the prevention and treatment of NEC in premature newborns.

  View details for DOI 10.1038/s41390-022-02333-z

  View details for PubMedID 36202969

• Single center blind testing of a US multi-center validated diagnostic algorithm for Kawasaki disease in Taiwan. Frontiers in immunology Kuo, H. C., Hao, S., Jin, B., Chou, C. J., Han, Z., Chang, L. S., Huang, Y. H., Hwa, K., Whitin, J. C., Sylvester, K. G., Reddy, C. D., Chubb, H., Ceresnak, S. R., Kanegaye, J. T., Tremoulet, A. H., Burns, J. C., McElhinney, D., Cohen, H. J., Ling, X. B. 2022; 13: 1031387

  Abstract

  Kawasaki disease (KD) is the leading cause of acquired heart disease in children. The major challenge in KD diagnosis is that it shares clinical signs with other childhood febrile control (FC) subjects. We sought to determine if our algorithmic approach applied to a Taiwan cohort.A single center (Chang Gung Memorial Hospital in Taiwan) cohort of patients suspected with acute KD were prospectively enrolled by local KD specialists for KD analysis. Our previously single-center developed computer-based two-step algorithm was further tested by a five-center validation in US. This first blinded multi-center trial validated our approach, with sufficient sensitivity and positive predictive value, to identify most patients with KD diagnosed at centers across the US. This study involved 418 KDs and 259 FCs from the Chang Gung Memorial Hospital in Taiwan.Our diagnostic algorithm retained sensitivity (379 of 418; 90.7%), specificity (223 of 259; 86.1%), PPV (379 of 409; 92.7%), and NPV (223 of 247; 90.3%) comparable to previous US 2016 single center and US 2020 fiver center results. Only 4.7% (15 of 418) of KD and 2.3% (6 of 259) of FC patients were identified as indeterminate. The algorithm identified 18 of 50 (36%) KD patients who presented 2 or 3 principal criteria. Of 418 KD patients, 157 were infants younger than one year and 89.2% (140 of 157) were classified correctly. Of the 44 patients with KD who had coronary artery abnormalities, our diagnostic algorithm correctly identified 43 (97.7%) including all patients with dilated coronary artery but one who found to resolve in 8 weeks.This work demonstrates the applicability of our algorithmic approach and diagnostic portability in Taiwan.

  View details for DOI 10.3389/fimmu.2022.1031387

  View details for PubMedID 36263040

  View details for PubMedCentralID PMC9575935

• Soluble Protein Hydrolysate Ameliorates Gastrointestinal Inflammation and Injury in 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis in Mice. Biomolecules Wei, J., Tao, G., Xu, B., Wang, K., Liu, J., Chen, C., Dunn, J. C., Currie, C., Framroze, B., Sylvester, K. G. 2022; 12 (9)

  Abstract

  Inflammatory bowel diseases (IBD) are chronic, recurring gastrointestinal diseases that severely impair health and quality of life. Although therapeutic options have significantly expanded in recent years, there is no effective therapy for a complete and permanent cure for IBD. Well tolerated dietary interventions to improve gastrointestinal health in IBD would be a welcome advance especially with anticipated favorable tolerability and affordability. Soluble protein hydrolysate (SPH) is produced by the enzymatic hydrolysis of commercial food industry salmon offcuts (consisting of the head, backbone and skin) and contains a multitude of bioactive peptides including those with anti-oxidant properties. This study aimed to investigate whether SPH ameliorates gastrointestinal injury in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis model. Mice were randomly assigned to four groups: Control (no colitis), Colitis, Colitis/CP (with control peptide treatment), and Colitis/SPH (with SPH treatment). Colitis was induced by cutaneous sensitization with 1% TNBS on day -8 followed by 2.5% TNBS enema challenge on day 0. Control peptides and SPH were provided to the mice in the Colitis/CP or Colitis/SPH group respectively by drinking water at the final concentration of 2% w/v daily from day -10 to day 4. Then, the colon was harvested on day 4 and examined macro- and microscopically. Relevant measures included disease activity index (DAI), colon histology injury, immune cells infiltration, pro- and anti-inflammatory cytokines and anti-oxidative gene expression. It was found that SPH treatment decreased the DAI score and colon tissue injury when compared to the colitis-only and CP groups. The protective mechanisms of SPH were associated with reduced infiltration of CD4+ T, CD8+ T and B220+ B lymphocytes but not macrophages, downregulated pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), and upregulated anti-inflammatory cytokines (transforming growth factor-beta1 and interleukin-10) in the colon tissue. Moreover, the upregulation of anti-oxidative genes, including ferritin heavy chain 1, heme oxygenase 1, NAD(P)H quinone oxidoreductase 1, and superoxide dismutase 1, in the colons of colitis/SPH group was observed compared with the control peptide treatment group. In conclusion, the protective mechanism of SPH is associated with anti-inflammatory and anti-oxidative effects as demonstrated herein in an established mice model of colitis. Clinical studies with SPH as a potential functional food for the prevention or as an adjuvant therapy in IBD may add an effective and targeted diet-based approach to IBD management in the future.

  View details for DOI 10.3390/biom12091287

  View details for PubMedID 36139127

• Progressive Metabolic Abnormalities Associated with the Development of Neonatal Bronchopulmonary Dysplasia. Nutrients Ye, C., Wu, J., Reiss, J. D., Sinclair, T. J., Stevenson, D. K., Shaw, G. M., Chace, D. H., Clark, R. H., Prince, L. S., Ling, X. B., Sylvester, K. G. 2022; 14 (17)

  Abstract

  Objective: To assess the longitudinal metabolic patterns during the evolution of bronchopulmonary dysplasia (BPD) development. Methods: A case-control dataset of preterm infants (<32-week gestation) was obtained from a multicenter database, including 355 BPD cases and 395 controls. A total of 72 amino acid (AA) and acylcarnitine (AC) variables, along with infants' calorie intake and growth outcomes, were measured on day of life 1, 7, 28, and 42. Logistic regression, clustering methods, and random forest statistical modeling were utilized to identify metabolic variables significantly associated with BPD development and to investigate their longitudinal patterns that are associated with BPD development. Results: A panel of 27 metabolic variables were observed to be longitudinally associated with BPD development. The involved metabolites increased from 1 predominant different AC by day 7 to 19 associated AA and AC compounds by day 28 and 16 metabolic features by day 42. Citrulline, alanine, glutamate, tyrosine, propionylcarnitine, free carnitine, acetylcarnitine, hydroxybutyrylcarnitine, and most median-chain ACs (C5:C10) were the most associated metabolites down-regulated in BPD babies over the early days of life, whereas phenylalanine, methionine, and hydroxypalmitoylcarnitine were observed to be up-regulated in BPD babies. Most calorie intake and growth outcomes revealed similar longitudinal patterns between BPD cases and controls over the first 6 weeks of life, after gestational adjustment. When combining with birth weight, the derived metabolic-based discriminative model observed some differences between those with and without BPD development, with c-statistics of 0.869 and 0.841 at day 7 and 28 of life on the test data. Conclusions: The metabolic panel we describe identified some metabolic differences in the blood associated with BPD pathogenesis. Further work is needed to determine whether these compounds could facilitate the monitoring and/or investigation of early-life metabolic status in the lung and other tissues for the prevention and management of BPD.

  View details for DOI 10.3390/nu14173547

  View details for PubMedID 36079804

• A data-driven health index for neonatal morbidities. iScience De Francesco, D., Blumenfeld, Y. J., Maric, I., Mayo, J. A., Chang, A. L., Fallahzadeh, R., Phongpreecha, T., Butwick, A. J., Xenochristou, M., Phibbs, C. S., Bidoki, N. H., Becker, M., Culos, A., Espinosa, C., Liu, Q., Sylvester, K. G., Gaudilliere, B., Angst, M. S., Stevenson, D. K., Shaw, G. M., Aghaeepour, N. 2022; 25 (4): 104143

  Abstract

  Whereas prematurity is a major cause of neonatal mortality, morbidity, and lifelong impairment, the degree of prematurity is usually defined by the gestational age (GA) at delivery rather than by neonatal morbidity. Here we propose a multi-task deep neural network model that simultaneously predicts twelve neonatal morbidities, as the basis for a new data-driven approach to define prematurity. Maternal demographics, medical history, obstetrical complications, and prenatal fetal findings were obtained from linked birth certificates and maternal/infant hospitalization records for 11,594,786 livebirths in California from 1991 to 2012. Overall, our model outperformed traditional models to assess prematurity which are based on GA and/or birthweight (area under the precision-recall curve was 0.326 for our model, 0.229 for GA, and 0.156 for small for GA). These findings highlight the potential of using machine learning techniques to predict multiple prematurity phenotypes and inform clinical decisions to prevent, diagnose and treat neonatal morbidities.

  View details for DOI 10.1016/j.isci.2022.104143

  View details for PubMedID 35402862

• Virtual reality experience for in utero fetal surgery: a new era of patient counselling and medical education BMJ INNOVATIONS Blumenfeld, Y. J., Axelrod, D. M., Sarno, D., Hintz, S. R., Sylvester, K. G., Grant, G. A., Belfort, M. A., Shamshirsaz, A. A., El-Sayed, Y. Y. 2022; 8 (2): 95-97

  View details for DOI 10.1136/bmjinnov-2021-000799

  View details for Web of Science ID 000823101300005

• Deviation from the precisely timed age-associated patterns revealed by blood metabolomics to find CRC patients at risk of relapse at the CRC diagnosis Thyparambil, S. P., Zhu, X., Zhang, Y., Sun, H., Peng, J., Cai, S., Li, Y., Fu, C., Bao, P., Hao, S., Li, Z., Ding, Y., Yao, X., Liao, W., Heaton, R., Han, Z., Tian, L., Schilling, J., Sylvester, K. G., Ling, X. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for DOI 10.1200/JCO.2022.40.4_suppl.206

  View details for Web of Science ID 000770995900202

• Metabolic model of necrotizing enterocolitis in the premature newborn gut resulting from enteric dysbiosis. Frontiers in pediatrics Casaburi, G., Wei, J., Kazi, S., Liu, J., Wang, K., Tao, G., Lin, P., Dunn, J. C., Henrick, B. M., Frese, S. A., Sylvester, K. G. 2022; 10: 893059

  Abstract

  Necrotizing enterocolitis (NEC) is a leading cause of premature newborn morbidity and mortality. The clinical features of NEC consistently include prematurity, gut dysbiosis and enteral inflammation, yet the pathogenesis remains obscure. Herein we combine metagenomics and targeted metabolomics, with functional in vivo and in vitro assessment, to define a novel molecular mechanism of NEC. One thousand six hundred and forty seven publicly available metagenomics datasets were analyzed (NEC = 245; healthy = 1,402) using artificial intelligence methodologies. Targeted metabolomic profiling was used to quantify the concentration of specified fecal metabolites at NEC onset (n = 8), during recovery (n = 6), and in age matched controls (n = 10). Toxicity assays of discovered metabolites were performed in vivo in mice and in vitro using human intestinal epithelial cells. Metagenomic and targeted metabolomic analyses revealed significant differences in pyruvate fermentation pathways and associated intermediates. Notably, the short chain fatty acid formate was elevated in the stool of NEC patients at disease onset (P = 0.005) dissipated during recovery (P = 0.02) and positively correlated with degree of intestinal injury (r 2 = 0.86). In vitro, formate caused enterocyte cytotoxicity in human cells through necroptosis (P < 0.01). In vivo, luminal formate caused significant dose and development dependent NEC-like injury in newborn mice. Enterobacter cloacae and Klebsiella pneumoniae were the most discriminatory taxa related to NEC dysbiosis and increased formate production. Together, these data suggest a novel biochemical mechanism of NEC through the microbial production of formate. Clinical efforts to prevent NEC should focus on reducing the functional consequences of newborn gut dysbiosis associated metabolic pathways.

  View details for DOI 10.3389/fped.2022.893059

  View details for PubMedID 36081629

• Serological Phenotyping Analysis Uncovers a Unique Metabolomic Pattern Associated With Early Onset of Type 2 Diabetes Mellitus. Frontiers in molecular biosciences Zhu, L., Huang, Q., Li, X., Jin, B., Ding, Y., Chou, C. J., Su, K., Zhang, Y., Chen, X., Hwa, K. Y., Thyparambil, S., Liao, W., Han, Z., Mortensen, R., Jin, Y., Li, Z., Schilling, J., Li, Z., Sylvester, K. G., Sun, X., Ling, X. B. 2022; 9: 841209

  Abstract

  Background: Type 2 diabetes mellitus (T2DM) is a multifaceted disorder affecting epidemic proportion at global scope. Defective insulin secretion by pancreatic beta-cells and the inability of insulin-sensitive tissues to respond effectively to insulin are the underlying biology of T2DM. However, circulating biomarkers indicative of early diabetic onset at the asymptomatic stage have not been well described. We hypothesized that global and targeted mass spectrometry (MS) based metabolomic discovery can identify novel serological metabolic biomarkers specifically associated with T2DM. We further hypothesized that these markers can have a unique pattern associated with latent or early asymptomatic stage, promising an effective liquid biopsy approach for population T2DM risk stratification and screening. Methods: Four independent cohorts were assembled for the study. The T2DM cohort included sera from 25 patients with T2DM and 25 healthy individuals for the biomarker discovery and sera from 15 patients with T2DM and 15 healthy controls for the testing. The Pre-T2DM cohort included sera from 76 with prediabetes and 62 healthy controls for the model training and sera from 35 patients with prediabetes and 27 healthy controls for the model testing. Both global and targeted (amino acid, acylcarnitine, and fatty acid) approaches were used to deep phenotype the serological metabolome by high performance liquid chromatography-high resolution mass spectrometry. Different machine learning approaches (Random Forest, XGBoost, and ElasticNet) were applied to model the unique T2DM/Pre-T2DM metabolic patterns and contrasted with their effectiness to differentiate T2DM/Pre-T2DM from controls. Results: The univariate analysis identified unique panel of metabolites (n = 22) significantly associated with T2DM. Global metabolomics and subsequent structure determination led to the identification of 8 T2DM biomarkers while targeted LCMS profiling discovered 14 T2DM biomarkers. Our panel can effectively differentiate T2DM (ROC AUC = 1.00) or Pre-T2DM (ROC AUC = 0.84) from the controls in the respective testing cohort. Conclusion: Our serological metabolite panel can be utilized to identifiy asymptomatic population at risk of T2DM, which may provide utility in identifying population at risk at an early stage of diabetic development to allow for clinical intervention. This early detection would guide ehanced levels of care and accelerate development of clinical strategies to prevent T2DM.

  View details for DOI 10.3389/fmolb.2022.841209

  View details for PubMedID 35463946

• Metabolic profiling of placental tissue and maternal plasma to identify biomarkers of placenta accreta spectrum Miller, S. E., Contrepois, K., Michael, B., Cruz, G., Simms, I., Datoc, I., Sylvester, K., Silver, R. M., Einerson, B. D., Bianco, K., Lyell, D. J. MOSBY-ELSEVIER. 2022: S14-S15

  View details for Web of Science ID 000737459400018

• Perinatal infection, inflammation, preterm birth, and brain injury: A review with proposals for future investigations. Experimental neurology Reiss, J. D., Peterson, L. S., Nesamoney, S. N., Chang, A. L., Pasca, A. M., Marić, I., Shaw, G. M., Gaudilliere, B., Wong, R. J., Sylvester, K. G., Bonifacio, S. L., Aghaeepour, N., Gibbs, R. S., Stevenson, D. K. 2022: 113988

  Abstract

  Preterm newborns are exposed to several risk factors for developing brain injury. Clinical studies have suggested that the presence of intrauterine infection is a consistent risk factor for preterm birth and white matter injury. Animal models have confirmed these associations by identifying inflammatory cascades originating at the maternofetal interface that penetrate the fetal blood-brain barrier and result in brain injury. Acquired diseases of prematurity further potentiate the risk for cerebral injury. Systems biology approaches incorporating ante- and post-natal risk factors and analyzing omic and multiomic data using machine learning are promising methodologies for further elucidating biologic mechanisms of fetal and neonatal brain injury.

  View details for DOI 10.1016/j.expneurol.2022.113988

  View details for PubMedID 35081400

• Early-pregnancy prediction of risk for pre-eclampsia using maternal blood leptin/ceramide ratio: discovery and confirmation. BMJ open Huang, Q., Hao, S., You, J., Yao, X., Li, Z., Schilling, J., Thyparambil, S., Liao, W., Zhou, X., Mo, L., Ladella, S., Davies-Balch, S. R., Zhao, H., Fan, D., Whitin, J. C., Cohen, H. J., McElhinney, D. B., Wong, R. J., Shaw, G. M., Stevenson, D. K., Sylvester, K. G., Ling, X. B. 2021; 11 (11): e050963

  Abstract

  OBJECTIVE: This study aimed to develop a blood test for the prediction of pre-eclampsia (PE) early in gestation. We hypothesised that the longitudinal measurements of circulating adipokines and sphingolipids in maternal serum over the course of pregnancy could identify novel prognostic biomarkers that are predictive of impending event of PE early in gestation.STUDY DESIGN: Retrospective discovery and longitudinal confirmation.SETTING: Maternity units from two US hospitals.PARTICIPANTS: Six previously published studies of placental tissue (78 PE and 95 non-PE) were compiled for genomic discovery, maternal sera from 15 women (7 non-PE and 8 PE) enrolled at ProMedDx were used for sphingolipidomic discovery, and maternal sera from 40 women (20 non-PE and 20 PE) enrolled at Stanford University were used for longitudinal observation.OUTCOME MEASURES: Biomarker candidates from discovery were longitudinally confirmed and compared in parallel to the ratio of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) using the same cohort. The datasets were generated by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays.RESULTS: Our discovery integrating genomic and sphingolipidomic analysis identified leptin (Lep) and ceramide (Cer) (d18:1/25:0) as novel biomarkers for early gestational assessment of PE. Our longitudinal observation revealed a marked elevation of Lep/Cer (d18:1/25:0) ratio in maternal serum at a median of 23 weeks' gestation among women with impending PE as compared with women with uncomplicated pregnancy. The Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting impending event of PE with superior sensitivity (85% vs 20%) and area under curve (0.92 vs 0.52) from 5 to 25 weeks of gestation.CONCLUSIONS: Our study demonstrated the longitudinal measurement of maternal Lep/Cer (d18:1/25:0) ratio allows the non-invasive assessment of PE to identify pregnancy at high risk in early gestation, outperforming the established sFlt-1/PlGF ratio test.

  View details for DOI 10.1136/bmjopen-2021-050963

  View details for PubMedID 34824115

• Newborn screen metabolic panels reflect the impact of common disorders of pregnancy. Pediatric research Reiss, J. D., Chang, A. L., Mayo, J. A., Bianco, K., Lee, H. C., Stevenson, D. K., Shaw, G. M., Aghaeepour, N., Sylvester, K. G. 2021

  Abstract

  BACKGROUND: Hypertensive disorders of pregnancy and maternal diabetes profoundly affect fetal and newborn growth, yet disturbances in intermediate metabolism and relevant mediators of fetal growth alterations remain poorly defined. We sought to determine whether there are distinct newborn screen metabolic patterns among newborns affected by maternal hypertensive disorders or diabetes in utero.METHODS: A retrospective observational study investigating distinct newborn screen metabolites in conjunction with data linked to birth and hospitalization records in the state of California between 2005 and 2010.RESULTS: A total of 41,333 maternal-infant dyads were included. Infants of diabetic mothers demonstrated associations with short-chain acylcarnitines and free carnitine. Infants born to mothers with preeclampsia with severe features and chronic hypertension with superimposed preeclampsia had alterations in acetylcarnitine, free carnitine, and ornithine levels. These results were further accentuated by size for gestational age designations.CONCLUSIONS: Infants of diabetic mothers demonstrate metabolic signs of incomplete beta oxidation and altered lipid metabolism. Infants of mothers with hypertensive disorders of pregnancy carry analyte signals that may reflect oxidative stress via altered nitric oxide signaling. The newborn screen analyte composition is influenced by the presence of these maternal conditions and is further associated with the newborn size designation at birth.IMPACT: Substantial differences in newborn screen analyte profiles were present based on the presence or absence of maternal diabetes or hypertensive disorder of pregnancy and this finding was further influenced by the newborn size designation at birth. The metabolic health of the newborn can be examined using the newborn screen and is heavily impacted by the condition of the mother during pregnancy. Utilizing the newborn screen to identify newborns affected by common conditions of pregnancy may help relate an infant's underlying biological disposition with their clinical phenotype allowing for greater risk stratification and intervention.

  View details for DOI 10.1038/s41390-021-01753-7

  View details for PubMedID 34671094

• Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial. Annals of surgery Blakely, M. L., Tyson, J. E., Lally, K. P., Hintz, S. R., Eggleston, B., Stevenson, D. K., Besner, G. E., Das, A., Ohls, R. K., Truog, W. E., Nelin, L. D., Poindexter, B. B., Pedroza, C., Walsh, M. C., Stoll, B. J., Geller, R., Kennedy, K. A., Dimmitt, R. A., Carlo, W. A., Cotten, C. M., Laptook, A. R., Van Meurs, K. P., Calkins, K. L., Sokol, G. M., Sanchez, P. J., Wyckoff, M. H., Patel, R. M., Frantz, I. D., Shankaran, S., D'Angio, C. T., Yoder, B. A., Bell, E. F., Watterberg, K. L., Martin, C. A., Harmon, C. M., Rice, H., Kurkchubasche, A. G., Sylvester, K., Dunn, J. C., Markel, T. A., Diesen, D. L., Bhatia, A. M., Flake, A., Chwals, W. J., Brown, R., Bass, K. D., St Peter, S. D., Shanti, C. M., Pegoli, W. J., Skarda, D., Shilyansky, J., Lemon, D. G., Mosquera, R. A., Peralta-Carcelen, M., Goldstein, R. F., Vohr, B. R., Purdy, I. B., Hines, A. C., Maitre, N. L., Heyne, R. J., DeMauro, S. B., McGowan, E. C., Yolton, K., Kilbride, H. W., Natarajan, G., Yost, K., Winter, S., Colaizy, T. T., Laughon, M. M., Lakshminrusimha, S., Higgins, R. D., Eunice Kennedy Shriver National Institute of Child Health, H. D. 2021; 274 (4): e370-e380

  Abstract

  OBJECTIVE: The aim of this study was to determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP).SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown.METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18 to 22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches.RESULTS: Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage [adjusted relative risk (aRR) 1.0; 95% confidence interval (CI): 0.87-1.14]. A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (P = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR 0.81; 95% CI: 0.64-1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference <0) for a preoperative diagnosis of NEC was 97%. For preoperative diagnosis of IP, death or NDI occurred in 69% after laparotomy versus 63% with drainage (aRR, 1.11; 95% CI: 0.95-1.31); Bayesian probability of benefit with laparotomy = 18%.CONCLUSIONS: There was no overall difference in death or NDI rates at 18 to 22 months corrected age between initial laparotomy versus drainage. However, the preoperative diagnosis of NEC or IP modified the impact of initial treatment.

  View details for DOI 10.1097/SLA.0000000000005099

  View details for PubMedID 34506326

• Novel Approaches to Develop Critical Reference Materials for Noninvasive Prenatal Testing: A Pilot Study. The journal of applied laboratory medicine Bianco, K., Sherwin, E. B., Konigshofer, Y., Girsen, A. I., Sylvester, K. G., Garlick, R. K. 2021

  Abstract

  BACKGROUND: Highly characterized reference materials are required to expand noninvasive prenatal testing (NIPT) for low incidence aneuploidies and microdeletions. The goal of this study was to develop reference materials for the development of next generation circulating cell-free DNA (ccfDNA) assays.METHODS: This was a prospective study of pregnancies complicated by positive prenatal genetic screening. ccfDNA was isolated from maternal plasma and amplified. Lymphoblastoid cell lines were prepared from maternal peripheral blood mononuclear cells and fetal cord blood cells. Cells were Epstein-Barr virus immortalized and expanded. Amplified DNA and to a limited extent formulated lymphoblastoid-derived ccfDNA was tested in SNP-based and chromosome counting (CC) based massively parallel sequencing assays.RESULTS: Enrolled cases included fetuses with: T21 (2), T18 (1), T18-XXX (1), XYY (1), microdeletions (1), and euploid (2). Three lymphoblastoid cells lines were prepared. Genomic DNA was extracted from cell lines and fragmented to simulate ccfDNA. ccfDNA isolation yielded about 2000 usable genome equivalents of DNA for each case for amplification. Although the sonicated genomic DNA derived from lymphoblastoid cell lines did not yield results compatible with NIPT assays, when blinded, NIPT platforms correctly identified the amplified ccfDNA isolated from blood in the majority of cases.CONCLUSIONS: This study showed that maternal blood samples from pregnancies complicated by common chromosomal abnormalities can be used to generate materials for the development and evaluation of NIPT assays.

  View details for DOI 10.1093/jalm/jfab037

  View details for PubMedID 34080621

• Author Correction: Metagenomic insights of the infant microbiome community structure and function across multiple sites in the United States. Scientific reports Casaburi, G., Duar, R. M., Brown, H., Mitchell, R. D., Kazi, S., Chew, S., Cagney, O., Flannery, R. L., Sylvester, K. G., Frese, S. A., Henrick, B. M., Freeman, S. L. 2021; 11 (1): 11050

  View details for DOI 10.1038/s41598-021-90391-4

  View details for PubMedID 34017057

• Multi-omics longitudinal analyses in stages I to III CRC patients: Surveillance liquid biopsy test to predict early recurrence and enable risk-stratified postoperative CRC management. Liu, X., Zhang, Y., Zhu, X., Thyparambil, S. P., Liao, W., Zheng, X., You, J., Masood, A., Li, Z., Yang, G., Yao, X., Hao, S., Heaton, R., Schilling, J., Sylvester, K. G., Liao, J., Gao, F., Lan, P., Ling, X., Wu, X. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.3613

  View details for Web of Science ID 000708120602102

• Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset. Science translational medicine Stelzer, I. A., Ghaemi, M. S., Han, X., Ando, K., Hedou, J. J., Feyaerts, D., Peterson, L. S., Rumer, K. K., Tsai, E. S., Ganio, E. A., Gaudilliere, D. K., Tsai, A. S., Choisy, B., Gaigne, L. P., Verdonk, F., Jacobsen, D., Gavasso, S., Traber, G. M., Ellenberger, M., Stanley, N., Becker, M., Culos, A., Fallahzadeh, R., Wong, R. J., Darmstadt, G. L., Druzin, M. L., Winn, V. D., Gibbs, R. S., Ling, X. B., Sylvester, K., Carvalho, B., Snyder, M. P., Shaw, G. M., Stevenson, D. K., Contrepois, K., Angst, M. S., Aghaeepour, N., Gaudilliere, B. 2021; 13 (592)

  Abstract

  Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [R = 0.85, 95% confidence interval (CI) [0.79 to 0.89], P = 1.2 * 10-40, N = 53, training set; R = 0.81, 95% CI [0.61 to 0.91], P = 3.9 * 10-7, N = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies.

  View details for DOI 10.1126/scitranslmed.abd9898

  View details for PubMedID 33952678

• Understanding how biologic and social determinants affect disparities in preterm birth and outcomes of preterm infants in the NICU. Seminars in perinatology Stevenson, D. K., Aghaeepour, N., Maric, I., Angst, M. S., Darmstadt, G. L., Druzin, M. L., Gaudilliere, B., Ling, X. B., Moufarrej, M. N., Peterson, L. S., Quake, S. R., Relman, D. A., Snyder, M. P., Sylvester, K. G., Shaw, G. M., Wong, R. J. 2021: 151408

  Abstract

  To understand the disparities in spontaneous preterm birth (sPTB) and/or its outcomes, biologic and social determinants as well as healthcare practice (such as those in neonatal intensive care units) should be considered. They have been largely intractable and remain obscure in most cases, despite a myriad of identified risk factors for and causes of sPTB. We still do not know how they might actually affect and lead to the different outcomes at different gestational ages and if they are independent of NICU practices. Here we describe an integrated approach to study the interplay between the genome and exposome, which may drive biochemistry and physiology, with health disparities.

  View details for DOI 10.1016/j.semperi.2021.151408

  View details for PubMedID 33875265

• Electronic Health Record-Based Prediction of 1-Year Risk of Incident Cardiac Dysrhythmia: Prospective Case-Finding Algorithm Development and Validation Study. JMIR medical informatics Zhang, Y., Han, Y., Gao, P., Mo, Y., Hao, S., Huang, J., Ye, F., Li, Z., Zheng, L., Yao, X., Li, Z., Li, X., Wang, X., Huang, C., Jin, B., Zhang, Y., Yang, G., Alfreds, S. T., Kanov, L., Sylvester, K. G., Widen, E., Li, L., Ling, X. 2021; 9 (2): e23606

  Abstract

  BACKGROUND: Cardiac dysrhythmia is currently an extremely common disease. Severe arrhythmias often cause a series of complications, including congestive heart failure, fainting or syncope, stroke, and sudden death.OBJECTIVE: The aim of this study was to predict incident arrhythmia prospectively within a 1-year period to provide early warning of impending arrhythmia.METHODS: Retrospective (1,033,856 individuals enrolled between October 1, 2016, and October 1, 2017) and prospective (1,040,767 individuals enrolled between October 1, 2017, and October 1, 2018) cohorts were constructed from integrated electronic health records in Maine, United States. An ensemble learning workflow was built through multiple machine learning algorithms. Differentiating features, including acute and chronic diseases, procedures, health status, laboratory tests, prescriptions, clinical utilization indicators, and socioeconomic determinants, were compiled for incident arrhythmia assessment. The predictive model was retrospectively trained and calibrated using an isotonic regression method and was prospectively validated. Model performance was evaluated using the area under the receiver operating characteristic curve (AUROC).RESULTS: The cardiac dysrhythmia case-finding algorithm (retrospective: AUROC 0.854; prospective: AUROC 0.827) stratified the population into 5 risk groups: 53.35% (555,233/1,040,767), 44.83% (466,594/1,040,767), 1.76% (18,290/1,040,767), 0.06% (623/1,040,767), and 0.003% (27/1,040,767) were in the very low-risk, low-risk, medium-risk, high-risk, and very high-risk groups, respectively; 51.85% (14/27) patients in the very high-risk subgroup were confirmed to have incident cardiac dysrhythmia within the subsequent 1 year.CONCLUSIONS: Our case-finding algorithm is promising for prospectively predicting 1-year incident cardiac dysrhythmias in a general population, and we believe that our case-finding algorithm can serve as an early warning system to allow statewide population-level screening and surveillance to improve cardiac dysrhythmia care.

  View details for DOI 10.2196/23606

  View details for PubMedID 33595452

• Metagenomic insights of the infant microbiome community structure and function across multiple sites in the United States. Scientific reports Casaburi, G. n., Duar, R. M., Brown, H. n., Mitchell, R. D., Kazi, S. n., Chew, S. n., Cagney, O. n., Flannery, R. L., Sylvester, K. G., Frese, S. A., Henrick, B. M., Freeman, S. L. 2021; 11 (1): 1472

  Abstract

  The gut microbiome plays an important role in early life, protecting newborns from enteric pathogens, promoting immune system development and providing key functions to the infant host. Currently, there are limited data to broadly assess the status of the US healthy infant gut microbiome. To address this gap, we performed a multi-state metagenomic survey and found high levels of bacteria associated with enteric inflammation (e.g. Escherichia, Klebsiella), antibiotic resistance genes, and signatures of dysbiosis, independent of location, age, and diet. Bifidobacterium were less abundant than generally expected and the species identified, including B. breve, B. longum and B. bifidum, had limited genetic capacity to metabolize human milk oligosaccharides (HMOs), while B. infantis strains with a complete capacity for HMOs utilization were found to be exceptionally rare. Considering microbiome composition and functional capacity, this survey revealed a previously unappreciated dysbiosis that is widespread in the contemporary US infant gut microbiome.

  View details for DOI 10.1038/s41598-020-80583-9

  View details for PubMedID 33479326

• Identification of patients at risk of new onset heart failure: Utilizing a large statewide health information exchange to train and validate a risk prediction model. PloS one Duong, S. Q., Zheng, L., Xia, M., Jin, B., Liu, M., Li, Z., Hao, S., Alfreds, S. T., Sylvester, K. G., Widen, E., Teuteberg, J. J., McElhinney, D. B., Ling, X. B. 2021; 16 (12): e0260885

  Abstract

  BACKGROUND: New-onset heart failure (HF) is associated with poor prognosis and high healthcare utilization. Early identification of patients at increased risk incident-HF may allow for focused allocation of preventative care resources. Health information exchange (HIE) data span the entire spectrum of clinical care, but there are no HIE-based clinical decision support tools for diagnosis of incident-HF. We applied machine-learning methods to model the one-year risk of incident-HF from the Maine statewide-HIE.METHODS AND RESULTS: We included subjects aged ≥ 40 years without prior HF ICD9/10 codes during a three-year period from 2015 to 2018, and incident-HF defined as assignment of two outpatient or one inpatient code in a year. A tree-boosting algorithm was used to model the probability of incident-HF in year two from data collected in year one, and then validated in year three. 5,668 of 521,347 patients (1.09%) developed incident-HF in the validation cohort. In the validation cohort, the model c-statistic was 0.824 and at a clinically predetermined risk threshold, 10% of patients identified by the model developed incident-HF and 29% of all incident-HF cases in the state of Maine were identified.CONCLUSIONS: Utilizing machine learning modeling techniques on passively collected clinical HIE data, we developed and validated an incident-HF prediction tool that performs on par with other models that require proactively collected clinical data. Our algorithm could be integrated into other HIEs to leverage the EMR resources to provide individuals, systems, and payors with a risk stratification tool to allow for targeted resource allocation to reduce incident-HF disease burden on individuals and health care systems.

  View details for DOI 10.1371/journal.pone.0260885

  View details for PubMedID 34890438

• Maternal metabolic profiling to assess fetal gestational age and predict preterm delivery: a two-centre retrospective cohort study in the US. BMJ open Sylvester, K. G., Hao, S., You, J., Zheng, L., Tian, L., Yao, X., Mo, L., Ladella, S., Wong, R. J., Shaw, G. M., Stevenson, D. K., Cohen, H. J., Whitin, J. C., McElhinney, D. B., Ling, X. B. 2020; 10 (12): e040647

  Abstract

  OBJECTIVES: The aim of this study was to develop a single blood test that could determine gestational age and estimate the risk of preterm birth by measuring serum metabolites. We hypothesised that serial metabolic modelling of serum analytes throughout pregnancy could be used to describe fetal gestational age and project preterm birth with a high degree of precision.STUDY DESIGN: A retrospective cohort study.SETTING: Two medical centres from the USA.PARTICIPANTS: Thirty-six patients (20 full-term, 16 preterm) enrolled at Stanford University were used to develop gestational age and preterm birth risk algorithms, 22 patients (9 full-term, 13 preterm) enrolled at the University of Alabama were used to validate the algorithms.OUTCOME MEASURES: Maternal blood was collected serially throughout pregnancy. Metabolic datasets were generated using mass spectrometry.RESULTS: A model to determine gestational age was developed (R2=0.98) and validated (R2=0.81). 66.7% of the estimates fell within ±1week of ultrasound results during model validation. Significant disruptions from full-term pregnancy metabolic patterns were observed in preterm pregnancies (R2=-0.68). A separate algorithm to predict preterm birth was developed using a set of 10 metabolic pathways that resulted in an area under the curve of 0.96 and 0.92, a sensitivity of 0.88 and 0.86, and a specificity of 0.96 and 0.92 during development and validation testing, respectively.CONCLUSIONS: In this study, metabolic profiling was used to develop and test a model for determining gestational age during full-term pregnancy progression, and to determine risk of preterm birth. With additional patient validation studies, these algorithms may be used to identify at-risk pregnancies prompting alterations in clinical care, and to gain biological insights into the pathophysiology of preterm birth. Metabolic pathway-based pregnancy modelling is a novel modality for investigation and clinical application development.

  View details for DOI 10.1136/bmjopen-2020-040647

  View details for PubMedID 33268420

• Towards personalized medicine in maternal and child health: integrating biologic and social determinants. Pediatric research Stevenson, D. K., Wong, R. J., Aghaeepour, N., Maric, I., Angst, M. S., Contrepois, K., Darmstadt, G. L., Druzin, M. L., Eisenberg, M. L., Gaudilliere, B., Gibbs, R. S., Gotlib, I. H., Gould, J. B., Lee, H. C., Ling, X. B., Mayo, J. A., Moufarrej, M. N., Quaintance, C. C., Quake, S. R., Relman, D. A., Sirota, M., Snyder, M. P., Sylvester, K. G., Hao, S., Wise, P. H., Shaw, G. M., Katz, M. 2020

  View details for DOI 10.1038/s41390-020-0981-8

  View details for PubMedID 32454518

• Proteomic profiling to identify therapeutics targets in glioblastoma (GBM). Thyparambil, S. P., Liao, W., An, E., Bhalkikar, A., Heaton, R., Sylvester, K. G., Ling, X. B. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368301250

• Deviation from the precisely timed phenomic ageotypes can assist in early CRC screening and reveal underlying pathophysiology. Thyparambil, S. P., You, J., Liu, K., Sun, H., Peng, J., Cai, S., Li, Y., Fu, C., Bao, P., Li, Q., Hao, S., Zhang, Y., Li, Z., Yang, J., Yin, Z., Yao, X., Zhu, X., Schilling, J., Sylvester, K. G., Ling, X. B. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368305453

• Treating Center Volume and Congenital Diaphragmatic Hernia Outcomes in California. The Journal of pediatrics Apfeld, J. C., Kastenberg, Z. J., Gibbons, A. T., Carmichael, S. L., Lee, H. C., Sylvester, K. G. 2020

  Abstract

  OBJECTIVE: To examined outcomes for infants born with congenital diaphragmatic hernias (CDH), according to specific treatment center volume indicators.STUDY DESIGN: A population-based retrospective cohort study was conducted involving neonatal intensive care units in California. Multivariable analysis was used to examine the outcomes of infants with CDH including mortality, total days on ventilation, and respiratory support at discharge. Significant covariables of interest included treatment center surgical and overall neonatal intensive care unit volumes.RESULTS: There were 728 infants in the overall CDH cohort, and 541 infants (74%) in the lower risk subcohort according to a severity-weighted congenital malformation score and never requiring extracorporeal membrane oxygenation. The overall cohort mortality was 28.3% (n=206), and 19.8% (n=107) for the subcohort. For the lower risk subcohort, the adjusted odds of mortality were significantly lower at treatment centers with higher CDH repair volume (OR, 0.41; 95% CI, 0.23-0.75; P=.003), ventilator days were significantly lower at centers with higher thoracic surgery volume (OR, 0.56; 9 5% CI, 0.33-0.95; P=.03), and respiratory support at discharge trended lower at centers with higher neonatal intensive care unit admission volumes (OR, 0.51; 9 5% CI, 0.26-1.02; P=.06).CONCLUSIONS: Overall and surgery-specific institutional experience significantly contribute to optimized outcomes for infants with CDH. These data and follow-on studies may help inform the ongoing debate over the optimal care setting and relevant quality indicators for newborn infants with major surgical anomalies.

  View details for DOI 10.1016/j.jpeds.2020.03.028

  View details for PubMedID 32418817

• Progressive Metabolic Dysfunction and Nutritional Variability Precedes Necrotizing Enterocolitis. Nutrients Sinclair, T. J., Ye, C., Chen, Y., Zhang, D., Li, T., Ling, X. B., Cohen, H. J., Shaw, G. M., Stevenson, D. K., Chace, D., Clark, R. H., Sylvester, K. G. 2020; 12 (5)

  Abstract

  Necrotizing Enterocolitis (NEC) is associated with prematurity, enteral feedings, and enteral dysbiosis. Accordingly, we hypothesized that along with nutritional variability, metabolic dysfunction would be associated with NEC onset. Methods: We queried a multicenter longitudinal database that included 995 preterm infants (<32 weeks gestation) and included 73 cases of NEC. Dried blood spot samples were obtained on day of life 1, 7, 28, and 42. Metabolite data from each time point included 72 amino acid (AA) and acylcarnitine (AC) measures. Nutrition data were averaged at each of the same time points. Odds ratios and 95% confidence intervals were calculated using samples obtained prior to NEC diagnosis and adjusted for potential confounding variables. Nutritional and metabolic data were plotted longitudinally to determine relationship to NEC onset. Results: Day 1 analyte levels of alanine, phenylalanine, free carnitine, C16, arginine, C14:1/C16, and citrulline/phenylalanine were associated with the subsequent development of NEC. Over time, differences in individual analyte levels associated with NEC onset shifted from predominantly AAs at birth to predominantly ACs by day 42. Subjects who developed NEC received significantly lower weight-adjusted total calories (p < 0.001) overall, a trend that emerged by day of life 7 (p = 0.020), and persisted until day of life 28 (p < 0.001) and 42 (p < 0.001). Conclusion: Premature infants demonstrate metabolic differences at birth. Metabolite abnormalities progress in parallel to significant differences in nutritional delivery signifying metabolic dysfunction in premature newborns prior to NEC onset. These observations provide new insights to potential contributing pathophysiology of NEC and opportunity for clinical care-based prevention.

  View details for DOI 10.3390/nu12051275

  View details for PubMedID 32365850

• Expression of antibody-drug conjugates (ADC) biomarkers in colorectal cancer. Thyparambil, S. P., Liao, W., An, E., Tian, Y., Heaton, R., Sylvester, K. G., Ling, X. B. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000530922700017

• High-throughput quantitation of serological ceramides/dihydroceramides by LC/MS/MS: Pregnancy baseline biomarkers and potential metabolic messengers. Journal of pharmaceutical and biomedical analysis Huang, Q. n., Hao, S. n., Yao, X. n., You, J. n., Li, X. n., Lai, D. n., Han, C. n., Schilling, J. n., Hwa, K. Y., Thyparambil, S. n., Whitin, J. n., Cohen, H. J., Chubb, H. n., Ceresnak, S. R., McElhinney, D. B., Wong, R. J., Shaw, G. M., Stevenson, D. K., Sylvester, K. G., Ling, X. B. 2020; 192: 113639

  Abstract

  Ceramides and dihydroceramides are sphingolipids that present in abundance at the cellular membrane of eukaryotes. Although their metabolic dysregulation has been implicated in many diseases, our knowledge about circulating ceramide changes during the pregnancy remains limited. In this study, we present the development and validation of a high-throughput liquid chromatography-tandem mass spectrometric method for simultaneous quantification of 16 ceramides and 10 dihydroceramides in human serum within 5 min. by using stable isotope-labeled ceramides as internal standards. This method employs a protein precipitation method for high throughput sample preparation, reverse phase isocratic elusion for chromatographic separation, and Multiple Reaction Monitoring for mass spectrometric detection. To qualify for clinical applications, our assay has been validated against the FDA guidelines for Lower Limit of Quantitation (1 nM), linearity (R2>0.99), precision (imprecision<15 %), accuracy (inaccuracy<15 %), extraction recovery (>90 %), stability (>85 %), and carryover (<0.01 %). With enhanced sensitivity and specificity from this method, we have, for the first time, determined the serological levels of ceramides and dihydroceramides to reveal unique temporal gestational patterns. Our approach could have value in providing insights into disorders of pregnancy.

  View details for DOI 10.1016/j.jpba.2020.113639

  View details for PubMedID 33017796

• Racial/ethnic disparities and human milk use in necrotizing enterocolitis. Pediatric research Goldstein, G. P., Pai, V. V., Liu, J. n., Sigurdson, K. n., Vernon, L. B., Lee, H. C., Sylvester, K. G., Shaw, G. M., Profit, J. n. 2020; 88 (Suppl 1): 3–9

  Abstract

  The impact of human milk use on racial/ethnic disparities in necrotizing enterocolitis (NEC) incidence is unknown.Trends in NEC incidence and human milk use at discharge were evaluated by race/ethnicity among 47,112 very low birth weight infants born in California from 2008 to 2017. We interrogated the association between race/ethnicity and NEC using multilevel regression analysis, and evaluated the effect of human milk use at discharge on the relationship between race/ethnicity and NEC using mediation analysis.Annual NEC incidence declined across all racial/ethnic groups from an aggregate average of 4.8% in 2008 to 2.6% in 2017. Human milk use at discharge increased over the time period across all racial groups, and non-Hispanic (NH) black infants received the least human milk each year. In multivariable analyses, Hispanic ethnicity (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.02-1.57) and Asian or Pacific Islander race (OR 1.35, 95% CI 1.01-1.80) were each associated with higher odds of NEC, while the association of NH black race with NEC was attenuated after adding human milk use at discharge to the model. Mediation analysis revealed that human milk use at discharge accounted for 22% of the total risk of NEC in non-white vs. white infants, and 44% in black vs. white infants.Although NEC incidence has declined substantially over the past decade, a sizable racial/ethnic disparity persists. Quality improvement initiatives augmenting human milk use may further reduce the incidence of NEC in vulnerable populations.

  View details for DOI 10.1038/s41390-020-1073-5

  View details for PubMedID 32855505

• Identification of elders at higher risk for fall with statewide electronic health records and a machine learning algorithm. International journal of medical informatics Ye, C. n., Li, J. n., Hao, S. n., Liu, M. n., Jin, H. n., Zheng, L. n., Xia, M. n., Jin, B. n., Zhu, C. n., Alfreds, S. T., Stearns, F. n., Kanov, L. n., Sylvester, K. G., Widen, E. n., McElhinney, D. n., Ling, X. B. 2020; 137: 104105

  Abstract

  Predicting the risk of falls in advance can benefit the quality of care and potentially reduce mortality and morbidity in the older population. The aim of this study was to construct and validate an electronic health record-based fall risk predictive tool to identify elders at a higher risk of falls.The one-year fall prediction model was developed using the machine-learning-based algorithm, XGBoost, and tested on an independent validation cohort. The data were collected from electronic health records (EHR) of Maine from 2016 to 2018, comprising 265,225 older patients (≥65 years of age).This model attained a validated C-statistic of 0.807, where 50 % of the identified high-risk true positives were confirmed to fall during the first 94 days of next year. The model also captured in advance 58.01 % and 54.93 % of falls that happened within the first 30 and 30-60 days of next year. The identified high-risk patients of fall showed conditions of severe disease comorbidities, an enrichment of fall-increasing cardiovascular and mental medication prescriptions and increased historical clinical utilization, revealing the complexity of the underlying fall etiology. The XGBoost algorithm captured 157 impactful predictors into the final predictive model, where cognitive disorders, abnormalities of gait and balance, Parkinson's disease, fall history and osteoporosis were identified as the top-5 strongest predictors of the future fall event.By using the EHR data, this risk assessment tool attained an improved discriminative ability and can be immediately deployed in the health system to provide automatic early warnings to older adults with increased fall risk and identify their personalized risk factors to facilitate customized fall interventions.

  View details for DOI 10.1016/j.ijmedinf.2020.104105

  View details for PubMedID 32193089

• Development of an early-warning system for high-risk patients for suicide attempt using deep learning and electronic health records. Translational psychiatry Zheng, L. n., Wang, O. n., Hao, S. n., Ye, C. n., Liu, M. n., Xia, M. n., Sabo, A. N., Markovic, L. n., Stearns, F. n., Kanov, L. n., Sylvester, K. G., Widen, E. n., McElhinney, D. B., Zhang, W. n., Liao, J. n., Ling, X. B. 2020; 10 (1): 72

  Abstract

  Suicide is the tenth leading cause of death in the United States (US). An early-warning system (EWS) for suicide attempt could prove valuable for identifying those at risk of suicide attempts, and analyzing the contribution of repeated attempts to the risk of eventual death by suicide. In this study we sought to develop an EWS for high-risk suicide attempt patients through the development of a population-based risk stratification surveillance system. Advanced machine-learning algorithms and deep neural networks were utilized to build models with the data from electronic health records (EHRs). A final risk score was calculated for each individual and calibrated to indicate the probability of a suicide attempt in the following 1-year time period. Risk scores were subjected to individual-level analysis in order to aid in the interpretation of the results for health-care providers managing the at-risk cohorts. The 1-year suicide attempt risk model attained an area under the curve (AUC ROC) of 0.792 and 0.769 in the retrospective and prospective cohorts, respectively. The suicide attempt rate in the "very high risk" category was 60 times greater than the population baseline when tested in the prospective cohorts. Mental health disorders including depression, bipolar disorders and anxiety, along with substance abuse, impulse control disorders, clinical utilization indicators, and socioeconomic determinants were recognized as significant features associated with incident suicide attempt.

  View details for DOI 10.1038/s41398-020-0684-2

  View details for PubMedID 32080165

• Survival of infants with congenital diaphragmatic hernia in California: impact of hospital, clinical, and sociodemographic factors. Journal of perinatology : official journal of the California Perinatal Association Carmichael, S. L., Ma, C. n., Lee, H. C., Shaw, G. M., Sylvester, K. G., Hintz, S. R. 2020

  Abstract

  To understand factors associated with care and survival among babies with congenital diaphragmatic hernia (CDH).We used data on California births (2006-2011) to examine birth hospital level of care, hospital transfer before repair, and survival.Among 577 infants, 25% were born at lower-level hospitals, 62% were transferred, and 31% died during infancy. Late or no prenatal care had the strongest association with birth at lower-level hospitals (adjusted relative risk (ARR) = 1.9, 95% confidence interval (CI) = 1.0-3.6). Birth at lower-level hospitals was associated with transfer (ARR = 1.2, CI = 1.1-1.4), and transferred infants tended to be less clinically complex. Infants with low birthweight, other birth defects, low Apgar scores, and late or no prenatal care had two- to fourfold higher risk of mortality than their comparison groups.These data support the importance of prenatal care and delivery planning into higher-level hospitals for optimal care and outcomes for newborns with CDH.

  View details for DOI 10.1038/s41372-020-0612-6

  View details for PubMedID 32086437

• Changes in pregnancy-related serum biomarkers early in gestation are associated with later development of preeclampsia. PloS one Hao, S. n., You, J. n., Chen, L. n., Zhao, H. n., Huang, Y. n., Zheng, L. n., Tian, L. n., Maric, I. n., Liu, X. n., Li, T. n., Bianco, Y. K., Winn, V. D., Aghaeepour, N. n., Gaudilliere, B. n., Angst, M. S., Zhou, X. n., Li, Y. M., Mo, L. n., Wong, R. J., Shaw, G. M., Stevenson, D. K., Cohen, H. J., Mcelhinney, D. B., Sylvester, K. G., Ling, X. B. 2020; 15 (3): e0230000

  Abstract

  Placental protein expression plays a crucial role during pregnancy. We hypothesized that: (1) circulating levels of pregnancy-associated, placenta-related proteins throughout gestation reflect the temporal progression of the uncomplicated, full-term pregnancy, and can effectively estimate gestational ages (GAs); and (2) preeclampsia (PE) is associated with disruptions in these protein levels early in gestation; and can identify impending PE. We also compared gestational profiles of proteins in the human and mouse, using pregnant heme oxygenase-1 (HO-1) heterozygote (Het) mice, a mouse model reflecting PE-like symptoms.Serum levels of placenta-related proteins-leptin (LEP), chorionic somatomammotropin hormone like 1 (CSHL1), elabela (ELA), activin A, soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF)-were quantified by ELISA in blood serially collected throughout human pregnancies (20 normal subjects with 66 samples, and 20 subjects who developed PE with 61 samples). Multivariate analysis was performed to estimate the GA in normal pregnancy. Mean-squared errors of GA estimations were used to identify impending PE. The human protein profiles were then compared with those in the pregnant HO-1 Het mice.An elastic net-based gestational dating model was developed (R2 = 0.76) and validated (R2 = 0.61) using serum levels of the 6 proteins measured at various GAs from women with normal uncomplicated pregnancies. In women who developed PE, the model was not (R2 = -0.17) associated with GA. Deviations from the model estimations were observed in women who developed PE (P = 0.01). The model developed with 5 proteins (ELA excluded) performed similarly from sera from normal human (R2 = 0.68) and WT mouse (R2 = 0.85) pregnancies. Disruptions of this model were observed in both human PE-associated (R2 = 0.27) and mouse HO-1 Het (R2 = 0.30) pregnancies. LEP outperformed sFlt-1 and PlGF in differentiating impending PE at early human and late mouse GAs.Serum placenta-related protein profiles are temporally regulated throughout normal pregnancies and significantly disrupted in women who develop PE. LEP changes earlier than the well-established biomarkers (sFlt-1 and PlGF). There may be evidence of a causative action of HO-1 deficiency in LEP upregulation in a PE-like murine model.

  View details for DOI 10.1371/journal.pone.0230000

  View details for PubMedID 32126118

• Kinetics of SARS-CoV-2 positivity of infected and recovered patients from a single center. Scientific reports Huang, J. n., Zheng, L. n., Li, Z. n., Hao, S. n., Ye, F. n., Chen, J. n., Gans, H. A., Yao, X. n., Liao, J. n., Wang, S. n., Zeng, M. n., Qiu, L. n., Li, C. n., Whitin, J. C., Tian, L. n., Chubb, H. n., Hwa, K. Y., Ceresnak, S. R., Zhang, W. n., Lu, Y. n., Maldonado, Y. A., McElhinney, D. B., Sylvester, K. G., Cohen, H. J., Liu, L. n., Ling, X. B. 2020; 10 (1): 18629

  Abstract

  Recurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive detection in infected but recovered individuals has been reported. Patients who have recovered from coronavirus disease 2019 (COVID-19) could profoundly impact the health care system. We sought to define the kinetics and relevance of PCR-positive recurrence during recovery from acute COVID-19 to better understand risks for prolonged infectivity and reinfection. A series of 414 patients with confirmed SARS-Cov-2 infection, at The Second Affiliated Hospital of Southern University of Science and Technology in Shenzhen, China from January 11 to April 23, 2020. Statistical analyses were performed of the clinical, laboratory, radiologic image, medical treatment, and clinical course of admission/quarantine/readmission data, and a recurrence predictive algorithm was developed. 16.7% recovered patients with PCR positive recurring one to three times, despite being in strict quarantine. Younger patients with mild pulmonary respiratory syndrome had higher risk of PCR positivity recurrence. The recurrence prediction model had an area under the ROC curve of 0.786. This case series provides characteristics of patients with recurrent SARS-CoV-2 positivity. Use of a prediction algorithm may identify patients at high risk of recurrent SARS-CoV-2 positivity and help to establish protocols for health policy.

  View details for DOI 10.1038/s41598-020-75629-x

  View details for PubMedID 33122706

• In fetuses with congenital lung masses, decreased ventricular and atrioventricular valve dimensions are associated with lesion size and clinical outcome. Prenatal diagnosis Mardy, C., Blumenfeld, Y. J., Arunamata, A. A., Girsen, A. I., Sylvester, K. G., Halabi, S., Rubesova, E., Hintz, S. R., Tacy, T. A., Maskatia, S. A. 2019

  Abstract

  INTRODUCTION: The clinical importance of mass effect from congenital lung masses on the fetal heart is unknown. We aimed to report cardiac measurements in fetuses with congenital lung masses, and correlate lung mass severity/size with cardiac dimensions and clinical outcomes.METHODS: Cases were identified from our institutional database between 2009 and 2016. We recorded: atrioventricular valve (AVVz) annulus dimensions and ventricular widths (VWz) converted into z-scores, ratio of aortic to total cardiac output (AoCO), lesion side, and congenital pulmonary airway malformation volume ratio (CVR). Respiratory intervention (RI) was defined as: intubation, ECMO use or surgical intervention prior to discharge.RESULTS: Fifty-two fetuses comprised the study cohort. Mean AVVz and VWz were below expected for gestational age. CVR correlated with ipsilateral AVVz (RS =-0.59, p<0.001) and ipsilateral VWz (-0.59, p<0.001). Lower AVVz, AoCO, and higher CVR were associated with RI. No patient had significant structural heart disease identified postnatally.CONCLUSION: In fetuses with left-sided lung masses, ipsilateral cardiac structures tend to be smaller, but in our cohort there were no patients with structural heart disease. However, smaller left-sided structures may contribute to the need for RI that affects a portion of these fetuses.

  View details for DOI 10.1002/pd.5612

  View details for PubMedID 31742724

• Recent Advances in Prevention and Therapies for Clinical or Experimental Necrotizing Enterocolitis DIGESTIVE DISEASES AND SCIENCES Wang, K., Tao, G., Sylvester, K. G. 2019; 64 (11): 3078–85

  View details for DOI 10.1007/s10620-019-05618-2

  View details for Web of Science ID 000495483700010

• Effects of gestational age at delivery and type of labor on neonatal outcomes among infants with gastroschisis. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians Girsen, A. I., Davis, A. S., Hintz, S. R., Fluharty, E., Sherwin, K., Trepman, P., Desai, A., Mansour, T., Sylvester, K. G., Oshiro, B., Blumenfeld, Y. J. 2019: 1–191

  Abstract

  Objective: To investigate the effect of preterm gestational age on neonatal outcomes of gastroschisis and to compare the neonatal outcomes after spontaneous labor versus iatrogenic delivery both in the preterm and early term gestational periods. Study design: A retrospective study of prenatally-diagnosed gastroschisis cases born at Loma Linda University Medical Center and Lucile Packard Children's Hospital (CA, USA) between January 2009 and October 2016. A total of 194 prenatally diagnosed gastroschisis cases were identified and included in the analysis. We compared infants delivered < 37 0/7 to those ≥ 37 0/7 weeks' gestation. Adverse neonatal outcome was defined as any of: sepsis, short bowel syndrome, prolonged ventilation or death. Prolonged length of stay (LOS) was defined as ≥ 75th percentile value. Outcomes following spontaneous versus iatrogenic delivery were compared. Analyses were performed using chi-squared test or Fisher's exact test for categorical variables, and Student's t-test or Wilcoxon rank-sum test for continuous variables. Results: One hundred six neonates were born < 37weeks and 88 at ≥ 37weeks. Adverse outcome was statistically similar among those born < 37weeks compared to ≥ 37weeks (48 versus 34%, p = 0.07). Prolonged LOS was more frequent among neonates delivered < 37weeks (p = 0.03). Among neonates born < 37weeks, bowel atresia was more frequent in those with spontaneous versus iatrogenic delivery (p = 0.04). There was no significant difference in the adverse neonatal composite outcome between those with spontaneous preterm labor versus planned iatrogenic delivery at < 37weeks (n = 30 (58%) versus n = 21 (39%), p = 0.08). Conclusion: Neonates with gastroschisis delivered < 37weeks had prolonged LOS whereas the rate of adverse neonatal outcomes was similar between those delivered preterm versus term. Neonates born after spontaneous preterm labor had a higher rate of bowel atresia compared to those born after planned iatrogenic preterm delivery.

  View details for DOI 10.1080/14767058.2019.1656191

  View details for PubMedID 31409162

• A Real-Time Early Warning System for Monitoring Inpatient Mortality Risk: Prospective Study Using Electronic Medical Record Data. Journal of medical Internet research Ye, C., Wang, O., Liu, M., Zheng, L., Xia, M., Hao, S., Jin, B., Jin, H., Zhu, C., Huang, C. J., Gao, P., Ellrodt, G., Brennan, D., Stearns, F., Sylvester, K. G., Widen, E., McElhinney, D. B., Ling, X. 2019; 21 (7): e13719

  Abstract

  BACKGROUND: The rapid deterioration observed in the condition of some hospitalized patients can be attributed to either disease progression or imperfect triage and level of care assignment after their admission. An early warning system (EWS) to identify patients at high risk of subsequent intrahospital death can be an effective tool for ensuring patient safety and quality of care and reducing avoidable harm and costs.OBJECTIVE: The aim of this study was to prospectively validate a real-time EWS designed to predict patients at high risk of inpatient mortality during their hospital episodes.METHODS: Data were collected from the system-wide electronic medical record (EMR) of two acute Berkshire Health System hospitals, comprising 54,246 inpatient admissions from January 1, 2015, to September 30, 2017, of which 2.30% (1248/54,246) resulted in intrahospital deaths. Multiple machine learning methods (linear and nonlinear) were explored and compared. The tree-based random forest method was selected to develop the predictive application for the intrahospital mortality assessment. After constructing the model, we prospectively validated the algorithms as a real-time inpatient EWS for mortality.RESULTS: The EWS algorithm scored patients' daily and long-term risk of inpatient mortality probability after admission and stratified them into distinct risk groups. In the prospective validation, the EWS prospectively attained a c-statistic of 0.884, where 99 encounters were captured in the highest risk group, 69% (68/99) of whom died during the episodes. It accurately predicted the possibility of death for the top 13.3% (34/255) of the patients at least 40.8 hours before death. Important clinical utilization features, together with coded diagnoses, vital signs, and laboratory test results were recognized as impactful predictors in the final EWS.CONCLUSIONS: In this study, we prospectively demonstrated the capability of the newly-designed EWS to monitor and alert clinicians about patients at high risk of in-hospital death in real time, thereby providing opportunities for timely interventions. This real-time EWS is able to assist clinical decision making and enable more actionable and effective individualized care for patients' better health outcomes in target medical facilities.

  View details for DOI 10.2196/13719

  View details for PubMedID 31278734

• Prenatally diagnosed omphalocele: characteristics associated with adverse neonatal outcomes. Journal of perinatology : official journal of the California Perinatal Association Chock, V. Y., Davis, A. S., Cho, S., Bax, C., Fluharty, E., Weigel, N., Homeyer, M., Hudgins, L., Jones, R., Rubesova, E., Sylvester, K. G., Blumenfeld, Y. J., Hintz, S. R. 2019

  Abstract

  OBJECTIVE: To characterize factors associated with adverse neonatal outcomes in prenatally diagnosed omphalocele cases.STUDY DESIGN: Prenatally diagnosed omphalocele cases at a single referral center from 1 January 2009 to 31 December 2017 were retrospectively reviewed. Clinical variables and antenatal imaging measurements were collected. Associations between prenatal and neonatal characteristics and the adverse outcome of death or prolonged length of stay (LOS) were analyzed.RESULTS: Out of 63 fetal cases, 33 were live-born, >50% had other anomalies, and neonatal mortality was 12%. Adverse outcomes were associated with neonatal variables, including lower median 1-min Apgar score, initial mechanical ventilation, and late-onset sepsis, but not approach toomphalocele closure. With multivariate analysis, death or prolonged LOS was associated only with low lung volumes by fetal MRI (OR 34 (3-422), p=0.006).CONCLUSION: Low lung volumes by fetal MRI were associated with death or prolonged LOS in neonates with prenatally diagnosed omphalocele and may guide clinicians with counseling families.

  View details for DOI 10.1038/s41372-019-0410-1

  View details for PubMedID 31227786

• The disproportionate cost of operation and congenital anomalies in infancy Apfeld, J. C., Kastenberg, Z. J., Gibbons, A. T., Phibbs, C. S., Lee, H. C., Sylvester, K. G. MOSBY-ELSEVIER. 2019: 1234–42

  View details for DOI 10.1016/j.surg.2018.12.022

  View details for Web of Science ID 000472984500028

• Prediction of the 1-Year Risk of Incident Lung Cancer: Prospective Study Using Electronic Health Records from the State of Maine JOURNAL OF MEDICAL INTERNET RESEARCH Wang, X., Zhang, Y., Hao, S., Zheng, L., Liao, J., Ye, C., Xia, M., Wang, O., Liu, M., Weng, C., Duong, S. Q., Jin, B., Alfreds, S. T., Stearns, F., Kanov, L., Sylvester, K. G., Widen, E., McElhinney, D. B., Ling, X. B. 2019; 21 (5)

  View details for DOI 10.2196/13260

  View details for Web of Science ID 000468102900001

• The disproportionate cost of operation and congenital anomalies ininfancy. Surgery Apfeld, J. C., Kastenberg, Z. J., Gibbons, A. T., Phibbs, C. S., Lee, H. C., Sylvester, K. G. 2019

  Abstract

  BACKGROUND: Congenital anomalies are the leading cause of infant death and pediatric hospitalization, but existing estimates of the associated costs of health care are either cross-sectional surveys or economic projections. We sought to determine the percent of total hospital health care expenditures attributable to major anomalies requiring surgery within the first year of life.METHODS: Utilizing comprehensive California statewide data from 2008 to 2012, cohorts of infants undergoing major surgery, with birth defects and with surgical anomalies, were constructed alongside a referent group of newborns with no anomalies or operations. Cost-to-charge and physician fee ratios were used to estimate hospital and professional costs, respectively. For each cohort, costs were broken down according to admission, birth episode, and first year of life, with additional stratifications by birth weight, gestational age, and organ system.RESULTS: In total, 68,126 of 2,205,070 infants (3.1%) underwent major surgery (n= 32,614) or had a diagnosis of a severe congenital anomaly (n= 57,793). These accounted for $7.7 billion of the $18.9 billion (40.7%) of the total health care costs/expenditures of the first-year-of-life hospitalizations, $7.0 billion (48.6%) of the costs for infants with comparatively long birth episodes, and $5.2 billion (54.7%) of the total neonatal intensive care unit admission costs. Infants with surgical anomalies (n= 21,264) totaled $4.1 billion (21.7%) at $80,872 per infant. Cardiovascular and gastrointestinal diseases accounted for most admission costs secondary to major surgery or congenital anomalies.CONCLUSION: In a population-based cohort of infant births compared with other critically ill neonates, surgical congenital anomalies are disproportionately costly within the United States health care system. The care of these infants, half of whom are covered by Medi-Cal or Medicaid, stands as a particular focus in an age of reform of health care payments.

  View details for PubMedID 31056199

• Recent Potential Noninvasive Biomarkers in Necrotizing Enterocolitis. Gastroenterology research and practice Wang, K., Tao, G., Sun, Z., Sylvester, K. G. 2019; 2019: 8413698

  Abstract

  Necrotizing enterocolitis (NEC) is a rare but devastating gastrointestinal disease that predominately affects preterm neonates. Numerous studies have revealed that NEC is strongly associated with very low birth weight, degree of prematurity, formula feeding, infection, hypoxic/ischemic injury, and enteric dysbiosis. Given these clinical associations, the search for a deeper understanding of disease pathogenesis has led to an intense interest in the discovery and development of noninvasive biomarkers of NEC from stool, urine, and serum. Biomarkers for NEC may serve at least two general purposes of urgent unmet need: to improve diagnostic accuracy and disease prediction and to reveal the mechanism of the disease. This review will provide an overview of recent research focused on clinical NEC and highlight the advances that were made within the past five years towards the development of noninvasive diagnostic biomarkers.

  View details for DOI 10.1155/2019/8413698

  View details for PubMedID 31178908

  View details for PubMedCentralID PMC6501130

• Recent Advances in Prevention and Therapies for Clinical or Experimental Necrotizing Enterocolitis. Digestive diseases and sciences Wang, K., Tao, G., Sylvester, K. G. 2019

  Abstract

  Necrotizing enterocolitis (NEC) is one of the most severe diseases of preterm neonates and has a high mortality rate. With the development of inspection techniques and new biomarkers, the diagnostic accuracy of NEC is constantly improving. The most recognized potential risk factors include prematurity, formula-feeding, infection, and microbial dysbiosis. With further understanding of the pathogenesis, more effective prevention and therapies will be applied to clinical or experimental NEC. At present, such new potential prevention and therapies for NEC are mainly focused on the Toll-like receptor 4 inflammatory signaling pathway, the repair of intestinal barrier function, probiotics, antioxidative stress, breast-feeding, and immunomodulatory agents. Many new studies have changed our understanding of the pathogenesis of NEC and improve our approaches for preventing and treating of NEC each year. This review provides an overview of the recent researches focused on clinical or experimental NEC and highlights the advances made within the past 5years toward the development of new potential preventive approaches and therapies for this disease.

  View details for PubMedID 30989465

• Predicting Pathology From Imaging in Children Undergoing Resection of Congenital Lung Lesions Narayan, R. R., Abadilla, N., Greenberg, D. R., Sylvester, K. G., Hintz, S. R., Barth, R. A., Bruzoni, M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2019: 68–73

  View details for DOI 10.1016/j.jss.2018.10.042

  View details for Web of Science ID 000458498300010

• Biomarker Discovery and Utility in Necrotizing Enterocolitis CLINICS IN PERINATOLOGY Goldstein, G. P., Sylvester, K. G. 2019; 46 (1): 1-+

  View details for DOI 10.1016/j.clp.2018.10.001

  View details for Web of Science ID 000461539400003

• Biomarker Discovery and Utility in Necrotizing Enterocolitis. Clinics in perinatology Goldstein, G. P., Sylvester, K. G. 2019; 46 (1): 1–17

  Abstract

  Necrotizing enterocolitis (NEC) is a devastating disease of prematurity, with no current method for early diagnosis. Diagnosis is particularly challenging, frequently occurring after the disease has progressed to the point of significant and often irreversible intestinal damage. Biomarker research has tremendous potential to advance clinical management of NEC and our understanding of its pathogenesis. This review discusses the need for novel biomarkers in NEC management, evaluates studies investigating such biomarkers, and explains the difficulties associated with translating biomarker discovery into clinical use.

  View details for PubMedID 30771811

• A proteomic clock for malignant gliomas: The role of the environment in tumorigenesis at the presymptomatic stage. PloS one Zheng, L. n., Zhang, Y. n., Hao, S. n., Chen, L. n., Sun, Z. n., Yan, C. n., Whitin, J. C., Jang, T. n., Merchant, M. n., McElhinney, D. B., Sylvester, K. G., Cohen, H. J., Recht, L. n., Yao, X. n., Ling, X. B. 2019; 14 (10): e0223558

  Abstract

  Malignant gliomas remain incurable with a poor prognosis despite of aggressive treatment. We have been studying the development of brain tumors in a glioma rat model, where rats develop brain tumors after prenatal exposure to ethylnitrosourea (ENU), and there is a sizable interval between when the first pathological changes are noted and tumors become detectable with MRI. Our aim to define a molecular timeline through proteomic profiling of the cerebrospinal fluid (CSF) such that brain tumor commitment can be revealed earlier than at the presymptomatic stage. A comparative proteomic approach was applied to profile CSF collected serially either before, at and after the time MRI becomes positive. Elastic net (EN) based models were developed to infer the timeline of normal or tumor development respectively, mirroring a chronology of precisely timed, "clocked", adaptations. These CSF changes were later quantified by longitudinal entropy analyses of the EN predictive metric. False discovery rates (FDR) were computed to control the expected proportion of the EN models that are due to multiple hypothesis testing. Our ENU rat brain tumor dating EN model indicated that protein content in CSF is programmed even before tumor MRI detection. The findings of the precisely timed CSF tumor microenvironment changes at presymptomatic stages, deviation from the normal development timeline, may provide the groundwork for the understanding of adaptation of the brain environment in tumorigenesis to devise effective brain tumor management strategies.

  View details for DOI 10.1371/journal.pone.0223558

  View details for PubMedID 31600288

• Obstetric and neonatal outcomes in pregnancies complicated by fetal lung masses: does final histology matter? The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians Anderson, J. N., Girsen, A. I., Hintz, S. R., El-Sayed, Y. Y., Davis, A. S., Barth, R. A., Halabi, S. n., Hazard, F. K., Sylvester, K. G., Bruzoni, M. n., Blumenfeld, Y. J. 2019: 1–7

  Abstract

  Purpose: Fetal lung masses complicate approximately 1 in 2000 live births. Our aim was to determine whether obstetric and neonatal outcomes differ by final fetal lung mass histology.Materials and methods: A review of all pregnancies complicated by a prenatally diagnosed fetal lung mass between 2009 and 2017 at a single academic center was conducted. All cases included in the final analysis underwent surgical resection and histology diagnosis was determined by a trained pathologist. Clinical data were obtained from review of stored electronic medical records which contained linked maternal and neonatal records. Imaging records included both prenatal ultrasound and magnetic resonance imaging. Fisher's exact test was used for categorical variables and the Kruskal-Wallis test was used for continuous variables. The level of significance was p<.05.Results: Of 61 pregnancies complicated by fetal lung mass during the study period, 45 cases underwent both prenatal care and postnatal resection. Final histology revealed 10 cases of congenital pulmonary airway malformation (CPAM) type 1, nine cases of CPAM type 2, and 16 cases of bronchopulmonary sequestration. There was no difference in initial, maximal, or final CPAM volume ratio between groups, with median final CPAM volume ratio of 0.6 for CPAM type 1, 0.7 for CPAM type 2, and 0.3 for bronchopulmonary sequestration (p = .12). There were no differences in any of the maternal or obstetric outcomes including gestational age at delivery and mode of delivery between the groups. The primary outcome of neonatal respiratory distress was not statistically different between groups (p = .66). Median neonatal length of stay following delivery ranged from 3 to 4 days, and time to postnatal resection was similar as well, with a median of 126 days for CPAM type 1, 122 days for CPAM type 2, and 132 days for bronchopulmonary sequestration (p = .76).Conclusions: In our cohort, there was no significant association between histologic lung mass subtypes and any obstetric or neonatal morbidity including respiratory distress.

  View details for DOI 10.1080/14767058.2019.1689559

  View details for PubMedID 31722592

• Congenital diaphragmatic hernia-associated neonatal morbidity and mortality based on TOTAL trial severity designation Boissiere, J. C., Anderson, J. N., Girsen, A. I., Hintz, S. R., El-Sayed, Y. Y., Van Meurs, K. P., Sylvester, K. G., Blumenfeld, Y. J. MOSBY-ELSEVIER. 2019: S667–S668

  View details for DOI 10.1016/j.ajog.2018.11.1064

  View details for Web of Science ID 000454249403200

• Obstetric and neonatal outcomes in pregnancies complicated by fetal lung masses: does final histology matter? Anderson, J. N., Girsen, A. I., Hintz, S. R., El-Sayed, Y. Y., Davis, A. S., Barth, R. A., Halabi, S., Sylvester, K. G., Bruzoni, M., Blumenfeld, Y. J. MOSBY-ELSEVIER. 2019: S151

  View details for DOI 10.1016/j.ajog.2018.11.230

  View details for Web of Science ID 000454249400210

• Recent Potential Noninvasive Biomarkers in Necrotizing Enterocolitis GASTROENTEROLOGY RESEARCH AND PRACTICE Wang, K., Tao, G., Sun, Z., Sylvester, K. G. 2019

  View details for DOI 10.1155/2019/8413698

  View details for Web of Science ID 000467099300001

• Prediction of the 1-Year Risk of Incident Lung Cancer: Prospective Study Using Electronic Health Records from the State of Maine. Journal of medical Internet research Wang, X. n., Zhang, Y. n., Hao, S. n., Zheng, L. n., Liao, J. n., Ye, C. n., Xia, M. n., Wang, O. n., Liu, M. n., Weng, C. H., Duong, S. Q., Jin, B. n., Alfreds, S. T., Stearns, F. n., Kanov, L. n., Sylvester, K. G., Widen, E. n., McElhinney, D. B., Ling, X. B. 2019; 21 (5): e13260

  Abstract

  Lung cancer is the leading cause of cancer death worldwide. Early detection of individuals at risk of lung cancer is critical to reduce the mortality rate.The aim of this study was to develop and validate a prospective risk prediction model to identify patients at risk of new incident lung cancer within the next 1 year in the general population.Data from individual patient electronic health records (EHRs) were extracted from the Maine Health Information Exchange network. The study population consisted of patients with at least one EHR between April 1, 2016, and March 31, 2018, who had no history of lung cancer. A retrospective cohort (N=873,598) and a prospective cohort (N=836,659) were formed for model construction and validation. An Extreme Gradient Boosting (XGBoost) algorithm was adopted to build the model. It assigned a score to each individual to quantify the probability of a new incident lung cancer diagnosis from October 1, 2016, to September 31, 2017. The model was trained with the clinical profile in the retrospective cohort from the preceding 6 months and validated with the prospective cohort to predict the risk of incident lung cancer from April 1, 2017, to March 31, 2018.The model had an area under the curve (AUC) of 0.881 (95% CI 0.873-0.889) in the prospective cohort. Two thresholds of 0.0045 and 0.01 were applied to the predictive scores to stratify the population into low-, medium-, and high-risk categories. The incidence of lung cancer in the high-risk category (579/53,922, 1.07%) was 7.7 times higher than that in the overall cohort (1167/836,659, 0.14%). Age, a history of pulmonary diseases and other chronic diseases, medications for mental disorders, and social disparities were found to be associated with new incident lung cancer.We retrospectively developed and prospectively validated an accurate risk prediction model of new incident lung cancer occurring in the next 1 year. Through statistical learning from the statewide EHR data in the preceding 6 months, our model was able to identify statewide high-risk patients, which will benefit the population health through establishment of preventive interventions or more intensive surveillance.

  View details for PubMedID 31099339

• Predicting Pathology From Imaging in Children Undergoing Resection of Congenital Lung Lesions. The Journal of surgical research Narayan, R. R., Abadilla, N., Greenberg, D. R., Sylvester, K. G., Hintz, S. R., Barth, R. A., Bruzoni, M. 2018; 236: 68–73

  Abstract

  BACKGROUND: Prenatal magnetic resonance imaging (MRI) is increasingly obtained to define congenital lung lesions (CLL) for surgical management. Postnatal, preoperative computed tomography (CT) provides further clarity at the cost of radiation. Depending on the lesion identified, the indication for resection remains controversial. We investigated the differences in detail found on prenatal MRI and postnatal CT compared with final pathology to determine their utility in preoperative decision-making.MATERIALS AND METHODS: All children undergoing resection of CLLs at a single institution between July 2009 and February 2018 were retrospectively identified. Their imaging, operative, and pathology reports were compared. All imaging studies were examined by pediatric radiologists with experience in prenatal CLL diagnosis.RESULTS: Fifty-five patients underwent CLL resection during the study period with 31 undergoing prenatal MRI, 45 postnatal CT, and 22 both. Resection was performed before 6 mo of age in 62% of patients. In the cohort undergoing both imaging studies, pathologic CLL diagnosis correlated with prenatal MRI and CT in 82% and 100% of patients, respectively (P=0.13). Eight patients had systemic feeding vessels, of which 38% were identified on MRI, and 88% on CT (P=0.13). Both studies had a specificity of 100% for detecting systemic feeding vessels.CONCLUSIONS: For children where prenatal MRI detected a systemic feeding vessel, CT was redundant for preoperative planning but had greater sensitivity. Ultimately, the CLL type predicted from postnatal CT was not significantly different from that predicted by prenatal MRI; however, both imaging modalities had some level of discrepancy with pathology.

  View details for PubMedID 30694781

• Donor-derived circulating cell-free DNA (ccfDNA) reference materials for concordance studies Konigshofer, Y., Butler, M. G., Dickens, J., Bianco, K., Sylvester, K. G., Anekella, B., Garlick, R. K. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-5569

  View details for Web of Science ID 000468819504548

• Point-of-Care Fecal Calprotectin Monitoring in Preterm Infants at Risk for Necrotizing Enterocolitis JOURNAL OF PEDIATRICS Nakayuenyongsuk, W., Christofferson, M., Stevenson, D. K., Sylvester, K., Lee, H. C., Park, K. T. 2018; 196: 98-+

  View details for DOI 10.1016/j.jpeds.2017.12.069

  View details for Web of Science ID 000432452300019

• Development of the necrotizing enterocolitis society registry and biorepository SEMINARS IN PEDIATRIC SURGERY Ralls, M. W., Gadepalli, S. K., Sylvester, K. G., Good, M. 2018; 27 (1): 25–28

  Abstract

  Necrotizing enterocolitis (NEC) is a devastating disease affecting premature infants. New advances in diagnostic and treatment options are desperately needed. Accordingly, the NEC Society initiated a research collaborative with a group of investigators dedicated to advancing the state of NEC-associated knowledge. Recent advances in high-content molecular interrogation and bio-computation (e.g., genomics, transcriptomics, proteomics, and metabolomics) can provide new insights from afflicted infants with NEC, however, individual centers do not have sufficient cases to conduct these studies independently. The development of a NEC Society Biorepository (NSB) has emerged to advance collaboration among institutions through the shared use of biologic samples in the dedicated pursuit of molecular indicators of disease and to gain greater pathophysiologic insights through research. The NSB will provide key infrastructure across several centers to harness the potential for new discoveries, while ensuring specimens are processed consistently, appropriate clinical data is collected, and privacy is maintained. The NSB will provide a comprehensive framework for sharing biological samples and clinical data through a robust and secure system that supports the investigation of research studies on NEC.

  View details for PubMedID 29275812

  View details for PubMedCentralID PMC5744883

• Changing the paradigm of defining, detecting, and diagnosing NEC: Perspectives on Bell's stages and biomarkers for NEC SEMINARS IN PEDIATRIC SURGERY Gephart, S. M., Gordon, P. V., Penn, A. H., Gregory, K. E., Swanson, J. R., Maheshwari, A., Sylvester, K. 2018; 27 (1): 3–10

  Abstract

  Better means to diagnose and define necrotizing enterocolitis are needed to guide clinical practice and research. Adequacy of Bell's staging system for clinical practice and clarity of cases used in NEC clinical datasets has been a topic of controversy for some time. This article provides reasons why a better global definition for NEC is needed and offers a simple alternative bedside definition for preterm NEC called the "Two out of Three" rule. Some argue that biomarkers may fill knowledge gaps and provide greater precision in defining relevant features of a clinical disease like NEC. NEC biomarkers include markers of inflammation, intestinal dysfunction, hematologic changes, and clinical features. Development and reporting of NEC biomarkers should be guided by the FDA's BEST Consensus resource, "Biomarkers, EndpointS, & other Tools" and consistently report metrics so that studies can be compared and results pooled. Current practice in the NICU would be enhanced by clinical tools that effectively inform the clinical team that a baby is at increasing risk of NEC. Ideally, these tools will incorporate both clinical information about the baby as well as molecular signals that are indicative of NEC. While meaningful biomarkers for NEC and clinical tools exist, translation into practice is mediocre.

  View details for PubMedID 29275814

• Prediction of Incident Hypertension Within the Next Year: Prospective Study Using Statewide Electronic Health Records and Machine Learning. Journal of medical Internet research Ye, C. n., Fu, T. n., Hao, S. n., Zhang, Y. n., Wang, O. n., Jin, B. n., Xia, M. n., Liu, M. n., Zhou, X. n., Wu, Q. n., Guo, Y. n., Zhu, C. n., Li, Y. M., Culver, D. S., Alfreds, S. T., Stearns, F. n., Sylvester, K. G., Widen, E. n., McElhinney, D. n., Ling, X. n. 2018; 20 (1): e22

  Abstract

  As a high-prevalence health condition, hypertension is clinically costly, difficult to manage, and often leads to severe and life-threatening diseases such as cardiovascular disease (CVD) and stroke.The aim of this study was to develop and validate prospectively a risk prediction model of incident essential hypertension within the following year.Data from individual patient electronic health records (EHRs) were extracted from the Maine Health Information Exchange network. Retrospective (N=823,627, calendar year 2013) and prospective (N=680,810, calendar year 2014) cohorts were formed. A machine learning algorithm, XGBoost, was adopted in the process of feature selection and model building. It generated an ensemble of classification trees and assigned a final predictive risk score to each individual.The 1-year incident hypertension risk model attained areas under the curve (AUCs) of 0.917 and 0.870 in the retrospective and prospective cohorts, respectively. Risk scores were calculated and stratified into five risk categories, with 4526 out of 381,544 patients (1.19%) in the lowest risk category (score 0-0.05) and 21,050 out of 41,329 patients (50.93%) in the highest risk category (score 0.4-1) receiving a diagnosis of incident hypertension in the following 1 year. Type 2 diabetes, lipid disorders, CVDs, mental illness, clinical utilization indicators, and socioeconomic determinants were recognized as driving or associated features of incident essential hypertension. The very high risk population mainly comprised elderly (age>50 years) individuals with multiple chronic conditions, especially those receiving medications for mental disorders. Disparities were also found in social determinants, including some community-level factors associated with higher risk and others that were protective against hypertension.With statewide EHR datasets, our study prospectively validated an accurate 1-year risk prediction model for incident essential hypertension. Our real-time predictive analytic model has been deployed in the state of Maine, providing implications in interventions for hypertension and related diseases and hopefully enhancing hypertension care.

  View details for PubMedID 29382633

• Assessing Statewide All-Cause Future One-Year Mortality: Prospective Study With Implications for Quality of Life, Resource Utilization, and Medical Futility. Journal of medical Internet research Guo, Y. n., Zheng, G. n., Fu, T. n., Hao, S. n., Ye, C. n., Zheng, L. n., Liu, M. n., Xia, M. n., Jin, B. n., Zhu, C. n., Wang, O. n., Wu, Q. n., Culver, D. S., Alfreds, S. T., Stearns, F. n., Kanov, L. n., Bhatia, A. n., Sylvester, K. G., Widen, E. n., McElhinney, D. B., Ling, X. B. 2018; 20 (6): e10311

  Abstract

  For many elderly patients, a disproportionate amount of health care resources and expenditures is spent during the last year of life, despite the discomfort and reduced quality of life associated with many aggressive medical approaches. However, few prognostic tools have focused on predicting all-cause 1-year mortality among elderly patients at a statewide level, an issue that has implications for improving quality of life while distributing scarce resources fairly.Using data from a statewide elderly population (aged ≥65 years), we sought to prospectively validate an algorithm to identify patients at risk for dying in the next year for the purpose of minimizing decision uncertainty, improving quality of life, and reducing futile treatment.Analysis was performed using electronic medical records from the Health Information Exchange in the state of Maine, which covered records of nearly 95% of the statewide population. The model was developed from 125,896 patients aged at least 65 years who were discharged from any care facility in the Health Information Exchange network from September 5, 2013, to September 4, 2015. Validation was conducted using 153,199 patients with same inclusion and exclusion criteria from September 5, 2014, to September 4, 2016. Patients were stratified into risk groups. The association between all-cause 1-year mortality and risk factors was screened by chi-squared test and manually reviewed by 2 clinicians. We calculated risk scores for individual patients using a gradient tree-based boost algorithm, which measured the probability of mortality within the next year based on the preceding 1-year clinical profile.The development sample included 125,896 patients (72,572 women, 57.64%; mean 74.2 [SD 7.7] years). The final validation cohort included 153,199 patients (88,177 women, 57.56%; mean 74.3 [SD 7.8] years). The c-statistic for discrimination was 0.96 (95% CI 0.93-0.98) in the development group and 0.91 (95% CI 0.90-0.94) in the validation cohort. The mortality was 0.99% in the low-risk group, 16.75% in the intermediate-risk group, and 72.12% in the high-risk group. A total of 99 independent risk factors (n=99) for mortality were identified (reported as odds ratios; 95% CI). Age was on the top of list (1.41; 1.06-1.48); congestive heart failure (20.90; 15.41-28.08) and different tumor sites were also recognized as driving risk factors, such as cancer of the ovaries (14.42; 2.24-53.04), colon (14.07; 10.08-19.08), and stomach (13.64; 3.26-86.57). Disparities were also found in patients' social determinants like respiratory hazard index (1.24; 0.92-1.40) and unemployment rate (1.18; 0.98-1.24). Among high-risk patients who expired in our dataset, cerebrovascular accident, amputation, and type 1 diabetes were the top 3 diseases in terms of average cost in the last year of life.Our study prospectively validated an accurate 1-year risk prediction model and stratification for the elderly population (≥65 years) at risk of mortality with statewide electronic medical record datasets. It should be a valuable adjunct for helping patients to make better quality-of-life choices and alerting care givers to target high-risk elderly for appropriate care and discussions, thus cutting back on futile treatment.

  View details for PubMedID 29866643

• Gene expression network analysis in aneuploid human trophoblast progenitor cells (TBPC) reveals modular structures Leon-Martinez, D., Ling, X., Hao, S., Sylvester, K., Bianco, K. MOSBY-ELSEVIER. 2018: S163–S164

  View details for Web of Science ID 000422946900255

• Point-of-Care Fecal Calprotectin Monitoring in Preterm Infants at Risk for Necrotizing Enterocolitis. The Journal of pediatrics Nakayuenyongsuk, W. n., Christofferson, M. n., Stevenson, D. K., Sylvester, K. n., Lee, H. C., Park, K. T. 2018

  Abstract

  To establish baseline trends in fecal calprotectin, a protein excreted into the stool when there is neutrophilic inflammation in the bowel, in infants at risk for necrotizing enterocolitis (NEC).We performed a prospective observational cohort study in infants with a birth weight of <1500 g without existing bowel disease at a level IV neonatal intensive care unit from October 2015 to September 2016. Stools were collected once daily for 30 days or until 32 weeks postmenstrual age and processed using the Fecal Calprotectin High Range Quantitative Quantum Blue assay.In 64 preterm infants, during the first week after birth, 62% of infants had an initial stool sample with high baseline calprotectin levels (≥200 µg/g). In assessment of maternal and neonatal risk factors, maternal etiology for preterm birth (ie, eclamplsia or preeclampsia) was the only significant factor associated with high baseline calprotectin level. Two patients in the cohort developed NEC. Calprotectin levels for the entire cohort fluctuated during the observed period but generally increased in the third and fourth weeks after birth.At-risk infants had highly variable fecal calprotectin levels, with maternal causes for preterm birth associated with higher baseline levels. More longitudinal data in infants with NEC are necessary to determine whether acute rises in fecal calprotectin levels prior to clinical diagnosis can be confirmed as a diagnostic or prognostic biomarker.

  View details for PubMedID 29519542

• FAM83H is involved in the progression of hepatocellular carcinoma and is regulated by MYC SCIENTIFIC REPORTS Kim, K., Park, S., Bae, J., Noh, S., Tao, G., Kim, J., Kwon, K., Park, H., Park, B., Lee, H., Chung, M., Moon, W., Sylvester, K. G., Jang, K. 2017; 7

  View details for DOI 10.1038/s41598-017-03639-3

  View details for Web of Science ID 000403081900065

• FAM83H is involved in the progression of hepatocellular carcinoma and is regulated by MYC. Scientific reports Kim, K. M., Park, S. H., Bae, J. S., Noh, S. J., Tao, G. Z., Kim, J. R., Kwon, K. S., Park, H. S., Park, B. H., Lee, H., Chung, M. J., Moon, W. S., Sylvester, K. G., Jang, K. Y. 2017; 7 (1): 3274

  Abstract

  Recently, the roles of FAM83H in tumorigenesis have been interested and increased expression of FAM83H and MYC in hepatocellular carcinoma (HCC) have been reported. Therefore, we investigated the expression and role of FAM83H in 163 human HCCs and further investigated the relationship between FAM83H and oncogene MYC. The expression of FAM83H is elevated in liver cancer cells, and nuclear expression of FAM83H predicted shorter survival of HCC patients. In HLE and HepG2 HCC cells, knock-down of FAM83H inhibited proliferation and invasive activity of HCC cells. FAM83H induced expression of cyclin-D1, cyclin-E1, snail and MMP2 and inhibited the expression of P53 and P27. In hepatic tumor cells derived from Tet-O-MYC mice, the expression of mRNA and protein of FAM83H were dependent on MYC expression. Moreover, a chromatin immunoprecipitation assay demonstrated that MYC binds to the promotor of FAM83H and that MYC promotes the transcription of FAM83H, which was supported by the results of a dual-luciferase reporter assay. In conclusion, we present an oncogenic role of FAM83H in liver cancer, which is closely associated with the oncogene MYC. In addition, our results suggest FAM83H expression as a poor prognostic indicator of HCC patients.

  View details for DOI 10.1038/s41598-017-03639-3

  View details for PubMedID 28607447

  View details for PubMedCentralID PMC5468291

• Advanced minimal access surgery in infants weighing less than 3kg: A single center experience. Journal of pediatric surgery Wall, J. K., Sinclair, T. J., Kethman, W., Williams, C., Albanese, C., Sylvester, K. G., Bruzoni, M. 2017

  Abstract

  Minimal access surgery (MAS) has gained popularity in infants less than 5kg, however, significant challenges still arise in very low weight infants.A retrospective chart review was performed to identify all infants weighing less than 3kg who underwent an advanced MAS or equivalent open procedure from 2009 to 2016. Advanced case types included Nissen fundoplication, duodenal atresia repair, Ladd procedure, congenital diaphragmatic hernia repair, esophageal atresia/tracheoesophageal fistula repair, diaphragmatic plication, and pyloric atresia repair. A comparative analysis was performed between the MAS and open cohorts.A total of 45 advanced MAS cases and 17 open cases met the inclusion criteria. Gestational age and age at operation were similar between the cohorts, while infants who underwent open procedures had significantly lower weight at operation (p=0.003). There were no deaths within 30days related to surgery in either group. Only 3 MAS cases required unintended conversion to open. There were 2 (4.4%) postoperative complications related to surgery in the MAS cohort and 2 (11.8%) in the open cohort.Advanced MAS may be performed in infants weighing less than 3kg with low mortality, acceptable rates of conversion, and similar rates of complications as open procedures.Prognosis study.Level III.

  View details for DOI 10.1016/j.jpedsurg.2017.05.006

  View details for PubMedID 28549685

• Advanced minimal access surgery in infants weighing less than 3kg: A single center experience. Journal of pediatric surgery Wall, J. K., Sinclair, T. J., Kethman, W., Williams, C., Albanese, C., Sylvester, K. G., Bruzoni, M. 2017

  Abstract

  Minimal access surgery (MAS) has gained popularity in infants less than 5kg, however, significant challenges still arise in very low weight infants.A retrospective chart review was performed to identify all infants weighing less than 3kg who underwent an advanced MAS or equivalent open procedure from 2009 to 2016. Advanced case types included Nissen fundoplication, duodenal atresia repair, Ladd procedure, congenital diaphragmatic hernia repair, esophageal atresia/tracheoesophageal fistula repair, diaphragmatic plication, and pyloric atresia repair. A comparative analysis was performed between the MAS and open cohorts.A total of 45 advanced MAS cases and 17 open cases met the inclusion criteria. Gestational age and age at operation were similar between the cohorts, while infants who underwent open procedures had significantly lower weight at operation (p=0.003). There were no deaths within 30days related to surgery in either group. Only 3 MAS cases required unintended conversion to open. There were 2 (4.4%) postoperative complications related to surgery in the MAS cohort and 2 (11.8%) in the open cohort.Advanced MAS may be performed in infants weighing less than 3kg with low mortality, acceptable rates of conversion, and similar rates of complications as open procedures.Prognosis study.Level III.

  View details for DOI 10.1016/j.jpedsurg.2017.05.006

  View details for PubMedID 28549685

• Acylcarnitine Profiles Reflect Metabolic Vulnerability for Necrotizing Enterocolitis in Newborns Born Premature. journal of pediatrics Sylvester, K. G., Kastenberg, Z. J., Moss, R. L., Enns, G. M., Cowan, T. M., Shaw, G. M., Stevenson, D. K., Sinclair, T. J., Scharfe, C., Ryckman, K. K., Jelliffe-Pawlowski, L. L. 2017; 181: 80-85 e1

  Abstract

  To evaluate the association between newborn acylcarnitine profiles and the subsequent development of necrotizing enterocolitis (NEC) with the use of routinely collected newborn screening data in infants born preterm.A retrospective cohort study was conducted with the use of discharge records for infants born preterm admitted to neonatal intensive care units in California from 2005 to 2009 who had linked state newborn screening results. A model-development cohort of 94 110 preterm births from 2005 to 2008 was used to develop a risk-stratification model that was then applied to a validation cohort of 22 992 births from 2009.Fourteen acylcarnitine levels and acylcarnitine ratios were associated with increased risk of developing NEC. Each log unit increase in C5 and free carnitine /(C16 + 18:1) was associated with a 78% and a 76% increased risk for developing NEC, respectively (OR 1.78, 95% CI 1.53-2.02, and OR 1.76, 95% CI 1.51-2.06). Six acylcarnitine levels, along with birth weight and total parenteral nutrition, identified 89.8% of newborns with NEC in the model-development cohort (area under the curve 0.898, 95% CI 0.889-0.907) and 90.8% of the newborns with NEC in the validation cohort (area under the curve 0.908, 95% CI 0.901-0.930).Abnormal fatty acid metabolism was associated with prematurity and the development of NEC. Metabolic profiling through newborn screening may serve as an objective biologic surrogate of risk for the development of disease and thus facilitate disease-prevention strategies.

  View details for DOI 10.1016/j.jpeds.2016.10.019

  View details for PubMedID 27836286

• Prediction of neonatal respiratory distress in pregnancies complicated by fetal lung masses. Prenatal diagnosis Girsen, A. I., Hintz, S. R., Sammour, R., Naqvi, A., El-Sayed, Y. Y., Sherwin, K., Davis, A. S., Chock, V. Y., Barth, R. A., Rubesova, E., Sylvester, K. G., Chitkara, R., Blumenfeld, Y. J. 2017

  Abstract

  The objective of this article is to evaluate the utility of fetal lung mass imaging for predicting neonatal respiratory distress.Pregnancies with fetal lung masses between 2009 and 2014 at a single center were analyzed. Neonatal respiratory distress was defined as intubation and mechanical ventilation at birth, surgery before discharge, or extracorporeal membrane oxygenation (ECMO). The predictive utility of the initial as well as maximal lung mass volume and congenital pulmonary airway malformation volume ratio by ultrasound (US) and magnetic resonance imaging (MRI) was analyzed.Forty-seven fetal lung mass cases were included; of those, eight (17%) had respiratory distress. The initial US was performed at similar gestational ages in pregnancies with and without respiratory distress (26.4 ± 5.6 vs 22.3 ± 3 weeks, p = 0.09); however, those with respiratory distress had higher congenital volume ratio at that time (1.0 vs 0.3, p = 0.01). The strongest predictors of respiratory distress were maximal volume >24.0 cm(3) by MRI (100% sensitivity, 91% specificity, 60% positive predictive value, and 100% negative predictive value) and maximal volume >34.0 cm(3) by US (100% sensitivity, 85% specificity, 54% positive predictive value, and 100% negative predictive value).Ultrasound and MRI parameters can predict neonatal respiratory distress, even when obtained before 24 weeks. Third trimester parameters demonstrated the best positive predictive value. © 2017 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/pd.5002

  View details for PubMedID 28061000

• Defining and characterizing the critical transition state prior to the type 2 diabetes disease. PloS one Jin, B. n., Liu, R. n., Hao, S. n., Li, Z. n., Zhu, C. n., Zhou, X. n., Chen, P. n., Fu, T. n., Hu, Z. n., Wu, Q. n., Liu, W. n., Liu, D. n., Yu, Y. n., Zhang, Y. n., McElhinney, D. B., Li, Y. M., Culver, D. S., Alfreds, S. T., Stearns, F. n., Sylvester, K. G., Widen, E. n., Ling, X. B. 2017; 12 (7): e0180937

  Abstract

  Type 2 diabetes mellitus (T2DM), with increased risk of serious long-term complications, currently represents 8.3% of the adult population. We hypothesized that a critical transition state prior to the new onset T2DM can be revealed through the longitudinal electronic medical record (EMR) analysis.We applied the transition-based network entropy methodology which previously identified a dynamic driver network (DDN) underlying the critical T2DM transition at the tissue molecular biological level. To profile pre-disease phenotypical changes that indicated a critical transition state, a cohort of 7,334 patients was assembled from the Maine State Health Information Exchange (HIE). These patients all had their first confirmative diagnosis of T2DM between January 1, 2013 and June 30, 2013. The cohort's EMRs from the 24 months preceding their date of first T2DM diagnosis were extracted.Analysis of these patients' pre-disease clinical history identified a dynamic driver network (DDN) and an associated critical transition state six months prior to their first confirmative T2DM state.This 6-month window before the disease state provides an early warning of the impending T2DM, warranting an opportunity to apply proactive interventions to prevent or delay the new onset of T2DM.

  View details for PubMedID 28686739

• Estimating One-Year Risk of Incident Chronic Kidney Disease: Retrospective Development and Validation Study Using Electronic Medical Record Data From the State of Maine. JMIR medical informatics Hao, S. n., Fu, T. n., Wu, Q. n., Jin, B. n., Zhu, C. n., Hu, Z. n., Guo, Y. n., Zhang, Y. n., Yu, Y. n., Fouts, T. n., Ng, P. n., Culver, D. S., Alfreds, S. T., Stearns, F. n., Sylvester, K. G., Widen, E. n., McElhinney, D. B., Ling, X. B. 2017; 5 (3): e21

  Abstract

  Chronic kidney disease (CKD) is a major public health concern in the United States with high prevalence, growing incidence, and serious adverse outcomes.We aimed to develop and validate a model to identify patients at risk of receiving a new diagnosis of CKD (incident CKD) during the next 1 year in a general population.The study population consisted of patients who had visited any care facility in the Maine Health Information Exchange network any time between January 1, 2013, and December 31, 2015, and had no history of CKD diagnosis. Two retrospective cohorts of electronic medical records (EMRs) were constructed for model derivation (N=1,310,363) and validation (N=1,430,772). The model was derived using a gradient tree-based boost algorithm to assign a score to each individual that measured the probability of receiving a new diagnosis of CKD from January 1, 2014, to December 31, 2014, based on the preceding 1-year clinical profile. A feature selection process was conducted to reduce the dimension of the data from 14,680 EMR features to 146 as predictors in the final model. Relative risk was calculated by the model to gauge the risk ratio of the individual to population mean of receiving a CKD diagnosis in next 1 year. The model was tested on the validation cohort to predict risk of CKD diagnosis in the period from January 1, 2015, to December 31, 2015, using the preceding 1-year clinical profile.The final model had a c-statistic of 0.871 in the validation cohort. It stratified patients into low-risk (score 0-0.005), intermediate-risk (score 0.005-0.05), and high-risk (score ≥ 0.05) levels. The incidence of CKD in the high-risk patient group was 7.94%, 13.7 times higher than the incidence in the overall cohort (0.58%). Survival analysis showed that patients in the 3 risk categories had significantly different CKD outcomes as a function of time (P<.001), indicating an effective classification of patients by the model.We developed and validated a model that is able to identify patients at high risk of having CKD in the next 1 year by statistically learning from the EMR-based clinical history in the preceding 1 year. Identification of these patients indicates care opportunities such as monitoring and adopting intervention plans that may benefit the quality of care and outcomes in the long term.

  View details for PubMedID 28747298

• Role of the Wnt/beta-Catenin Pathway in the Pathogenesis of Alcoholic Liver Disease CURRENT MOLECULAR PHARMACOLOGY Behari, J., Sylvester, K. G. 2017; 10 (3): 186–94

  Abstract

  The Wnt pathway is a highly conserved signal transduction pathway that plays an important role in diverse aspects of hepatic physiology. The Wnt pathway, consisting of canonical and noncanonical arms, is composed of secreted glycoproteins, cell surface receptors and co-receptors, and complex intracellular regulatory machinery that regulate a large number of cellular functions. β-Catenin is the main effector of the canonical Wnt pathway and hepatocyte-specific loss of the protein leads to increased susceptibility to alcoholic steatohepatitis. Hepatocytes with disrupted β-catenin demonstrate mitochondrial dysfunction, defective oxidative phosphorylation, and increased oxidative stress. β- Catenin knockout mice have decreased expression of alcohol metabolizing enzymes and increased blood alcohol levels that along with hypoglycemia and hyperammonemia, lead to increased mortality upon alcohol exposure. Disruption of hepatic β-catenin affects fatty acid oxidation and fasting ketogenesis and thereby profoundly affects systemic energy homeostasis. Given the combined roles of Wnt/β-catenin signaling in hepatocellular bioenergetics and regeneration, the Wnt pathway also contributes to alcohol-induced hepatic fibrogenesis and hepatocarcinogenesis. Targeting the Wnt/β-catenin pathway represents an attractive strategy for the treatment of alcohol-induced liver disease.

  View details for PubMedID 26278392

• Identification of independent metabolic risk groups for necrotizing enterocolitis through machine learning Oltman, S. P., Rogers, E. E., Pantell, M., Baer, R. J., Rand, L., Ryckman, K. K., Kastenberg, Z., Sylvester, K., Jeliffe-Pawlowski, L. MOSBY-ELSEVIER. 2017: S372

  View details for Web of Science ID 000414256402258

• The Effect of Level of Care on Gastroschisis Outcomes. The Journal of pediatrics Apfeld, J. C., Kastenberg, Z. J., Sylvester, K. G., Lee, H. C. 2017; 190: 79–84.e1

  Abstract

  To examine the relationship between level of care in neonatal intensive care units (NICUs) and outcomes for newborns with gastroschisis.A retrospective cohort study was conducted at 130 California Perinatal Quality Care Collaborative NICUs from 2008 to 2014. All gastroschisis births were examined according to American Academy of Pediatrics NICU level of care at the birth hospital. Multivariate analyses examined odds of mortality, duration of mechanical ventilation, and duration of stay.For 1588 newborns with gastroschisis, the adjusted odds of death were higher for those born into a center with a level IIA/B NICU (OR, 6.66; P = .004), a level IIIA NICU (OR, 5.95; P = .008), or a level IIIB NICU (OR, 5.85; P = .002), when compared with level IIIC centers. The odds of having more days on ventilation were significantly higher for births at IIA/B and IIIB centers (OR, 2.05 [P < .001] and OR, 1.91 [P < .001], respectively). The odds of having longer duration of stay were significantly higher at IIA/B and IIIB centers (OR, 1.71 [P < .004]; OR, 1.77 [P < .001]).NICU level of care was associated with significant disparities in odds of mortality for newborns with gastroschisis.

  View details for PubMedID 29144275

• Heme Oxygenase Activity and Heme Binding in a Neonatal Mouse Model NEONATOLOGY Kourula, S., Ang, J., Zhao, H., Kalish, F., Vandenabeele, P., Sylvester, K. G., Wong, R. J., Stevenson, D. K. 2017; 112 (4): 376–83

  Abstract

  Severe hemolytic disease of the newborn leads to the release of pro-oxidative free heme (FH). Heme oxygenase (HO) is primarily responsible for detoxifying FH.To investigate the protective effects of HO in a model of heme overload.For in vitro studies, NIH3T3 HO-1-luc cells were incubated with 10, 30, or 60 µM FH or methemalbumin (MHA). HO-1 promoter activity was assessed 3, 6, and 24 h after treatment. Cell survival was indexed by viability assays. For in vivo studies, 1- and 5-week-old wild-type (Wt) or HO-1-heterozygous (Het, HO-1+/-) mice were given 60 µmol FH or MHA/kg intraperitoneally. After 24 h, plasma aspartate aminotransferease (AST)/alanine transaminase (ALT) and hemopexin, liver HO activity, and lipid peroxidation (LP) were determined.In HO-1-luc cells, HO-1 promoter activity peaked 6 h after incubation with 30 µM FH (1.6-fold) or 60 µM MHA (2.1-fold) over baseline. Twenty-four hours after exposure to 60 µM FH, a decrease in viability of 80% was found, compared with no decrease after exposure to 60 µM MHA. In 1-week-old Wt and HO-1 Het pups given 60 µmol FH/kg, HO activity significantly increased 3.5- and 3.1-fold, respectively. No changes in LP or AST/ALT levels were observed. In adult Wt and HO-1 Het mice, HO activity increased (3.0- and 2.6-fold, respectively). LP and AST levels significantly increased 28.4- and 2.7-fold, respectively, in adult HO-1 Het mice. Hemopexin levels at baseline were higher in adults compared with newborns for both Wt and Het mice. In addition, FH induced hemopexin levels in both adults and newborns, but to a lesser degree in newborns.FH is highly toxic in vitro, but its toxicity is abolished when bound to albumin. Newborns appear to be protected from the pro-oxidative effects of FH, which may be mediated by heme binding and a higher absolute HO activity at baseline and after FH-mediated induction.

  View details for PubMedID 28926834

• Involvement of prolyl isomerase PIN1 in the cell cycle progression and proliferation of hepatic oval cells PATHOLOGY RESEARCH AND PRACTICE Risal, P., Shrestha, N., Chand, L., Sylvester, K. G., Jeong, Y. J. 2017; 213 (4): 373-380

  Abstract

  Liver regenerates remarkably after toxic injury or surgical resection. In the case of failure of resident hepatocytes to restore loss, repopulation is carried out by induction, proliferation, and differentiation of the progenitor cell. Although, some signaling pathways have been verified to contribute oval cell-mediated liver regeneration, role of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1(Pin1) in the oval cells proliferation is unknown. In the present study, we evaluate the role of Pin1 in oval cells proliferation. In our study, the expression of Pin1 in the mice liver increased after three weeks feeding of 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) diet along with the proliferation of oval cells. The expression of Pin1 was higher in oval cells compared to the hepatocytes.Pin1 inhibition by Juglone reduced oval cell proliferation, which was restored to normal when oval cells were treated with IGF-1. Consistent with increased cell growth, expression of Pin1, β-catenin and PCNA were increased in IGF-1 treated cells in a time dependent manner. In FACS analysis, siRNA-mediated knockdown of the Pin1 protein in the oval cells significantly increased the numbers of cells in G0/G1 phase. Furthermore, hepatocyte when treated with TGF-β showed marked reduction in cell proliferation and expression of Pin1 whereas this effect was not seen in the oval cells treated with TGF-β. In conclusion, Pin1 plays important role in the cell cycle progression and increase oval cells proliferation which may be crucial in chronic liver injury.

  View details for DOI 10.1016/j.prp.2017.01.005

  View details for Web of Science ID 000399513100014

  View details for PubMedID 28214206

• Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness PLOS ONE Wang, Y., Li, Z., Hu, G., Hao, S., Deng, X., Huang, M., Ren, M., Jiang, X., Kanegaye, J. T., Ha, K., Lee, J., Li, X., Jiang, X., Yu, Y., Tremoulet, A. H., Burns, J. C., Whitin, J. C., Shin, A. Y., Sylvester, K. G., McElhinney, D. B., Cohen, H. J., Ling, X. B. 2016; 11 (12)

  Abstract

  Resistance to intravenous immunoglobulin (IVIG) occurs in 10-20% of patients with Kawasaki disease (KD). The risk of resistance is about two-fold higher in patients with elevated gamma glutamyl transferase (GGT) levels. We sought to understand the biological mechanisms underlying IVIG resistance in patients with elevated GGT levels.We explored the association between elevated GGT levels and IVIG-resistance with a cohort of 686 KD patients (Cohort I). Gene expression data from 130 children with acute KD (Cohort II) were analyzed using the R square statistic and false discovery analysis to identify genes that were differentially represented in patients with elevated GGT levels with regard to IVIG responsiveness. Two additional KD cohorts (Cohort III and IV) were used to test the hypothesis that sialylation and GGT may be involved in IVIG resistance through neutrophil apoptosis.Thirty-six genes were identified that significantly explained the variations of both GGT levels and IVIG responsiveness in KD patients. After Bonferroni correction, significant associations with IVIG resistance persisted for 12 out of 36 genes among patients with elevated GGT levels and none among patients with normal GGT levels. With the discovery of ST6GALNAC3, a sialyltransferase, as the most differentially expressed gene, we hypothesized that sialylation and GGT are involved in IVIG resistance through neutrophil apoptosis. We then confirmed that in Cohort III and IV there was significantly less reduction in neutrophil count in IVIG non-responders.Gene expression analyses combining molecular and clinical datasets support the hypotheses that: (1) neutrophil apoptosis induced by IVIG may be a mechanism of action of IVIG in KD; (2) changes in sialylation and GGT level in KD patients may contribute synergistically to IVIG resistance through blocking IVIG-induced neutrophil apoptosis. These findings have implications for understanding the mechanism of action in IVIG resistance, and possibly for development of novel therapeutics.

  View details for DOI 10.1371/journal.pone.0167434

  View details for Web of Science ID 000392853100008

  View details for PubMedID 28002448

  View details for PubMedCentralID PMC5176264

• CK2 alpha/CSNK2A1 Phosphorylates SIRT6 and Is Involved in the Progression of Breast Carcinoma and Predicts Shorter Survival of Diagnosed Patients AMERICAN JOURNAL OF PATHOLOGY Bae, J. S., Park, S., Jamiyandorj, U., Kim, K. M., Noh, S. J., Kim, J. R., Park, H. J., Kwon, K. S., Jung, S. H., Park, H. S., Park, B., Lee, H., Moon, W. S., Sylvester, K. G., Jang, K. Y. 2016; 186 (12): 3297-3315

  Abstract

  Recently, the roles of sirtuins (SIRTs) in tumorigenesis have been of interest to oncologists, and protein kinase CK2 α1 (CSNK2A1) has been shown to be involved in tumorigenesis by phosphorylating various proteins, including SIRT1. Therefore, we evaluated the roles of CSNK2A1, SIRT6, and phosphorylated SIRT6 and their relationships in breast carcinoma. Nuclear expression of CSNK2A1 and SIRT6 predicted shorter overall survival and relapse-free survival by multivariate analysis. Inhibition of CSNK2A1 decreased the proliferative and invasive activity of cancer cells. In addition, CSNK2A1 was bound to SIRT6 and phosphorylated SIRT6; evidence for this is provided from immunofluorescence staining, co-immunoprecipitation of CSNK2A1 and SIRT6, a glutathione S-transferase pull-down assay, an in vitro kinase assay, and transfection of mutant CSNK2A1. Knockdown of SIRT6 decreased the proliferation and invasiveness of cancer cells. Overexpression of SIRT6 increased proliferation, but mutation at the Ser338 phosphorylation site of SIRT6 inhibited the proliferation of MCF7 cells. Moreover, both knockdown of SIRT6 and a mutation at the phosphorylation site of SIRT6 decreased expression of matrix metallopeptidase 9, β-catenin, cyclin D1, and NF-κB. Especially, SIRT6 expression was associated with the nuclear localization of β-catenin. This study demonstrates that CSNK2A1 and SIRT6 are indicators of poor prognosis for breast carcinomas and that CSNK2A1-mediated phosphorylation of SIRT6 might be involved in the progression of breast carcinoma.

  View details for DOI 10.1016/j.ajpath.2016.08.007

  View details for PubMedID 27746184

• Web-based Real-Time Case Finding for the Population Health Management of Patients With Diabetes Mellitus: A Prospective Validation of the Natural Language Processing-Based Algorithm With Statewide Electronic Medical Records. JMIR medical informatics Zheng, L., Wang, Y., Hao, S., Shin, A. Y., Jin, B., Ngo, A. D., Jackson-Browne, M. S., Feller, D. J., Fu, T., Zhang, K., Zhou, X., Zhu, C., Dai, D., Yu, Y., Zheng, G., Li, Y., McElhinney, D. B., Culver, D. S., Alfreds, S. T., Stearns, F., Sylvester, K. G., Widen, E., Ling, X. B. 2016; 4 (4)

  Abstract

  Diabetes case finding based on structured medical records does not fully identify diabetic patients whose medical histories related to diabetes are available in the form of free text. Manual chart reviews have been used but involve high labor costs and long latency.This study developed and tested a Web-based diabetes case finding algorithm using both structured and unstructured electronic medical records (EMRs).This study was based on the health information exchange (HIE) EMR database that covers almost all health facilities in the state of Maine, United States. Using narrative clinical notes, a Web-based natural language processing (NLP) case finding algorithm was retrospectively (July 1, 2012, to June 30, 2013) developed with a random subset of HIE-associated facilities, which was then blind tested with the remaining facilities. The NLP-based algorithm was subsequently integrated into the HIE database and validated prospectively (July 1, 2013, to June 30, 2014).Of the 935,891 patients in the prospective cohort, 64,168 diabetes cases were identified using diagnosis codes alone. Our NLP-based case finding algorithm prospectively found an additional 5756 uncodified cases (5756/64,168, 8.97% increase) with a positive predictive value of .90. Of the 21,720 diabetic patients identified by both methods, 6616 patients (6616/21,720, 30.46%) were identified by the NLP-based algorithm before a diabetes diagnosis was noted in the structured EMR (mean time difference = 48 days).The online NLP algorithm was effective in identifying uncodified diabetes cases in real time, leading to a significant improvement in diabetes case finding. The successful integration of the NLP-based case finding algorithm into the Maine HIE database indicates a strong potential for application of this novel method to achieve a more complete ascertainment of diagnoses of diabetes mellitus.

  View details for PubMedID 27836816

• Mapping the Fetomaternal Peripheral Immune System at Term Pregnancy. Journal of immunology Fragiadakis, G. K., Baca, Q. J., Gherardini, P. F., Ganio, E. A., Gaudilliere, D. K., Tingle, M., Lancero, H. L., McNeil, L. S., Spitzer, M. H., Wong, R. J., Shaw, G. M., Darmstadt, G. L., Sylvester, K. G., Winn, V. D., Carvalho, B., Lewis, D. B., Stevenson, D. K., Nolan, G. P., Aghaeepour, N., Angst, M. S., Gaudilliere, B. L. 2016

  Abstract

  Preterm labor and infections are the leading causes of neonatal deaths worldwide. During pregnancy, immunological cross talk between the mother and her fetus is critical for the maintenance of pregnancy and the delivery of an immunocompetent neonate. A precise understanding of healthy fetomaternal immunity is the important first step to identifying dysregulated immune mechanisms driving adverse maternal or neonatal outcomes. This study combined single-cell mass cytometry of paired peripheral and umbilical cord blood samples from mothers and their neonates with a graphical approach developed for the visualization of high-dimensional data to provide a high-resolution reference map of the cellular composition and functional organization of the healthy fetal and maternal immune systems at birth. The approach enabled mapping of known phenotypical and functional characteristics of fetal immunity (including the functional hyperresponsiveness of CD4(+) and CD8(+) T cells and the global blunting of innate immune responses). It also allowed discovery of new properties that distinguish the fetal and maternal immune systems. For example, examination of paired samples revealed differences in endogenous signaling tone that are unique to a mother and her offspring, including increased ERK1/2, MAPK-activated protein kinase 2, rpS6, and CREB phosphorylation in fetal Tbet(+)CD4(+) T cells, CD8(+) T cells, B cells, and CD56(lo)CD16(+) NK cells and decreased ERK1/2, MAPK-activated protein kinase 2, and STAT1 phosphorylation in fetal intermediate and nonclassical monocytes. This highly interactive functional map of healthy fetomaternal immunity builds the core reference for a growing data repository that will allow inferring deviations from normal associated with adverse maternal and neonatal outcomes.

  View details for PubMedID 27793998

• Necroptosis is Associated with Development Dependent Enterocyte Death in a Mouse Model of Intestinal Injury and Human Necrotizing Enterocolitis Sinclair, T., Tao, G., Liu, B., Zhang, R., Lu, C., Sylvester, K. G. ELSEVIER SCIENCE INC. 2016: E157–E158

  View details for DOI 10.1016/j.jamcollsurg.2016.08.401

  View details for Web of Science ID 000395825100346

• Advanced Minimal Access Surgery in Infants Weighing Less Than 3 Kilograms: A Single Center Experience Sinclair, T., Wall, J. K., Albanese, C., Sylvester, K. G., Bruzoni, M. ELSEVIER SCIENCE INC. 2016: E153

  View details for DOI 10.1016/j.jamcollsurg.2016.08.391

  View details for Web of Science ID 000395825100336

• A Multi-Omics Analysis of Human Nucleus-Coded Mitochondrial Genes with Mouse Extraembryonic Tissue/Placenta Phenotypes: Implications in Mitochondria-Mediated Maternal and Fetal Complications. Hu, G., Chen, R., Deng, X., Li, Z., Mo, L., Hao, S., Shaw, G. M., Stevenson, D. K., Cohen, H. J., Jiang, X., Sylvester, K. G., Ling, X. B. SAGE PUBLICATIONS INC. 2016: 320A

  View details for Web of Science ID 000372879200871

• Prospective stratification of patients at risk for emergency department revisit: resource utilization and population management strategy implications. BMC emergency medicine Jin, B., Zhao, Y., Hao, S., Shin, A. Y., Wang, Y., Zhu, C., Hu, Z., Fu, C., Ji, J., Wang, Y., Zhao, Y., Jiang, Y., Dai, D., Culver, D. S., Alfreds, S. T., Rogow, T., Stearns, F., Sylvester, K. G., Widen, E., Ling, X. B. 2016; 16 (1): 10-?

  Abstract

  Estimating patient risk of future emergency department (ED) revisits can guide the allocation of resources, e.g. local primary care and/or specialty, to better manage ED high utilization patient populations and thereby improve patient life qualities.We set to develop and validate a method to estimate patient ED revisit risk in the subsequent 6 months from an ED discharge date. An ensemble decision-tree-based model with Electronic Medical Record (EMR) encounter data from HealthInfoNet (HIN), Maine's Health Information Exchange (HIE), was developed and validated, assessing patient risk for a subsequent 6 month return ED visit based on the ED encounter-associated demographic and EMR clinical history data. A retrospective cohort of 293,461 ED encounters that occurred between January 1, 2012 and December 31, 2012, was assembled with the associated patients' 1-year clinical histories before the ED discharge date, for model training and calibration purposes. To validate, a prospective cohort of 193,886 ED encounters that occurred between January 1, 2013 and June 30, 2013 was constructed.Statistical learning that was utilized to construct the prediction model identified 152 variables that included the following data domains: demographics groups (12), different encounter history (104), care facilities (12), primary and secondary diagnoses (10), primary and secondary procedures (2), chronic disease condition (1), laboratory test results (2), and outpatient prescription medications (9). The c-statistics for the retrospective and prospective cohorts were 0.742 and 0.730 respectively. Total medical expense and ED utilization by risk score 6 months after the discharge were analyzed. Cluster analysis identified discrete subpopulations of high-risk patients with distinctive resource utilization patterns, suggesting the need for diversified care management strategies.Integration of our method into the HIN secure statewide data system in real time prospectively validated its performance. It promises to provide increased opportunity for high ED utilization identification, and optimized resource and population management.

  View details for DOI 10.1186/s12873-016-0074-5

  View details for PubMedID 26842066

  View details for PubMedCentralID PMC4739399

• NLP based congestive heart failure case finding: A prospective analysis on statewide electronic medical records. International journal of medical informatics Wang, Y., Luo, J., Hao, S., Xu, H., Shin, A. Y., Jin, B., Liu, R., Deng, X., Wang, L., Zheng, L., Zhao, Y., Zhu, C., Hu, Z., Fu, C., Hao, Y., Zhao, Y., Jiang, Y., Dai, D., Culver, D. S., Alfreds, S. T., Todd, R., Stearns, F., Sylvester, K. G., Widen, E., Ling, X. B. 2015; 84 (12): 1039-1047

  Abstract

  In order to proactively manage congestive heart failure (CHF) patients, an effective CHF case finding algorithm is required to process both structured and unstructured electronic medical records (EMR) to allow complementary and cost-efficient identification of CHF patients.We set to identify CHF cases from both EMR codified and natural language processing (NLP) found cases. Using narrative clinical notes from all Maine Health Information Exchange (HIE) patients, the NLP case finding algorithm was retrospectively (July 1, 2012-June 30, 2013) developed with a random subset of HIE associated facilities, and blind-tested with the remaining facilities. The NLP based method was integrated into a live HIE population exploration system and validated prospectively (July 1, 2013-June 30, 2014). Total of 18,295 codified CHF patients were included in Maine HIE. Among the 253,803 subjects without CHF codings, our case finding algorithm prospectively identified 2411 uncodified CHF cases. The positive predictive value (PPV) is 0.914, and 70.1% of these 2411 cases were found to be with CHF histories in the clinical notes.A CHF case finding algorithm was developed, tested and prospectively validated. The successful integration of the CHF case findings algorithm into the Maine HIE live system is expected to improve the Maine CHF care.

  View details for DOI 10.1016/j.ijmedinf.2015.06.007

  View details for PubMedID 26254876

• Augmented Wnt signaling as a therapeutic tool to prevent ischemia/reperfusion injury in liver: Preclinical studies in a mouse model. Liver transplantation Liu, B., Zhang, R., Tao, G., Lehwald, N. C., Liu, B., Koh, Y., Sylvester, K. G. 2015; 21 (12): 1533-1542

  Abstract

  The Wnt signaling pathway has established biological roles in liver development, regeneration, and carcinogenesis. Given the common need for cellular energy utilization in each of these processes, we hypothesized that Wnt signaling would directly regulate hepatocyte mitochondrial function. Mice were engineered to overexpress Wnt1 in hepatocytes under the control of a tetracycline analogue. Wnt1 and wild-type mice underwent ischemia/reperfusion injury (IRI) to induce oxidative mitochondrial injury. Alpha mouse liver 12 (AML12) hepatocytes were exposed to Wnt agonists for in vitro hypoxia/reoxygenation (H-R) experiments. We observed stabilized mitochondrial membrane potential and reduced levels of hepatocyte apoptosis involving the mitochondrial pathway in Wnt1 mice compared to controls following IRI. Wnt1 mice also demonstrated increased mitochondrial DNA copy number, as well as an increased tricarboxylic acid cycle activity and adenosine triphosphate levels indicating that mitochondrial function is preserved by Wnt1 overexpression following IRI. AML12 cells treated by Wnt3a or the glycogen synthase kinase 3β inhibitor LiCl exposed to H-R demonstrated decreased reactive oxygen species and reduced apoptosis compared to controls. Increased nucleus-localized PGC-1α and phosphorylated SIRT1 was observed in both Wnt1+ mice as well as AML12 cells treated with Wnt3a or LiCl. Activated Wnt signaling protects hepatocytes against oxidative injury and apoptosis through mitochondrial stabilization and preserved oxidative phosphorylation function. Mechanistically, these effects are accompanied by an increase in phosphorylated SIRT1 and nucleus-localized PGC-1α. These findings expand the understanding of Wnt signaling biology in hepatocytes and suggest the potential for the therapeutic application of Wnt pathway manipulation in a variety of clinical applications including organ transplantation. Liver Transpl 21:1533-1542, 2015. © 2015 AASLD.

  View details for DOI 10.1002/lt.24331

  View details for PubMedID 26335930

• Infant, maternal, and geographic factors influencing gastroschisis related mortality in Zimbabwe SURGERY Apfeld, J. C., Wren, S. M., Macheka, N., Mbuwayesango, B. A., Bruzoni, M., Sylvester, K. G., Kastenberg, Z. J. 2015; 158 (6): 1476-1481

  Abstract

  Survival for infants with gastroschisis in developed countries has improved dramatically in recent decades with reported mortality rates of 4-7%. Conversely, mortality rates for gastroschisis in sub-Saharan Africa remain as great as 60% in contemporary series. This study describes the burden of gastroschisis at the major pediatric hospital in Zimbabwe with the goal of identifying modifiable factors influencing gastroschisis-related infant mortality.We performed a retrospective cohort study of all cases of gastroschisis admitted to Harare Children's Hospital in 2013. Univariate and multivariate analyses were performed to describe infant, maternal, and geographic factors influencing survival.A total of 5,585 neonatal unit admissions were identified including 95 (1.7%) infants born with gastroschisis. Gastroschisis-related mortality was 84% (n = 80). Of infants with gastroschisis, 96% (n = 91) were born outside Harare Hospital, 82% (n = 78) were born outside Harare Province, and 23% (n = 25) were home births. The unadjusted odds of survival for these neonates with gastroschisis were decreased for low birth weight infants (<2,500 grams; odds ratio [OR], 0.15; 95% CI, 0.05-0.51), preterm births (<37 weeks gestational age; OR, 0.06; 95% CI, 0.01-0.50), and for those born to teenage mothers (<20 years of age; OR, 0.05; 95% CI, 0.01-0.46). There was also a trend toward decreased odds of survival for home births (OR, 0.16; 95% CI, 0.02-1.34) and for those born outside Harare Province (OR, 0.35; 95% CI, 0.10-1.22).Gastroschisis-related infant mortality in Zimbabwe is associated with well-known risk factors, including low birth weight, prematurity, and teenage mothers. However, modifiable factors identified in this study signify potential opportunities for developing innovative approaches to perinatal care in such a resource-constrained environment.

  View details for DOI 10.1016/j.surg.2015.04.037

  View details for Web of Science ID 000364612200004

• Infant, maternal, and geographic factors influencing gastroschisis related mortality in Zimbabwe. Surgery Apfeld, J. C., Wren, S. M., Macheka, N., Mbuwayesango, B. A., Bruzoni, M., Sylvester, K. G., Kastenberg, Z. J. 2015; 158 (6): 1475-1480

  Abstract

  Survival for infants with gastroschisis in developed countries has improved dramatically in recent decades with reported mortality rates of 4-7%. Conversely, mortality rates for gastroschisis in sub-Saharan Africa remain as great as 60% in contemporary series. This study describes the burden of gastroschisis at the major pediatric hospital in Zimbabwe with the goal of identifying modifiable factors influencing gastroschisis-related infant mortality.We performed a retrospective cohort study of all cases of gastroschisis admitted to Harare Children's Hospital in 2013. Univariate and multivariate analyses were performed to describe infant, maternal, and geographic factors influencing survival.A total of 5,585 neonatal unit admissions were identified including 95 (1.7%) infants born with gastroschisis. Gastroschisis-related mortality was 84% (n = 80). Of infants with gastroschisis, 96% (n = 91) were born outside Harare Hospital, 82% (n = 78) were born outside Harare Province, and 23% (n = 25) were home births. The unadjusted odds of survival for these neonates with gastroschisis were decreased for low birth weight infants (<2,500 grams; odds ratio [OR], 0.15; 95% CI, 0.05-0.51), preterm births (<37 weeks gestational age; OR, 0.06; 95% CI, 0.01-0.50), and for those born to teenage mothers (<20 years of age; OR, 0.05; 95% CI, 0.01-0.46). There was also a trend toward decreased odds of survival for home births (OR, 0.16; 95% CI, 0.02-1.34) and for those born outside Harare Province (OR, 0.35; 95% CI, 0.10-1.22).Gastroschisis-related infant mortality in Zimbabwe is associated with well-known risk factors, including low birth weight, prematurity, and teenage mothers. However, modifiable factors identified in this study signify potential opportunities for developing innovative approaches to perinatal care in such a resource-constrained environment.

  View details for DOI 10.1016/j.surg.2015.04.037

  View details for PubMedID 26071924

• Augmented Wnt Signaling as a Therapeutic Tool to Prevent Ischemia/Reperfusion Injury in Liver: Preclinical Studies in a Mouse Model LIVER TRANSPLANTATION Liu, B., Zhang, R., Tao, G., Lehwald, N. C., Liu, B., Koh, Y., Sylvester, K. G. 2015; 21 (12): 1533-1542

  Abstract

  The Wnt signaling pathway has established biological roles in liver development, regeneration, and carcinogenesis. Given the common need for cellular energy utilization in each of these processes, we hypothesized that Wnt signaling would directly regulate hepatocyte mitochondrial function. Mice were engineered to overexpress Wnt1 in hepatocytes under the control of a tetracycline analogue. Wnt1 and wild-type mice underwent ischemia/reperfusion injury (IRI) to induce oxidative mitochondrial injury. Alpha mouse liver 12 (AML12) hepatocytes were exposed to Wnt agonists for in vitro hypoxia/reoxygenation (H-R) experiments. We observed stabilized mitochondrial membrane potential and reduced levels of hepatocyte apoptosis involving the mitochondrial pathway in Wnt1 mice compared to controls following IRI. Wnt1 mice also demonstrated increased mitochondrial DNA copy number, as well as an increased tricarboxylic acid cycle activity and adenosine triphosphate levels indicating that mitochondrial function is preserved by Wnt1 overexpression following IRI. AML12 cells treated by Wnt3a or the glycogen synthase kinase 3β inhibitor LiCl exposed to H-R demonstrated decreased reactive oxygen species and reduced apoptosis compared to controls. Increased nucleus-localized PGC-1α and phosphorylated SIRT1 was observed in both Wnt1+ mice as well as AML12 cells treated with Wnt3a or LiCl. Activated Wnt signaling protects hepatocytes against oxidative injury and apoptosis through mitochondrial stabilization and preserved oxidative phosphorylation function. Mechanistically, these effects are accompanied by an increase in phosphorylated SIRT1 and nucleus-localized PGC-1α. These findings expand the understanding of Wnt signaling biology in hepatocytes and suggest the potential for the therapeutic application of Wnt pathway manipulation in a variety of clinical applications including organ transplantation. Liver Transpl 21:1533-1542, 2015. © 2015 AASLD.

  View details for DOI 10.1002/lt.24331

  View details for Web of Science ID 000368138700011

• Development, Validation and Deployment of a Real Time 30 Day Hospital Readmission Risk Assessment Tool in the Maine Healthcare Information Exchange PLOS ONE Hao, S., Wang, Y., Jin, B., Shin, A. Y., Zhu, C., Huang, M., Zheng, L., Luo, J., Hu, Z., Fu, C., Dai, D., Wang, Y., Culver, D. S., Alfreds, S. T., Rogow, T., Stearns, F., Sylvester, K. G., Widen, E., Ling, X. B. 2015; 10 (10)

  Abstract

  Identifying patients at risk of a 30-day readmission can help providers design interventions, and provide targeted care to improve clinical effectiveness. This study developed a risk model to predict a 30-day inpatient hospital readmission for patients in Maine, across all payers, all diseases and all demographic groups.Our objective was to develop a model to determine the risk for inpatient hospital readmission within 30 days post discharge. All patients within the Maine Health Information Exchange (HIE) system were included. The model was retrospectively developed on inpatient encounters between January 1, 2012 to December 31, 2012 from 24 randomly chosen hospitals, and then prospectively validated on inpatient encounters from January 1, 2013 to December 31, 2013 using all HIE patients.A risk assessment tool partitioned the entire HIE population into subgroups that corresponded to probability of hospital readmission as determined by a corresponding positive predictive value (PPV). An overall model c-statistic of 0.72 was achieved. The total 30-day readmission rates in low (score of 0-30), intermediate (score of 30-70) and high (score of 70-100) risk groupings were 8.67%, 24.10% and 74.10%, respectively. A time to event analysis revealed the higher risk groups readmitted to a hospital earlier than the lower risk groups. Six high-risk patient subgroup patterns were revealed through unsupervised clustering. Our model was successfully integrated into the statewide HIE to identify patient readmission risk upon admission and daily during hospitalization or for 30 days subsequently, providing daily risk score updates.The risk model was validated as an effective tool for predicting 30-day readmissions for patients across all payer, disease and demographic groups within the Maine HIE. Exposing the key clinical, demographic and utilization profiles driving each patient's risk of readmission score may be useful to providers in developing individualized post discharge care plans.

  View details for DOI 10.1371/journal.pone.0140271

  View details for Web of Science ID 000362511000113

  View details for PubMedID 26448562

• Serological Targeted Analysis of an ITIH4 Peptide Isoform: A Preterm Birth Biomarker and Its Associated SNP Implications JOURNAL OF GENETICS AND GENOMICS Tan, Z., Hu, Z., Cai, E. Y., Alev, C., Yang, T., Li, Z., Sung, J., El-Sayed, Y. Y., Shaw, G. M., Stevenson, D. K., Butte, A. J., Sheng, G., Sylvester, K. G., Cohen, H. J., Ling, X. B. 2015; 42 (9): 507-510

  View details for DOI 10.1016/j.jgg.2015.06.001

  View details for PubMedID 26408095

• A robust estimation model for surgery durations with temporal, operational, and surgery team effects HEALTH CARE MANAGEMENT SCIENCE Kayis, E., Khaniyev, T. T., Suermondt, J., Sylvester, K. 2015; 18 (3): 222-233

  Abstract

  For effective operating room (OR) planning, surgery duration estimation is critical. Overestimation leads to underutilization of expensive hospital resources (e.g., OR time) whereas underestimation leads to overtime and high waiting times for the patients. In this paper, we consider a particular estimation method currently in use and using additional temporal, operational, and staff-related factors provide a statistical model to adjust these estimates for higher accuracy.The results show that our method increases the accuracy of the estimates, in particular by reducing large errors. For the 8093 cases we have in our data, our model decreases the mean absolute deviation of the currently used scheduled duration (42.65 ± 0.59 minutes) by 1.98 ± 0.28 minutes. For the cases with large negative errors, however, the decrease in the mean absolute deviation is 20.35 ± 0.74 minutes (with a respective increase of 0.89 ± 0.66 minutes in large positive errors). We find that not only operational and temporal factors, but also medical staff and team experience related factors (such as number of nurses and the frequency of the medical team working together) could be used to improve the currently used estimates. Finally, we conclude that one could further improve these predictions by combining our model with other good prediction models proposed in the literature. Specifically, one could decrease the mean absolute deviation of 39.98 ± 0.58 minutes obtained via the method of Dexter et al (Anesth Analg 117(1):204-209, 2013) by 1.02 ± 0.21 minutes by combining our method with theirs.

  View details for DOI 10.1007/s10729-014-9309-8

  View details for Web of Science ID 000360082100002

• Online Prediction of Health Care Utilization in the Next Six Months Based on Electronic Health Record Information: A Cohort and Validation Study JOURNAL OF MEDICAL INTERNET RESEARCH Hu, Z., Hao, S., Jin, B., Shin, A. Y., Zhu, C., Huang, M., Wang, Y., Zheng, L., Dai, D., Culver, D. S., Alfreds, S. T., Rogow, T., Stearns, F., Sylvester, K. G., Widen, E., Ling, X. 2015; 17 (9)

  Abstract

  The increasing rate of health care expenditures in the United States has placed a significant burden on the nation's economy. Predicting future health care utilization of patients can provide useful information to better understand and manage overall health care deliveries and clinical resource allocation.This study developed an electronic medical record (EMR)-based online risk model predictive of resource utilization for patients in Maine in the next 6 months across all payers, all diseases, and all demographic groups.In the HealthInfoNet, Maine's health information exchange (HIE), a retrospective cohort of 1,273,114 patients was constructed with the preceding 12-month EMR. Each patient's next 6-month (between January 1, 2013 and June 30, 2013) health care resource utilization was retrospectively scored ranging from 0 to 100 and a decision tree-based predictive model was developed. Our model was later integrated in the Maine HIE population exploration system to allow a prospective validation analysis of 1,358,153 patients by forecasting their next 6-month risk of resource utilization between July 1, 2013 and December 31, 2013.Prospectively predicted risks, on either an individual level or a population (per 1000 patients) level, were consistent with the next 6-month resource utilization distributions and the clinical patterns at the population level. Results demonstrated the strong correlation between its care resource utilization and our risk scores, supporting the effectiveness of our model. With the online population risk monitoring enterprise dashboards, the effectiveness of the predictive algorithm has been validated by clinicians and caregivers in the State of Maine.The model and associated online applications were designed for tracking the evolving nature of total population risk, in a longitudinal manner, for health care resource utilization. It will enable more effective care management strategies driving improved patient outcomes.

  View details for DOI 10.2196/jmir.4976

  View details for Web of Science ID 000361809800005

  View details for PubMedID 26395541

• Impaired Activity of Blood Coagulant Factor XIII in Patients with Necrotizing Enterocolitis SCIENTIFIC REPORTS Tao, G., Liu, B., Zhang, R., Liu, G., Abdullah, F., Harris, M. C., Brandt, M. L., Ehrenkranz, R. A., Bowers, C., Martin, C. R., Moss, R. L., Sylvester, K. G. 2015; 5

  Abstract

  Necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) medical/surgical emergency of the newborn and a leading cause of preterm neonate morbidity and mortality. NEC is a challenge to diagnose since it often shares similar clinical features with neonatal sepsis. In the present study, plasma protein profiling was compared among NEC, sepsis and control cohorts using gel electrophoresis, immunoblot and mass spectrometry. We observed significant impairment in the formation of fibrinogen-γ dimers (FGG-dimer) in the plasma of newborns with NEC that could efficiently differentiate NEC and sepsis with a high level of sensitivity and specificity. Interestingly, the impaired FGG-dimer formation could be restored in NEC plasma by the addition of exogenous active factor XIII (FXIII). Enzymatic activity of FXIII was determined to be significantly lower in NEC subject plasma for crosslinking FGG when compared to sepsis. These findings demonstrate a potential novel biomarker and related biologic mechanism for diagnosing NEC, as well as suggest a possible therapeutic strategy.

  View details for DOI 10.1038/srep13119

  View details for Web of Science ID 000359525400001

• Urine biomarkers for necrotizing enterocolitis PEDIATRIC SURGERY INTERNATIONAL Sylvester, K. G., Moss, R. L. 2015; 31 (5): 421-429

  Abstract

  Necrotizing enterocolitis (NEC) remains a significant cause of morbidity and mortality in premature neonates. Despite decades of investigation, treating clinicians are still not able to determine which premature infants are at greatest risk of developing NEC and which of the affected infants will develop severe NEC requiring operation. A biomarker is a specific molecular indicator that can be used to identify or measure the progress of a disease. Many potential biomarkers have been studied for their potential relevance to NEC. Those showing promise include C-reactive protein, intestinal fatty acid-binding protein, platelet-activating factor and many others. None to date have achieved sufficient predictive value to be clinically useful. Distinguishing between the specific changes in NEC and the non-specific inflammation of sepsis has proven challenging. Urine is a particularly attractive site for potential biomarkers. It can be collected readily and non-invasively, and it is a rich source of both proteins and peptides. Preliminary work has revealed some promising biomarkers of NEC in urine. Combined with clinical data, they have been shown to be highly predictive in small series of patients. Advances in high-throughput molecular analysis have opened the door to finding biomarkers that may meaningfully improve the outcome of infants at risk for NEC.

  View details for DOI 10.1007/s00383-015-3693-0

  View details for Web of Science ID 000353218200001

  View details for PubMedID 25807901

• CK2 alpha phosphorylates DBC1 and is involved in the progression of gastric carcinoma and predicts poor survival of gastric carcinoma patients INTERNATIONAL JOURNAL OF CANCER Bae, J. S., Park, S., Kim, K. M., Kwon, K. S., Kim, C. Y., Lee, H. K., Park, B., Park, H. S., Lee, H., Moon, W. S., Chung, M. J., Sylvester, K. G., Jang, K. Y. 2015; 136 (4): 797-809

  Abstract

  CK2α has diverse effects on the tumorigenesis owing to its kinase activity, which phosphorylates various proteins involved in tumorigenesis. We, therefore, investigated the expression and role of CK2α in the phosphorylation of deleted in breast cancer 1 (DBC1) in gastric carcinomas. We used 187 gastric carcinomas and human gastric cancer cells to investigate the roles and relationship between CK2α and DBC1 in gastric carcinomas. Positive expression of CK2α and phospho-DBC1 predicted shorter overall survival and relapse-free survival by univariate analysis. Especially, CK2α expression was an independent prognostic indicator for gastric carcinoma patients. In gastric carcinoma cells, CK2α was bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2α was evidenced by co-immunoprecipitation of CK2α and DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. Inhibition of both CK2α and DBC1 decreased proliferation and invasive activity of cancer cells. Decreased migration and invasive activity was associated with a downregulation of MMP2, MMP9 and the epithelial-mesenchymal transition. A mutation at the phosphorylation site of DBC1 also downregulated the signals related with the epithelial-mesenchymal transition. Our study demonstrated that CK2α is an independent prognostic indicator for gastric carcinoma patients and is involved in tumorigenesis by regulating the phosphorylation of DBC1. In addition, the blocking of CK2α and DBC1 inhibited the proliferation and invasive potential of gastric cancer cells. Therefore, our study suggests that CK2α-DBC1 pathway might be a new therapeutic target for the treatment of gastric carcinoma.

  View details for DOI 10.1002/ijc.29043

  View details for Web of Science ID 000346089900027

  View details for PubMedID 24962073

• Effect of deregionalized care on mortality in very low-birth-weight infants with necrotizing enterocolitis. JAMA pediatrics Kastenberg, Z. J., Lee, H. C., Profit, J., Gould, J. B., Sylvester, K. G. 2015; 169 (1): 26-32

  Abstract

  There has been a significant expansion in the number of low-level and midlevel neonatal intensive care units (NICUs) in recent decades. Infants with necrotizing enterocolitis represent a high-risk subgroup of the very low-birth-weight (VLBW) (<1500 g) population that would benefit from focused regionalization.To describe the current trend toward deregionalization and to test the hypothesis that infants with necrotizing enterocolitis represent a particularly high-risk subgroup of the VLBW population that would benefit from early identification, increased intensity of early management, and possible targeted triage to tertiary hospitals.A retrospective cohort study was conducted of NICUs in California. We used data collected by the California Perinatal Quality Care Collaborative from 2005 to 2011 to assess mortality rates among a population-based sample of 30 566 VLBW infants, 1879 with necrotizing enterocolitis, according to the level of care and VLBW case volume at the hospital of birth.Level and volume of neonatal intensive care at the hospital of birth.In-hospital mortality.There was a persistent trend toward deregionalization during the study period and mortality rates varied according to the level of care. High-level, high-volume (level IIIB with >100 VLBW cases per year and level IIIC) hospitals achieved the lowest risk-adjusted mortality. Infants with necrotizing enterocolitis born into midlevel hospitals (low-volume level IIIB and level IIIA NICUs) had odds of death ranging from 1.42 (95% CI, 1.08-1.87) to 1.51 (95% CI, 1.05-2.15, respectively). In the final year of the study, just 28.6% of the infants with necrotizing enterocolitis were born into high-level, high-volume hospitals. For infants born into lower level centers, transfer to a higher level of care frequently occurred well into the third week of life.These findings represent an immediate opportunity for local quality improvement initiatives and potential impetus for the regionalization of important NICU resources.

  View details for DOI 10.1001/jamapediatrics.2014.2085

  View details for PubMedID 25383940

• CVR at the time of mid-trimester diagnosis of congenital lung lesions as a predictor of adverse neonatal outcomes Sammour, R., Hintz, S., Davis, A., Riley, K., Barth, R., Rubesova, E., Sylvester, K., Girsen, A., Blumenfeld, Y. MOSBY-ELSEVIER. 2015: S197

  View details for DOI 10.1016/j.ajog.2014.10.423

  View details for Web of Science ID 000361140900373

• Risk Prediction of Stroke: A Prospective Statewide Study on Patients in Maine Zheng, L., Wang, V., Hao, S., Sylvester, K. G., Ling, X. B., Jin, B., Zhu, C., Jin, H., Dai, D., Xu, H., Steams, F., Widen, E., Shin, A., Culver, D. S., Alfreds, S. T., Rogow, T., Huan, J., Miyano, S., Shehu, A., Hu, Ma, B., Rajasekaran, S., Gombar, V. K., Schapranow, I. M., Yoo, I. H., Zhou, J. Y., Chen, B., Pai, Pierce, B. IEEE. 2015: 853–55

  View details for Web of Science ID 000377335600153

• Real-time web-based assessment of total population risk of future emergency department utilization: statewide prospective active case finding study. Interactive journal of medical research Hu, Z., Jin, B., Shin, A. Y., Zhu, C., Zhao, Y., Hao, S., Zheng, L., Fu, C., Wen, Q., Ji, J., Li, Z., Wang, Y., Zheng, X., Dai, D., Culver, D. S., Alfreds, S. T., Rogow, T., Stearns, F., Sylvester, K. G., Widen, E., Ling, X. B. 2015; 4 (1)

  Abstract

  An easily accessible real-time Web-based utility to assess patient risks of future emergency department (ED) visits can help the health care provider guide the allocation of resources to better manage higher-risk patient populations and thereby reduce unnecessary use of EDs.Our main objective was to develop a Health Information Exchange-based, next 6-month ED risk surveillance system in the state of Maine.Data on electronic medical record (EMR) encounters integrated by HealthInfoNet (HIN), Maine's Health Information Exchange, were used to develop the Web-based surveillance system for a population ED future 6-month risk prediction. To model, a retrospective cohort of 829,641 patients with comprehensive clinical histories from January 1 to December 31, 2012 was used for training and then tested with a prospective cohort of 875,979 patients from July 1, 2012, to June 30, 2013.The multivariate statistical analysis identified 101 variables predictive of future defined 6-month risk of ED visit: 4 age groups, history of 8 different encounter types, history of 17 primary and 8 secondary diagnoses, 8 specific chronic diseases, 28 laboratory test results, history of 3 radiographic tests, and history of 25 outpatient prescription medications. The c-statistics for the retrospective and prospective cohorts were 0.739 and 0.732 respectively. Integration of our method into the HIN secure statewide data system in real time prospectively validated its performance. Cluster analysis in both the retrospective and prospective analyses revealed discrete subpopulations of high-risk patients, grouped around multiple "anchoring" demographics and chronic conditions. With the Web-based population risk-monitoring enterprise dashboards, the effectiveness of the active case finding algorithm has been validated by clinicians and caregivers in Maine.The active case finding model and associated real-time Web-based app were designed to track the evolving nature of total population risk, in a longitudinal manner, for ED visits across all payers, all diseases, and all age groups. Therefore, providers can implement targeted care management strategies to the patient subgroups with similar patterns of clinical histories, driving the delivery of more efficient and effective health care interventions. To the best of our knowledge, this prospectively validated EMR-based, Web-based tool is the first one to allow real-time total population risk assessment for statewide ED visits.

  View details for DOI 10.2196/ijmr.4022

  View details for PubMedID 25586600

  View details for PubMedCentralID PMC4319080

• Pilot Application of Magnetic Nanoparticle-Based Biosensor for Necrotizing Enterocolitis. Journal of proteomics & bioinformatics Kim, D., Fu, C., Ling, X. B., Hu, Z., Tao, G., Zhao, Y., Kastenberg, Z. J., Sylvester, K. G., Wang, S. X. 2015

  Abstract

  Necrotizing Enterocolitis (NEC) is a major source of neonatal morbidity and mortality. There is an ongoing need for a sensitive diagnostic instrument to discriminate NEC from neonatal sepsis. We hypothesized that magnetic nanopartile-based biosensor analysis of gut injury-associated biomarkers would provide such an instrument.We designed a magnetic multiplexed biosensor platform, allowing the parallel plasma analysis of C-reactive protein (CRP), matrix metalloproteinase-7 (MMp7), and epithelial cell adhesion molecule (EpCAM). Neonatal subjects with sepsis (n=5) or NEC (n=10) were compared to control (n=5) subjects to perform a proof of concept pilot study for the diagnosis of NEC using our ultra-sensitive biosensor platform.Our multiplexed NEC magnetic nanoparticle-based biosensor platform was robust, ultrasensitive (Limit of detection LOD: CRP 0.6 pg/ml; MMp7 20 pg/ml; and EpCAM 20 pg/ml), and displayed no cross-reactivity among analyte reporting regents. To gauge the diagnostic performance, bootstrapping procedure (500 runs) was applied: MMp7 and EpCAM collectively differentiated infants with NEC from control infants with ROC AUC of 0.96, and infants with NEC from those with sepsis with ROC AUC of 1.00. The 3-marker panel comprising of EpCAM, MMp7 and CRP had a corresponding ROC AUC of 0.956 and 0.975, respectively.The exploration of the multiplexed nano-biosensor platform shows promise to deliver an ultrasensitive instrument for the diagnosis of NEC in the clinical setting.

  View details for PubMedID 26798207

• Development, Validation and Deployment of a Real Time 30 Day Hospital Readmission Risk Assessment Tool in the Maine Healthcare Information Exchange. PloS one Hao, S., Wang, Y., Jin, B., Shin, A. Y., Zhu, C., Huang, M., Zheng, L., Luo, J., Hu, Z., Fu, C., Dai, D., Wang, Y., Culver, D. S., Alfreds, S. T., Rogow, T., Stearns, F., Sylvester, K. G., Widen, E., Ling, X. B. 2015; 10 (10)

  Abstract

  Identifying patients at risk of a 30-day readmission can help providers design interventions, and provide targeted care to improve clinical effectiveness. This study developed a risk model to predict a 30-day inpatient hospital readmission for patients in Maine, across all payers, all diseases and all demographic groups.Our objective was to develop a model to determine the risk for inpatient hospital readmission within 30 days post discharge. All patients within the Maine Health Information Exchange (HIE) system were included. The model was retrospectively developed on inpatient encounters between January 1, 2012 to December 31, 2012 from 24 randomly chosen hospitals, and then prospectively validated on inpatient encounters from January 1, 2013 to December 31, 2013 using all HIE patients.A risk assessment tool partitioned the entire HIE population into subgroups that corresponded to probability of hospital readmission as determined by a corresponding positive predictive value (PPV). An overall model c-statistic of 0.72 was achieved. The total 30-day readmission rates in low (score of 0-30), intermediate (score of 30-70) and high (score of 70-100) risk groupings were 8.67%, 24.10% and 74.10%, respectively. A time to event analysis revealed the higher risk groups readmitted to a hospital earlier than the lower risk groups. Six high-risk patient subgroup patterns were revealed through unsupervised clustering. Our model was successfully integrated into the statewide HIE to identify patient readmission risk upon admission and daily during hospitalization or for 30 days subsequently, providing daily risk score updates.The risk model was validated as an effective tool for predicting 30-day readmissions for patients across all payer, disease and demographic groups within the Maine HIE. Exposing the key clinical, demographic and utilization profiles driving each patient's risk of readmission score may be useful to providers in developing individualized post discharge care plans.

  View details for DOI 10.1371/journal.pone.0140271

  View details for PubMedID 26448562

• Impaired Activity of Blood Coagulant Factor XIII in Patients with Necrotizing Enterocolitis. Scientific reports Tao, G., Liu, B., Zhang, R., Liu, G., Abdullah, F., Harris, M. C., Brandt, M. L., Ehrenkranz, R. A., Bowers, C., Martin, C. R., Moss, R. L., Sylvester, K. G. 2015; 5: 13119-?

  Abstract

  Necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) medical/surgical emergency of the newborn and a leading cause of preterm neonate morbidity and mortality. NEC is a challenge to diagnose since it often shares similar clinical features with neonatal sepsis. In the present study, plasma protein profiling was compared among NEC, sepsis and control cohorts using gel electrophoresis, immunoblot and mass spectrometry. We observed significant impairment in the formation of fibrinogen-γ dimers (FGG-dimer) in the plasma of newborns with NEC that could efficiently differentiate NEC and sepsis with a high level of sensitivity and specificity. Interestingly, the impaired FGG-dimer formation could be restored in NEC plasma by the addition of exogenous active factor XIII (FXIII). Enzymatic activity of FXIII was determined to be significantly lower in NEC subject plasma for crosslinking FGG when compared to sepsis. These findings demonstrate a potential novel biomarker and related biologic mechanism for diagnosing NEC, as well as suggest a possible therapeutic strategy.

  View details for DOI 10.1038/srep13119

  View details for PubMedID 26277871

• Hippo/YAP, ß-catenin, and the cancer cell: a "ménage à trois" in hepatoblastoma. Gastroenterology Sylvester, K. G., Colnot, S. 2014; 147 (3): 562-565

  View details for DOI 10.1053/j.gastro.2014.07.026

  View details for PubMedID 25072176

• A novel urine peptide biomarker-based algorithm for the prognosis of necrotising enterocolitis in human infants. Gut Sylvester, K. G., Ling, X. B., Liu, G. Y., Kastenberg, Z. J., Ji, J., Hu, Z., Peng, S., Lau, K., Abdullah, F., Brandt, M. L., Ehrenkranz, R. A., Harris, M. C., Lee, T. C., Simpson, J., Bowers, C., Moss, R. L. 2014; 63 (8): 1284-1292

  Abstract

  Necrotising enterocolitis (NEC) is a major source of neonatal morbidity and mortality. The management of infants with NEC is currently complicated by our inability to accurately identify those at risk for progression of disease prior to the development of irreversible intestinal necrosis. We hypothesised that integrated analysis of clinical parameters in combination with urine peptide biomarkers would lead to improved prognostic accuracy in the NEC population.Infants under suspicion of having NEC (n=550) were prospectively enrolled from a consortium consisting of eight university-based paediatric teaching hospitals. Twenty-seven clinical parameters were used to construct a multivariate predictor of NEC progression. Liquid chromatography/mass spectrometry was used to profile the urine peptidomes from a subset of this population (n=65) to discover novel biomarkers of NEC progression. An ensemble model for the prediction of disease progression was then created using clinical and biomarker data.The use of clinical parameters alone resulted in a receiver-operator characteristic curve with an area under the curve of 0.817 and left 40.1% of all patients in an 'indeterminate' risk group. Three validated urine peptide biomarkers (fibrinogen peptides: FGA1826, FGA1883 and FGA2659) produced a receiver-operator characteristic area under the curve of 0.856. The integration of clinical parameters with urine biomarkers in an ensemble model resulted in the correct prediction of NEC outcomes in all cases tested.Ensemble modelling combining clinical parameters with biomarker analysis dramatically improves our ability to identify the population at risk for developing progressive NEC.

  View details for DOI 10.1136/gutjnl-2013-305130

  View details for PubMedID 24048736

• Heterotaxy syndromes and abnormal bowel rotation. Pediatric radiology Newman, B., Koppolu, R., Murphy, D., Sylvester, K. 2014; 44 (5): 542-551

  Abstract

  Bowel rotation abnormalities in heterotaxy are common. As more children survive cardiac surgery, the management of gastrointestinal abnormalities has become controversial.To evaluate imaging of malrotation in heterotaxy with surgical correlation and provide an algorithm for management.Imaging reports of heterotaxic children with upper gastrointestinal (UGI) and/or small bowel follow-through (SBFT) were reviewed. Subsequently, fluoroscopic images were re-reviewed in conjunction with CT/MR studies. The original reports and re-reviewed images were compared and correlated with surgical findings.Nineteen of 34 children with heterotaxy underwent UGI, 13/19 also had SBFT. In 15/19 reports, bowel rotation was called abnormal: 11 malrotation, 4 non-rotation, no cases of volvulus. Re-review, including CT (10/19) and MR (2/19), designated 17/19 (90%) as abnormal, 10 malrotation (abnormal bowel arrangement, narrow or uncertain length of mesentery) and 7 non-rotation (small bowel and colon on opposite sides plus low cecum with probable broad mesentery). The most useful CT/MR findings were absence of retroperitoneal duodenum in most abnormal cases and location of bowel, especially cecum. Abnormal orientation of mesenteric vessels suggested malrotation but was not universal. Nine children had elective bowel surgery; non-rotation was found in 4/9 and malrotation was found in 5/9, with discrepancies (non-rotation at surgery, malrotation on imaging) with 4 original interpretations and 1 re-review.We recommend routine, early UGI and SBFT studies once other, urgent clinical concerns have been stabilized, with elective laparoscopic surgery in abnormal or equivocal cases. Cross-sectional imaging, usually obtained for other reasons, can contribute diagnostically. Attempting to assess mesenteric width is important in differentiating non-rotation from malrotation and more accurately identifies appropriate surgical candidates.

  View details for DOI 10.1007/s00247-013-2861-4

  View details for PubMedID 24419494

• Urine protein biomarkers for the diagnosis and prognosis of necrotizing enterocolitis in infants. journal of pediatrics Sylvester, K. G., Ling, X. B., Liu, G. Y., Kastenberg, Z. J., Ji, J., Hu, Z., Wu, S., Peng, S., Abdullah, F., Brandt, M. L., Ehrenkranz, R. A., Harris, M. C., Lee, T. C., Simpson, B. J., Bowers, C., Moss, R. L. 2014; 164 (3): 607-12 e1 7

  Abstract

  To test the hypothesis that an exploratory proteomics analysis of urine proteins with subsequent development of validated urine biomarker panels would produce molecular classifiers for both the diagnosis and prognosis of infants with necrotizing enterocolitis (NEC).Urine samples were collected from 119 premature infants (85 NEC, 17 sepsis, 17 control) at the time of initial clinical concern for disease. The urine from 59 infants was used for candidate biomarker discovery by liquid chromatography/mass spectrometry. The remaining 60 samples were subject to enzyme-linked immunosorbent assay for quantitative biomarker validation.A panel of 7 biomarkers (alpha-2-macroglobulin-like protein 1, cluster of differentiation protein 14, cystatin 3, fibrinogen alpha chain, pigment epithelium-derived factor, retinol binding protein 4, and vasolin) was identified by liquid chromatography/mass spectrometry and subsequently validated by enzyme-linked immunosorbent assay. These proteins were consistently found to be either up- or down-regulated depending on the presence, absence, or severity of disease. Biomarker panel validation resulted in a receiver-operator characteristic area under the curve of 98.2% for NEC vs sepsis and an area under the curve of 98.4% for medical NEC vs surgical NEC.We identified 7 urine proteins capable of providing highly accurate diagnostic and prognostic information for infants with suspected NEC. This work represents a novel approach to improving the efficiency with which we diagnose early NEC and identify those at risk for developing severe, or surgical, disease.

  View details for DOI 10.1016/j.jpeds.2013.10.091

  View details for PubMedID 24433829

• Urine protein biomarkers for the diagnosis and prognosis of necrotizing enterocolitis in infants. journal of pediatrics Sylvester, K. G., Ling, X. B., Liu, G. Y., Kastenberg, Z. J., Ji, J., Hu, Z., Wu, S., Peng, S., Abdullah, F., Brandt, M. L., Ehrenkranz, R. A., Harris, M. C., Lee, T. C., Simpson, B. J., Bowers, C., Moss, R. L. 2014; 164 (3): 607-612 e7

  Abstract

  To test the hypothesis that an exploratory proteomics analysis of urine proteins with subsequent development of validated urine biomarker panels would produce molecular classifiers for both the diagnosis and prognosis of infants with necrotizing enterocolitis (NEC).Urine samples were collected from 119 premature infants (85 NEC, 17 sepsis, 17 control) at the time of initial clinical concern for disease. The urine from 59 infants was used for candidate biomarker discovery by liquid chromatography/mass spectrometry. The remaining 60 samples were subject to enzyme-linked immunosorbent assay for quantitative biomarker validation.A panel of 7 biomarkers (alpha-2-macroglobulin-like protein 1, cluster of differentiation protein 14, cystatin 3, fibrinogen alpha chain, pigment epithelium-derived factor, retinol binding protein 4, and vasolin) was identified by liquid chromatography/mass spectrometry and subsequently validated by enzyme-linked immunosorbent assay. These proteins were consistently found to be either up- or down-regulated depending on the presence, absence, or severity of disease. Biomarker panel validation resulted in a receiver-operator characteristic area under the curve of 98.2% for NEC vs sepsis and an area under the curve of 98.4% for medical NEC vs surgical NEC.We identified 7 urine proteins capable of providing highly accurate diagnostic and prognostic information for infants with suspected NEC. This work represents a novel approach to improving the efficiency with which we diagnose early NEC and identify those at risk for developing severe, or surgical, disease.

  View details for DOI 10.1016/j.jpeds.2013.10.091

  View details for PubMedID 24433829

• A data-driven algorithm integrating clinical and laboratory features for the diagnosis and prognosis of necrotizing enterocolitis. PloS one Ji, J., Ling, X. B., Zhao, Y., Hu, Z., Zheng, X., Xu, Z., Wen, Q., Kastenberg, Z. J., Li, P., Abdullah, F., Brandt, M. L., Ehrenkranz, R. A., Harris, M. C., Lee, T. C., Simpson, B. J., Bowers, C., Moss, R. L., Sylvester, K. G. 2014; 9 (2)

  Abstract

  Necrotizing enterocolitis (NEC) is a major source of neonatal morbidity and mortality. Since there is no specific diagnostic test or risk of progression model available for NEC, the diagnosis and outcome prediction of NEC is made on clinical grounds. The objective in this study was to develop and validate new NEC scoring systems for automated staging and prognostic forecasting.A six-center consortium of university based pediatric teaching hospitals prospectively collected data on infants under suspicion of having NEC over a 7-year period. A database comprised of 520 infants was utilized to develop the NEC diagnostic and prognostic models by dividing the entire dataset into training and testing cohorts of demographically matched subjects. Developed on the training cohort and validated on the blind testing cohort, our multivariate analyses led to NEC scoring metrics integrating clinical data.MACHINE LEARNING USING CLINICAL AND LABORATORY RESULTS AT THE TIME OF CLINICAL PRESENTATION LED TO TWO NEC MODELS: (1) an automated diagnostic classification scheme; (2) a dynamic prognostic method for risk-stratifying patients into low, intermediate and high NEC scores to determine the risk for disease progression. We submit that dynamic risk stratification of infants with NEC will assist clinicians in determining the need for additional diagnostic testing and guide potential therapies in a dynamic manner.http://translationalmedicine.stanford.edu/cgi-bin/NEC/index.pl and smartphone application upon request.

  View details for DOI 10.1371/journal.pone.0089860

  View details for PubMedID 24587080

• Pilot Application of Magnetic Nanoparticle-Based Biosensor for Necrotizing Enterocolitis Journal of Proteomics and Bioinformatics Kim, D., Fu, C., Ling, X. B., Hu, Z., Tao, G., Zhao, Y., Kastenberg, Z. J., Sylvester, K. G., Wang, S. X. 2014

  View details for DOI 10.4172/jpb.S5-002

• Risk prediction of emergency department revisit 30 days post discharge: a prospective study. PloS one Hao, S., Jin, B., Shin, A. Y., Zhao, Y., Zhu, C., Li, Z., Hu, Z., Fu, C., Ji, J., Wang, Y., Zhao, Y., Dai, D., Culver, D. S., Alfreds, S. T., Rogow, T., Stearns, F., Sylvester, K. G., Widen, E., Ling, X. B. 2014; 9 (11): e112944

  Abstract

  Among patients who are discharged from the Emergency Department (ED), about 3% return within 30 days. Revisits can be related to the nature of the disease, medical errors, and/or inadequate diagnoses and treatment during their initial ED visit. Identification of high-risk patient population can help device new strategies for improved ED care with reduced ED utilization.A decision tree based model with discriminant Electronic Medical Record (EMR) features was developed and validated, estimating patient ED 30 day revisit risk. A retrospective cohort of 293,461 ED encounters from HealthInfoNet (HIN), Maine's Health Information Exchange (HIE), between January 1, 2012 and December 31, 2012, was assembled with the associated patients' demographic information and one-year clinical histories before the discharge date as the inputs. To validate, a prospective cohort of 193,886 encounters between January 1, 2013 and June 30, 2013 was constructed. The c-statistics for the retrospective and prospective predictions were 0.710 and 0.704 respectively. Clinical resource utilization, including ED use, was analyzed as a function of the ED risk score. Cluster analysis of high-risk patients identified discrete sub-populations with distinctive demographic, clinical and resource utilization patterns.Our ED 30-day revisit model was prospectively validated on the Maine State HIN secure statewide data system. Future integration of our ED predictive analytics into the ED care work flow may lead to increased opportunities for targeted care intervention to reduce ED resource burden and overall healthcare expense, and improve outcomes.

  View details for DOI 10.1371/journal.pone.0112944

  View details for PubMedID 25393305

  View details for PubMedCentralID PMC4231082

• Risk prediction of emergency department revisit 30 days post discharge: a prospective study. PloS one Hao, S., Jin, B., Shin, A. Y., Zhao, Y., Zhu, C., Li, Z., Hu, Z., Fu, C., Ji, J., Wang, Y., Zhao, Y., Dai, D., Culver, D. S., Alfreds, S. T., Rogow, T., Stearns, F., Sylvester, K. G., Widen, E., Ling, X. B. 2014; 9 (11)

  Abstract

  Among patients who are discharged from the Emergency Department (ED), about 3% return within 30 days. Revisits can be related to the nature of the disease, medical errors, and/or inadequate diagnoses and treatment during their initial ED visit. Identification of high-risk patient population can help device new strategies for improved ED care with reduced ED utilization.A decision tree based model with discriminant Electronic Medical Record (EMR) features was developed and validated, estimating patient ED 30 day revisit risk. A retrospective cohort of 293,461 ED encounters from HealthInfoNet (HIN), Maine's Health Information Exchange (HIE), between January 1, 2012 and December 31, 2012, was assembled with the associated patients' demographic information and one-year clinical histories before the discharge date as the inputs. To validate, a prospective cohort of 193,886 encounters between January 1, 2013 and June 30, 2013 was constructed. The c-statistics for the retrospective and prospective predictions were 0.710 and 0.704 respectively. Clinical resource utilization, including ED use, was analyzed as a function of the ED risk score. Cluster analysis of high-risk patients identified discrete sub-populations with distinctive demographic, clinical and resource utilization patterns.Our ED 30-day revisit model was prospectively validated on the Maine State HIN secure statewide data system. Future integration of our ED predictive analytics into the ED care work flow may lead to increased opportunities for targeted care intervention to reduce ED resource burden and overall healthcare expense, and improve outcomes.

  View details for DOI 10.1371/journal.pone.0112944

  View details for PubMedID 25393305

  View details for PubMedCentralID PMC4231082

• A data-driven algorithm integrating clinical and laboratory features for the diagnosis and prognosis of necrotizing enterocolitis. PloS one Ji, J., Ling, X. B., Zhao, Y., Hu, Z., Zheng, X., Xu, Z., Wen, Q., Kastenberg, Z. J., Li, P., Abdullah, F., Brandt, M. L., Ehrenkranz, R. A., Harris, M. C., Lee, T. C., Simpson, B. J., Bowers, C., Moss, R. L., Sylvester, K. G. 2014; 9 (2)

  View details for DOI 10.1371/journal.pone.0089860

  View details for PubMedID 24587080

• Wnt/ß-Catenin Signaling Protects Mouse Liver against Oxidative Stress-induced Apoptosis through the Inhibition of Forkhead Transcription Factor FoxO3. journal of biological chemistry Tao, G., Lehwald, N., Jang, K. Y., Baek, J., Xu, B., Omary, M. B., Sylvester, K. G. 2013; 288 (24): 17214-17224

  Abstract

  Numerous liver diseases are associated with extensive oxidative tissue damage. It is well established that Wnt/β-catenin signaling directs multiple hepatocellular processes, including development, proliferation, regeneration, nutrient homeostasis, and carcinogenesis. It remains unexplored whether Wnt/β-catenin signaling provides hepatocyte protection against hepatotoxin-induced apoptosis. Conditional, liver-specific β-catenin knockdown (KD) mice and their wild-type littermates were challenged by feeding with a hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to induce chronic oxidative liver injury. Following the DDC diet, mice with β-catenin-deficient hepatocytes demonstrate increased liver injury, indicating an important role of β-catenin signaling for liver protection against oxidative stress. This finding was further confirmed in AML12 hepatocytes with β-catenin signaling manipulation in vitro using paraquat, a known oxidative stress inducer. Immunofluorescence staining revealed an intense nuclear FoxO3 staining in β-catenin-deficient livers, suggesting active FoxO3 signaling in response to DDC-induced liver injury when compared with wild-type controls. Consistently, FoxO3 target genes p27 and Bim were significantly induced in β-catenin KD livers. Conversely, SGK1, a β-catenin target gene, was significantly impaired in β-catenin KD hepatocytes that failed to inactivate FoxO3. Furthermore, shRNA-mediated deletion of FoxO3 increased hepatocyte resistance to oxidative stress-induced apoptosis, confirming a proapoptotic role of FoxO3 in the stressed liver. Our findings suggest that Wnt/β-catenin signaling is required for hepatocyte protection against oxidative stress-induced apoptosis. The inhibition of FoxO through its phosphorylation by β-catenin-induced SGK1 expression reduces the apoptotic function of FoxO3, resulting in increased hepatocyte survival. These findings have relevance for future therapies directed at hepatocyte protection, regeneration, and anti-cancer treatment.

  View details for DOI 10.1074/jbc.M112.445965

  View details for PubMedID 23620592

  View details for PubMedCentralID PMC3682526

• Heme oxygenase-1 deficiency promotes the development of necrotizing enterocolitis-like intestinal injury in a newborn mouse model. American journal of physiology. Gastrointestinal and liver physiology Schulz, S., Wong, R. J., Jang, K. Y., Kalish, F., Chisholm, K. M., Zhao, H., Vreman, H. J., Sylvester, K. G., Stevenson, D. K. 2013; 304 (11): G991-G1001

  Abstract

  Necrotizing enterocolitis (NEC) is typified by mucosal destruction, which subsequently can lead to intestinal necrosis. Prematurity, enteral feeding, and bacterial colonization are the main risk factors and, combined with other stressors, can cause increased intestinal permeability, injury, and an exaggerated inflammatory response. Heme oxygenase-1 (HO-1) mediates intestinal protection due to anti-inflammatory, antioxidative, and antiapoptotic effects of its products carbon monoxide, biliverdin, and bilirubin. This study investigates a possible role of HO-1 in the pathogenesis of NEC using a newborn mouse model. We induced NEC-like intestinal injury in 7-day-old HO-1 heterozygous (HO-1 Het, Hmox1(+/-)) and wild-type (Wt, Hmox1(+/+)) mice by gavage feeding and hypoxic exposures. Control (Con) pups of both genotypes were dam-fed. Intestines of HO-1 Het Con pups appeared predisposed to injury, with higher histological damage scores, more TUNEL-positive cells, and a significant reduction in muscularis externa thickness compared with Wt Con pups. The increase in HO activity after HO-1 induction by the substrate heme or by hypoxic stress was significantly impaired in HO-1 Het pups. After induction of intestinal injury, HO-1 Het pups displayed significantly higher NEC incidence (78 vs. 43%), mortality (83 vs. 54%), and median scores (2.5 vs. 1.5) than Wt NEC pups. PCR array analyses revealed increased expressions of IL-1β, P-selectin, matrix metallopeptidase 2, collagen type XVIII-α1, serpine 1, and others in NEC-induced HO-1 Het ileal and jejunal tissues. We conclude that a partial HO-1 deficiency promotes experimental NEC-like intestinal injury, possibly mediated by exaggerated inflammation and disruption in tissue repair.

  View details for DOI 10.1152/ajpgi.00363.2012

  View details for PubMedID 23578787

• WNT/B-CATENIN AND MITOCHONDRIAL FUNCTION IN RESPONSE TO METABOLIC STRESS AND ALD 36th Annual Scientific Meeting of the Research-Society-on-Alcoholism Liu, B., Zhang, R., Tao, G., Lehwald, N. C., Liu, B., Sylvester, K. G. WILEY-BLACKWELL. 2013: 297A–297A

  View details for Web of Science ID 000318998301328

• The surgical management of necrotizing enterocolitis. Clinics in perinatology Kastenberg, Z. J., Sylvester, K. G. 2013; 40 (1): 135-148

  Abstract

  Necrotizing enterocolitis (NEC), a common cause of neonatal morbidity and mortality, is strongly associated with prematurity and typically occurs following initiation of enteral feeds. Mild NEC is adequately treated by cessation of enteral feeding, empiric antibiotics, and supportive care. Approximately 50% of affected infants will develop progressive intestinal necrosis requiring urgent operation. Several surgical techniques have been described, but there is no clear survival benefit for any single operative approach. While debate continues regarding the optimal surgical management for infants with severe NEC, future progress will likely depend on the development of improved diagnostic tools and preventive therapies.

  View details for DOI 10.1016/j.clp.2012.12.011

  View details for PubMedID 23415269

• SIRT1 and c-Myc Promote Liver Tumor Cell Survival and Predict Poor Survival of Human Hepatocellular Carcinomas PLOS ONE Jang, K. Y., Noh, S. J., Lehwald, N., Tao, G., Bellovin, D. I., Park, H. S., Moon, W. S., Felsher, D. W., Sylvester, K. G. 2012; 7 (9)

  Abstract

  The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c-Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high á-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma.

  View details for DOI 10.1371/journal.pone.0045119

  View details for Web of Science ID 000308860100058

  View details for PubMedID 23024800

  View details for PubMedCentralID PMC3443243

• beta-Catenin Regulates Hepatic Mitochondrial Function and Energy Balance in Mice GASTROENTEROLOGY Lehwald, N., Tao, G., Jang, K. Y., Papandreou, I., Liu, B., Liu, B., Pysz, M. A., Willmann, J. K., Knoefel, W. T., Denko, N. C., Sylvester, K. G. 2012; 143 (3): 754-764

  Abstract

  Wnt signaling regulates hepatic function and nutrient homeostasis. However, little is known about the roles of β-catenin in cellular respiration or mitochondria of hepatocytes.We investigated β-catenin's role in the metabolic function of hepatocytes under homeostatic conditions and in response to metabolic stress using mice with hepatocyte-specific deletion of β-catenin and their wild-type littermates, given either saline (sham) or ethanol (as a model of binge drinking and acute ethanol intoxication).Under homeostatic conditions, β-catenin-deficient hepatocytes demonstrated mitochondrial dysfunctions that included impairments to the tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS) and decreased production of adenosine triphosphate (ATP). There was no evidence for redox imbalance or oxidative cellular injury in the absence of metabolic stress. In mice with β-catenin-deficient hepatocytes, ethanol intoxication led to significant redox imbalance in the hepatocytes and further deterioration in mitochondrial function that included reduced OXPHOS, fatty acid oxidation (FAO), and ATP production. Ethanol feeding significantly increased liver steatosis and oxidative damage, compared with wild-type mice, and disrupted the ratio of nicotinamide adenine dinucleotide. β-catenin-deficient hepatocytes also had showed disrupted signaling of Sirt1/peroxisome proliferator-activated receptor-α signaling.β-catenin has an important role in the maintenance of mitochondrial homeostasis, regulating ATP production via the tricarboxylic acid cycle, OXPHOS, and fatty acid oxidation; β-catenin function in these systems is compromised under conditions of nutrient oxidative stress. Reagents that alter Wnt-β-catenin signaling might be developed as a useful new therapeutic strategy for treatment of liver disease.

  View details for DOI 10.1053/j.gastro.2012.05.048

  View details for Web of Science ID 000308399300039

  View details for PubMedID 22684045

• Improving prediction of surgery duration using operational and temporal factors. AMIA ... Annual Symposium proceedings / AMIA Symposium. AMIA Symposium Kayis, E., Wang, H., Patel, M., Gonzalez, T., Jain, S., Ramamurthi, R. J., Santos, C., Singhal, S., Suermondt, J., Sylvester, K. 2012; 2012: 456-462

  Abstract

  Inherent uncertainties in surgery durations impact many critical metrics about the performance of an operating room (OR) environment. OR schedules that are robust to natural variability in surgery durations require surgery duration estimates that are unbiased, with high accuracy, and with few cases with large absolute errors. Earlier studies have shown that factors such as patient severity, personnel, and procedure type greatly affect the accuracy of such estimations. In this paper we investigate whether operational and temporal factors can be used to improve these estimates further. We present an adjustment method based on a combination of these operational and temporal factors. We validate our method with two years of detailed operational data from an electronic medical record. We conclude that while improving estimates of surgery durations is possible, the inherent variability in such estimates remains high, necessitating caution in their use when optimizing OR schedules.

  View details for PubMedID 23304316

  View details for PubMedCentralID PMC3540440

• HEME OXYGENASE-1 DEFICIENCY PROMOTES NECROTIZING ENTEROCOLITIS DEVELOPMENT IN A MURINE MOUSE MODEL Western Regional Meeting of the American-Federation-for-Medical-Research Schulz, S., Jang, K., Kalish, F. S., Zhao, H., Vreman, H. J., Sylvester, K. S., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2012: 158–58

  View details for Web of Science ID 000298634401114

• Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway JOURNAL OF EXPERIMENTAL MEDICINE Viatour, P., Ehmer, U., Saddic, L. A., Dorrell, C., Andersen, J. B., Lin, C., Zmoos, A., Mazur, P. K., Schaffer, B. E., Ostermeier, A., Vogel, H., Sylvester, K. G., Thorgeirsson, S. S., Grompe, M., Sage, J. 2011; 208 (10): 1963-1976

  Abstract

  Hepatocellular carcinoma (HCC) is the third cancer killer worldwide with >600,000 deaths every year. Although the major risk factors are known, therapeutic options in patients remain limited in part because of our incomplete understanding of the cellular and molecular mechanisms influencing HCC development. Evidence indicates that the retinoblastoma (RB) pathway is functionally inactivated in most cases of HCC by genetic, epigenetic, and/or viral mechanisms. To investigate the functional relevance of this observation, we inactivated the RB pathway in the liver of adult mice by deleting the three members of the Rb (Rb1) gene family: Rb, p107, and p130. Rb family triple knockout mice develop liver tumors with histopathological features and gene expression profiles similar to human HCC. In this mouse model, cancer initiation is associated with the specific expansion of populations of liver stem/progenitor cells, indicating that the RB pathway may prevent HCC development by maintaining the quiescence of adult liver progenitor cells. In addition, we show that during tumor progression, activation of the Notch pathway via E2F transcription factors serves as a negative feedback mechanism to slow HCC growth. The level of Notch activity is also able to predict survival of HCC patients, suggesting novel means to diagnose and treat HCC.

  View details for DOI 10.1084/jem.20110198

  View details for PubMedID 21875955

• Wnt-beta-catenin Signaling Protects Against Hepatic Ischemia and Reperfusion Injury in Mice GASTROENTEROLOGY Lehwald, N., Tao, G., Jang, K. Y., Sorkin, M., Knoefel, W. T., Sylvester, K. G. 2011; 141 (2): 707-U417

  Abstract

  Ischemia and reperfusion injury are common causes of oxidative tissue damage associated with many liver diseases and hepatic surgery. The Wnt-β-catenin signaling pathway is an important regulator of hepatic development, regeneration, and carcinogenesis. However, the role of Wnt signaling in the hepatocellular response to ischemia-reperfusion (I/R) injury has not been determined.Hepatic injury following ischemia or I/R was investigated in hepatocyte-specific, β-catenin-deficient mice, as well as Wnt1-overexpressing and wild-type (control) mice.Wnt-β-catenin signaling was affected by the cellular redox balance in hepatocytes. Following ischemia or I/R, mice with β-catenin-deficient hepatocytes were significantly more susceptible to liver injury. Conversely, mice that overexpressed Wnt1 in hepatocytes were resistant to hepatic I/R injury. Hypoxia inducible factor (HIF)-1α signaling was reduced in β-catenin-deficient liver but increased in hepatocytes that overexpressed Wnt1 under hypoxia and following I/R, indicating an interaction between β-catenin and HIF-1α signaling in the liver. The mechanism by which Wnt signaling protects against liver injury involves the role of β-catenin as a transcriptional coactivator of HIF-1α signaling, which promotes hepatocyte survival under hypoxic conditions.Cellular redox balance affects Wnt-β-catenin signaling, which protects against hypoxia and I/R injury. These findings might be used to develop strategies for protection of hepatocytes, regeneration of liver, and inhibition of carcinogenesis.

  View details for DOI 10.1053/j.gastro.2011.04.051

  View details for Web of Science ID 000293523300049

  View details for PubMedID 21679710

  View details for PubMedCentralID PMC4084974

• Intestinal involvement during 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced chronic liver injury in a mouse model JOURNAL OF PEDIATRIC SURGERY Sukhotnik, I., Kuscuoglu, U., Altindag, B., Tao, G., Lehwald, N., Sylvester, K. G. 2011; 46 (8): 1495-1502

  Abstract

  Although a physiologic relationship between intestinal mucosal integrity and hepatic function has been previously described, the effect of primary liver disease on intestinal mucosal homeostasis has not been previously well documented. In the current study, we studied the effects of chronic liver injury as a primary injury on enterocyte turnover (proliferation and apoptosis) in a mouse model.The liver toxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-enriched diet was used to induce chronic cholestatic liver injury in mice. Livers and intestine were harvested after 3 weeks of dietary treatment of histologic analysis and a determination of cell proliferation (immunohistochemistry for Ki67), or apoptosis (immunohistochemistry for caspase-3), as well as a determination of Wnt/β-catenin signaling activity.All DDC-fed animals exhibited histologic evidence of liver damage that was associated with the expansion of atypical ductal proliferation near the periportal areas and increased oxidative stress. In the intestine, DDC-induced liver damage was associated with decreased villus height, decreased enterocyte proliferation, and increased cell apoptosis compared with control animals. There was also evidence for decreased β-catenin expression by immunostaining in crypt and villus cells of DDC-fed mice compared with control animals.Primary liver injury and cholestasis is associated with intestinal mucosal hypoplasia. Decreased cell proliferation and increased cell apoptosis may be responsible for decreased intestinal epithelial cell mass. The observed decrease in cell turnover is accompanied by an alteration in Wnt/β-catenin signaling.

  View details for DOI 10.1016/j.jpedsurg.2011.04.007

  View details for Web of Science ID 000293950100014

  View details for PubMedID 21843714

• Risk Factors for Parenteral Nutrition-associated Liver Disease Following Surgical Therapy for Necrotizing Enterocolitis JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION Duro, D., Mitchell, P. D., Kalish, L. A., Martin, C., Mccarthy, M., Jaksic, T., Dunn, J., Brandt, M. L., Nobuhara, K. K., Sylvester, K. G., Moss, R. L., Duggan, C. 2011; 52 (5): 595-600

  Abstract

  The aim of the study was to prospectively determine risk factors for the development of parenteral nutrition-associated liver disease (PNALD) in infants who underwent surgery for necrotizing enterocolitis (NEC), the most common cause of intestinal failure in children.: From February 2004 to February 2007, we diagnosed 464 infants with NEC, of whom 180 had surgery. One hundred twenty-seven patients were available for full analysis. PNALD was defined as serum direct bilirubin ≥ 2 mg/dL or ALT ≥ 2 × the upper limit of normal in the absence of sepsis after ≥ 14 days of exposure to PN.Median gestational age was 26 weeks and 68% were boys. Seventy percent of the cohort developed PNALD and the incidence of PNALD varied significantly across the 6 study sites, ranging from 56% to 85% (P = 0.05). Multivariable logistic regression analysis identified small-bowel resection or creation of jejunostomy (odds ratio [OR] 4.96, 95% confidence interval [CI] 1.97-12.51, P = 0.0007) and duration of PN in weeks (OR 2.37, 95% CI 1.56-3.60, P < 0.0001) as independent risk factors for PNALD. Preoperative exposure to PN was also associated with the development of PNALD; the risk of PNALD was 2.6 (95% CI 1.5-4.7; P = 0.001) times greater in patients with ≥ 4 weeks of preoperative PN compared with those with less preoperative PN use. Breast milk feedings, episodes of infection, and gestational age were not related to the development of PNALD.The incidence of PNALD is high in infants with NEC undergoing surgical treatment. Risk factors for PNALD are related to signs of NEC severity, including the need for small-bowel resection or proximal jejunostomy, as well as longer exposure to PN. Identification of these and other risk factors can help in the design of clinical trials for the prevention and treatment of PNALD and for clinical assessment of patients with NEC and prolonged PN dependence.

  View details for DOI 10.1097/MPG.0b013e31820e8396

  View details for Web of Science ID 000289671900018

  View details for PubMedID 21464752

  View details for PubMedCentralID PMC3444282

• ROLE OF IIEME OXYGENASE IN A MURINE MODEL OF EARLY NECROTIZING ENTEROCOLITIS Western Regional Meeting of the American-Federation-for-Medical-Research Schulz-Geske, S., Kalish, F. S., Jang, K. Y., Zhao, H., Huey, M., Vreman, H. J., Sylvester, K. S., Wong, R. J., Stevenson, D. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: 126–27

  View details for Web of Science ID 000285542500153

• Risk Factors for Intestinal Failure in Infants with Necrotizing Enterocolitis: A Glaser Pediatric Research Network Study JOURNAL OF PEDIATRICS Duro, D., Kalish, L. A., Johnston, P., Jaksic, T., Mccarthy, M., Martin, C., Dunn, J. C., Brandt, M., Nobuhara, K. K., Sylvester, K. G., Moss, R. L., Duggan, C. 2010; 157 (2): 203-U50

  Abstract

  To determine risk factors for intestinal failure (IF) in infants undergoing surgery for necrotizing enterocolitis (NEC).Infants were enrolled in a multicenter prospective cohort study. IF was defined as the requirement for parenteral nutrition for >or= 90 days. Logistic regression was used to identify predictors of IF.Among 473 patients enrolled, 129 had surgery and had adequate follow-up data, and of these patients, 54 (42%) developed IF. Of the 265 patients who did not require surgery, 6 (2%) developed IF (OR 31.1, 95% CI, 12.9 - 75.1, P < .001). Multivariate analysis identified the following risk factors for IF: use of parenteral antibiotics on the day of NEC diagnosis (OR = 16.61, P = .022); birth weight < 750 grams, (OR = 9.09, P < .001); requirement for mechanical ventilation on the day of NEC diagnosis (OR = 6.16, P = .009); exposure to enteral feeding before NEC diagnosis (OR=4.05, P = .048); and percentage of small bowel resected (OR = 1.85 per 10 percentage point greater resection, P = .031).The incidence of IF among infants undergoing surgical treatment for NEC is high. Variables characteristic of severe NEC (low birth weight, antibiotic use, ventilator use, and greater extent of bowel resection) were associated with the development of IF.

  View details for DOI 10.1016/j.jpeds.2010.02.023

  View details for Web of Science ID 000279871700011

  View details for PubMedID 20447649

  View details for PubMedCentralID PMC3217834

• URINE PEPTIDOMICS FOR CLINICAL BIOMARKER DISCOVERY ADVANCES IN CLINICAL CHEMISTRY, VOL 51 Ling, X. B., Mellins, E. D., Sylvester, K. G., Cohen, H. J. 2010; 51: 181-213

  Abstract

  Urine-based proteomic profiling is a novel approach that may result in the discovery of noninvasive biomarkers for diagnosing patients with different diseases, with the aim to ultimately improve clinical outcomes. Given new and emerging analytical technologies and data mining algorithms, the urine peptidome has become a rich resource to uncover naturally occurring peptide biomarkers for both systemic and renal diseases. However, significant analytical hurdles remain in sample collection and storage, experimental design, data analysis, and statistical inference. This study summarizes, focusing on our experiences and perspectives, the progress in addressing these challenges to enable high-throughput urine peptidomics-based biomarker discovery.

  View details for DOI 10.1016/S0065-2423(10)51007-2

  View details for Web of Science ID 000281865700007

  View details for PubMedID 20857622

• Clinical parameters do not adequately predict outcome in necrotizing enterocolitis: a multi-institutional study JOURNAL OF PERINATOLOGY Moss, R. L., Kalish, L. A., Duggan, C., Johnston, P., Brandt, M. L., Dunn, J. C., Ehrenkranz, R. A., Jaksic, T., Nobuhara, K., Simpson, B. J., McCarthy, M. C., Sylvester, K. G. 2008; 28 (10): 665-674

  Abstract

  Necrotizing enterocolitis (NEC) remains a major cause of neonatal morbidity and mortality. Some infants recover uneventfully with medical therapy whereas others develop severe disease (that is, NEC requiring surgery or resulting in death). Repeated attempts to identify clinical parameters that would reliably identify infants with NEC most likely to progress to severe disease have been unsuccessful. We hypothesized that comprehensive prospective data collection at multiple centers would allow us to develop a model which would identify those babies at risk for progressive NEC.This prospective, observational study was conducted at six university children's hospitals. Study subjects were neonates with suspected or confirmed NEC. Comprehensive maternal and newborn histories were collected at the time of enrollment, and newborn clinical data were collected prospectively, thereafter. Multivariate logistic regression analysis was used to develop a predictive model of risk factors for progression.Of 455 neonates analyzed, 192 (42%) progressed to severe disease, and 263 (58%) advanced to full feedings without operation. The vast majority of the variables studied proved not to be associated with progression to severe disease. A total of 12 independent predictors for progression were identified, including only 3 not previously described: having a teenaged mother (odds ratio, OR, 3.14; 95% confidence interval, CI, 1.45 to 6.96), receiving cardiac compressions and/or resuscitative drugs at birth (OR, 2.51; 95% CI, 1.17 to 5.48), and having never received enteral feeding before diagnosis (OR, 2.41; 95% CI, 1.08 to 5.52).Our hypothesis proved false. Rigorous prospective data collection of a sufficient number of patients did not allow us to create a model sufficiently predictive of progressive NEC to be clinically useful. It appears increasingly likely that further analysis of clinical parameters alone will not lead to a significant improvement in our understanding of NEC. We believe that future studies must focus on advanced biologic parameters in conjunction with clinical findings.

  View details for DOI 10.1038/jp.2008.119

  View details for Web of Science ID 000259675900003

  View details for PubMedID 18784730

• The role of Wnt signaling in maintaining the neuroblast phenotype in neuroblastomas Ghole, S. A., Kuscuoglu, U., Sylvester, K. ELSEVIER SCIENCE INC. 2008: S53

  View details for DOI 10.1016/j.jamcollsurg.2008.06.113

  View details for Web of Science ID 000259288500106

• Hepatotoxin-Induced Changes in the Adult Murine Liver Promote MYC-Induced Tumorigenesis PLOS ONE Beer, S., Komatsubara, K., Bellovin, D. I., Kurobe, M., Sylvester, K., Felsher, D. W. 2008; 3 (6)

  Abstract

  Overexpression of the human c-MYC (MYC) oncogene is one of the most frequently implicated events in the pathogenesis of hepatocellular carcinoma (HCC). Previously, we have shown in a conditional transgenic mouse model that MYC overexpression is restrained from inducing mitotic cellular division and tumorigenesis in the adult liver; whereas, in marked contrast, MYC induces robust proliferation associated with the very rapid onset of tumorigenesis in embryonic and neonatal mice.Here, we show that non-genotoxic hepatotoxins induce changes in the liver cellular context associated with increased cellular proliferation and enhanced tumorigenesis. Both 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl(4)) cooperate with MYC to greatly accelerate the onset of liver cancer in an adult host to less than 7 days versus a mean latency of onset of over 35 weeks for MYC alone. These hepatotoxin-enhanced liver tumors grossly and histologically resemble embryonic and neonatal liver tumors. Importantly, we found that MYC overexpression is only capable of inducing expression of the mitotic Cyclin B1 in embryonic/neonatal hosts or adult hosts that were treated with either carcinogen.Our results suggest a model whereby oncogenes can remain latently activated, but exposure of the adult liver to hepatotoxins that promote hepatocyte proliferation can rapidly uncover their malignant potential.

  View details for DOI 10.1371/journal.pone.0002493

  View details for Web of Science ID 000263280700056

  View details for PubMedID 18560566

  View details for PubMedCentralID PMC2423614

• Doxycycline sclerotherapy as primary treatment of head and neck lymphatic malformations in children JOURNAL OF PEDIATRIC SURGERY Nehra, D., Jacobson, L., Barnes, P., Mallory, B., Albanese, C. T., Sylvester, K. G. 2008; 43 (3): 451-460

  Abstract

  The authors report their experience with doxycycline sclerotherapy as primary treatment of head and neck lymphatic malformations (LMs) in children.A retrospective chart review was used to collect data on 11 patients treated with doxycycline sclerotherapy for LMs of the head and neck at our institution since 2003. Radiographic imaging allowed classification of patient LM as macrocystic, microcystic, or mixed according to previously published guidelines. Only patients with macrocystic or mixed lesions were offered doxycycline sclerotherapy. Radiographic imaging and physical examination were used to determine efficacy of treatment. After each treatment, the clinical and radiographic response was characterized as excellent (> or = 95% decrease in lesion size), satisfactory (> or = 50% decrease in volume and asymptomatic), or poor (< 50% decrease in volume or symptomatic).Eleven patients underwent a total of 23 sclerotherapies with an average of 2 treatments per patient (range, 1-4). All 7 patients with macrocystic lesions achieved complete clinical resolution with an average radiographic resolution of 93%. The 4 patients with mixed lesions achieved only partial clinical resolution and an average of 73% radiographic resolution. No patient experienced any adverse effects related to the treatment. At a median follow-up of 8 months, 2 patients (18%) experienced lesion recurrence in the setting of concomitant infection.Doxycycline sclerotherapy is safe and effective as a primary treatment modality for macrocystic and mixed LMs of the head and neck in the pediatric population.

  View details for DOI 10.1016/j.jpedsurg.2007.10.009

  View details for Web of Science ID 000254803500008

  View details for PubMedID 18358281

• Hepatic parenchymal replacement in mice by transplanted allogeneic hepatocytes is facilitated by bone marrow transplantation and mediated by CD4 cells HEPATOLOGY Streetz, K. L., Doyonnas, R., Grimm, D., Jenkins, D. D., Fuess, S., Perryman, S., Lin, J., Trautwein, C., Shizuru, J., Blau, H., Sylvester, K. G., Kay, M. A. 2008; 47 (2): 706-718

  Abstract

  The lack of adequate donor organs is a major limitation to the successful widespread use of liver transplantation for numerous human hepatic diseases. A desirable alternative therapeutic option is hepatocyte transplantation (HT), but this approach is similarly restricted by a shortage of donor cells and by immunological barriers. Therefore, in vivo expansion of tolerized transplanted cells is emerging as a novel and clinically relevant potential alternative cellular therapy. Toward this aim, in the present study we established a new mouse model that combines HT with prior bone marrow transplantation (BMT). Donor hepatocytes were derived from human alpha(1)-antitrypsin (hAAT) transgenic mice of the FVB strain. Serial serum enzyme-linked immunosorbent assays for hAAT protein were used to monitor hepatocyte engraftment and expansion. In control recipient mice lacking BMT, we observed long-term yet modest hepatocyte engraftment. In contrast, animals undergoing additional syngeneic BMT prior to HT showed a 3- to 5-fold increase in serum hAAT levels after 24 weeks. Moreover, complete liver repopulation was observed in hepatocyte-transplanted Balb/C mice that had been transplanted with allogeneic FVB-derived bone marrow. These findings were validated by a comparison of hAAT levels between donor and recipient mice and by hAAT-specific immunostaining. Taken together, these findings suggest a synergistic effect of BMT on transplanted hepatocytes for expansion and tolerance induction. Livers of repopulated animals displayed substantial mononuclear infiltrates, consisting predominantly of CD4(+) cells. Blocking the latter prior to HT abrogated proliferation of transplanted hepatocytes, and this implied an essential role played by CD4(+) cells for in vivo hepatocyte selection following allogeneic BMT.The present mouse model provides a versatile platform for investigation of the mechanisms governing HT with direct relevance to the development of clinical strategies for the treatment of human hepatic failure.

  View details for DOI 10.1002/hep.22012

  View details for Web of Science ID 000252939500040

  View details for PubMedID 18220289

• Wnt/beta-catenin signaling in murine hepatic transit amplifying progenitor cells GASTROENTEROLOGY Hu, M., Kurobe, M., Jeong, Y. J., Fuerer, C., Ghole, S., Nusse, R., Sylvester, K. G. 2007; 133 (5): 1579-1591

  Abstract

  Oval cells are postnatal hepatic progenitors with high proliferative potential and bipotent differentiation ability to become hepatocytes and cholangiocytes. Because Wnt/beta-catenin signaling is a known regulatory pathway for liver development and regeneration, we studied the role of Wnt signaling in oval cells using a mouse model of chronic liver injury.A 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-enriched diet was used to stimulate oval cell proliferation. Livers were harvested for histologic analysis and determination of Wnt family gene expression by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. The transgenic beta-catenin reporter mouse (TOPGAL) was use to confirm canonical Wnt/beta-catenin signal transduction in proliferating oval cells within atypical ductal proliferations (ADPs). Confocal fluorescence microscopy and immunohistochemistry was used to confirm colocalization of beta-catenin with the oval cell antigen A-6.Several Wnt ligands were significantly induced in the liver of DDC-fed mice and localized to proliferating cells in and adjacent to the ADPs. Oval cells isolated from DDC-fed mouse livers showed the presence of active beta-catenin in the nucleus along with cell-cycle entry in response to purified Wnt3a in vitro. Moreover, Wnt3a-induced beta-catenin/T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activation was quantified by TCF/LEF luciferase reporter assays.From these data, we conclude that oval cells respond to Wnt ligands (Wnt3a) in vitro with an increase in amino-terminus dephosphorylated beta-catenin and cell-cycle entry and that canonical Wnt/beta-catenin/TCF signaling is active in proliferating facultative hepatic progenitor cells in vivo. These findings may lend insight to the consequences of increased canonical Wnt signaling during periods of chronic liver injury.

  View details for DOI 10.1053/j.gastro.2007.08.036

  View details for Web of Science ID 000250820100025

  View details for PubMedID 17983805

• Evidence for canonical beta-catenin signaling in neuroblastomas 93rd Annual Clinical Congress of the American-College-of-Surgeons Ghole, S. A., Kuscuoglu, U., Hu, M., Jeong, Y. J., Sylvester, K. G. ELSEVIER SCIENCE INC. 2007: S66–S66

  View details for Web of Science ID 000249397300140

• Risk factors for the development of abdominal abscess following operation for perforated appendicitis in children - A multicenter case-control study 86th Annual Meeting of the New-England-Surgical-Society Henry, M. C., Walker, A., Silverman, B. L., Gollin, G., Islam, S., Sylvester, K., Moss, R. L. AMER MEDICAL ASSOC. 2007: 236–41

  Abstract

  The morbidity following treatment for perforated appendicitis in children is significant, with intra-abdominal abscess being one of the more serious complications. This can lead to prolonged hospitalizations and antibiotic administration, multiple computed tomographic scans, and invasive procedures. The purpose of our study was to determine risk factors for developing an intra-abdominal abscess following treatment for perforated appendicitis.Case-control study.Four tertiary care children's hospitals.Children aged 1 to 18 years with appendicitis.Multivariable logistic regression.Development of postoperative abscess, length of hospital stay, presence or absence of fever, and tolerance of diet on postoperative day 3.Thirty-five (13.2%) of 265 children developed an abscess. Ten factors with a bivariate P value <.20 were included in the regression model. The final multivariable model revealed only 2 factors influencing abscess development: an intraoperative fecalith (odds ratio, 8.77 [95% confidence interval, 1.50-51.40]) and diarrhea at presentation. Many factors proposed to be associated with abscess were not, including pain history, type and timing of preoperative antibiotics, abscess at operation, laparoscopic procedure, and length of antibiotics postoperatively. Thiry-seven children were discharged on or before postoperative day 3. Another 21 children were afebrile and tolerating a diet at that time but remained in the hospital. There were no significant differences between the 2 groups. None of the early-discharge group developed an abscess, and 2 of those remaining in the hospital developed an abscess (P = .06).Clinical factors commonly thought to be predictive of abscess formation following perforated appendicitis were not reliable predictors of this outcome. Our results suggest that if children are afebrile and eating on postoperative day 3 they can be discharged with a low rate of abscess development.

  View details for Web of Science ID 000244717700006

  View details for PubMedID 17372047

• Matched analysis of nonoperative management vs immediate appendectomy for perforated appendicitis 37th Annual Meeting of the American-Pediatric-Surgical-Association Henry, M. C., Gollin, G., Islam, S., Sylvester, K., Walker, A., Silverman, B. L., Moss, R. L. W B SAUNDERS CO-ELSEVIER INC. 2007: 19–24

  Abstract

  The role of nonoperative therapy vs immediate appendectomy in the management of children with perforated appendicitis remains undefined. The objective of this study was to rigorously compare these management options in groups of patients with matched clinical characteristics.Multicenter case-control study was conducted from 1998 to 2003. We compared patients treated nonoperatively vs those undergoing appendectomy to identify differences in 12 clinical parameters. We then generated a second control group of patients matched for these variables and compared the following outcomes in these clinically similar groups: complication rate, abscess rate, and length of stay (LOS). Analysis was performed according to intention-to-treat principles, using chi2, Fisher exact, and Student t tests.The only significant difference between patients treated nonoperatively and those treated by appendectomy was the duration of pain on presentation (6.8 vs 3.1 days of pain). We created a second control group of patients undergoing immediate appendectomy matched on duration of pain on presentation to patients treated nonoperatively. These groups continued to be clinically comparable for the other 11 parameters. Compared to this matched control group, the nonoperative group had fewer complications (19% vs 43%, P < .01), fewer abscesses (4% vs 24%, P < .01), and a trend for shorter LOS (6.5 +/- 5.7 vs 8.8 +/- 6.7 days, P = .08).When nonoperative management for perforated appendicitis was studied using appropriately matched clinical controls, we found that it resulted in a lower complication rate and shorter LOS in the subset of patients presenting with a long duration of pain. Our data suggest that nonoperative management should be prospectively evaluated in children with perforated appendicitis presenting with a history of pain exceeding 5 days.

  View details for DOI 10.1016/j.jpedsurg.2006.09.005

  View details for Web of Science ID 000243707100003

  View details for PubMedID 17208535

• Stem cells: tissue regeneration and cancer. Seminars in pediatric surgery Tataria, M., Perryman, S. V., Sylvester, K. G. 2006; 15 (4): 284-292

  Abstract

  Regenerative medicine is the promised paradigm of replacement and repair of damaged or senescent tissues. As the building blocks for organ development and tissue repair, stem cells have unique and wide-ranging capabilities, thus delineating their potential application to regenerative medicine. The recognition that consistent patterns of molecular mechanisms drive organ development and postnatal tissue regeneration has significant implications for a variety of pediatric diseases beyond replacement biology. The observation that organ-specific stem cells derive all of the differentiated cells within a given tissue has led to the acceptance of a stem cell hierarchy model for tissue development, maintenance, and repair. Extending the tissue stem cell hierarchical model to tissue carcinogenesis may revolutionize the manner in which we conceptualize cancer therapeutics. In this review, the clinical promise of these technologies and the emerging concept of "cancer stem cells" are examined. A basic understanding of stem cell biology is paramount to stay informed of this emerging technology and the accompanying research in this area with the potential for clinical application.

  View details for PubMedID 17055959

• Laparotomy versus peritoneal drainage for necrotizing enterocolitis and perforation NEW ENGLAND JOURNAL OF MEDICINE Moss, R. L., Dimmitt, R. A., Barnhart, D. C., Sylvester, K. G., Brown, R. L., Powell, D. M., Islam, S., Langer, J. C., Sato, T. T., Brandt, M. L., Lee, H., Blakely, M. L., Lazar, E. L., Hirschl, R. B., Kenney, B. D., Hackam, D. J., Zelterman, D., Silverman, B. L. 2006; 354 (21): 2225-2234

  Abstract

  Perforated necrotizing enterocolitis is a major cause of morbidity and mortality in premature infants, and the optimal treatment is uncertain. We designed this multicenter randomized trial to compare outcomes of primary peritoneal drainage with laparotomy and bowel resection in preterm infants with perforated necrotizing enterocolitis.We randomly assigned 117 preterm infants (delivered before 34 weeks of gestation) with birth weights less than 1500 g and perforated necrotizing enterocolitis at 15 pediatric centers to undergo primary peritoneal drainage or laparotomy with bowel resection. Postoperative care was standardized. The primary outcome was survival at 90 days postoperatively. Secondary outcomes included dependence on parenteral nutrition 90 days postoperatively and length of hospital stay.At 90 days postoperatively, 19 of 55 infants assigned to primary peritoneal drainage had died (34.5 percent), as compared with 22 of 62 infants assigned to laparotomy (35.5 percent, P=0.92). The percentages of infants who depended on total parenteral nutrition were 17 of 36 (47.2 percent) in the peritoneal-drainage group and 16 of 40 (40.0 percent) in the laparotomy group (P=0.53). The mean (+/-SD) length of hospitalization for the 76 infants who were alive 90 days after operation was similar in the primary peritoneal-drainage and laparotomy groups (126+/-58 days and 116+/-56 days, respectively; P=0.43). Subgroup analyses stratified according to the presence or absence of radiographic evidence of extensive necrotizing enterocolitis (pneumatosis intestinalis), gestational age of less than 25 weeks, and serum pH less than 7.30 at presentation showed no significant advantage of either treatment in any group.The type of operation performed for perforated necrotizing enterocolitis does not influence survival or other clinically important early outcomes in preterm infants. (ClinicalTrials.gov number, NCT00252681.).

  View details for Web of Science ID 000237758900004

  View details for PubMedID 16723614

• Absence of the p53 tumor suppressor gene promotes osteogenesis in mesenchymal stem cells 57th Annual Meeting of the American-Academy-of-Pediatrics Tataria, M., Quarto, N., Longaker, M. T., Sylvester, K. G. W B SAUNDERS CO-ELSEVIER INC. 2006: 624–32

  Abstract

  Osteosarcoma arises predominantly in the metaphyseal growth plate of children during the growth spurt years. These tumors develop during physiological growth from an expanding cell population, suggesting that the transformed cell is a bone-forming progenitor. An absence of the p53 oncogene has been implicated in the origin and progression of osteosarcoma, and because mesenchymal stem cells (MSCs) are the physiological osteogenic progenitor cell population, we hypothesized that a p53-/- mutation would enhance bone differentiation of MSC in a mouse model of in vitro osteogenesis.Clonal MSC populations were derived from p53-/- mice. P53-/- and wild-type cells were placed in osteogenic culture and assessed via Alizarin Red quantification and alkaline phosphatase staining. The osteogenic marker genes Cbfa1, osteopontin, and osteocalcin were assessed by quantitative real time polymerase chain reaction during differentiation.Bone nodule formation and alkaline phosphatase staining was accelerated and enhanced in the p53-/- cells. The early and intermediate osteogenic markers, Cbfa1 and osteopontin, were upregulated in p53-/- MSCs compared with wild-type cells during osteogenesis. The terminal osteogenic marker gene osteocalcin was paradoxically lower in p53-/- MSCs indicating impaired terminal differentiation.The p53-/- mutation enhances and accelerates early osteogenesis in MSCs, but prevents terminal differentiation toward a mature osteocyte phenotype. These findings may have important implications for the regulation of the MSC compartment during the derivation of osteosarcoma in children.

  View details for DOI 10.1016/j.jpedsurg.2005.12.001

  View details for Web of Science ID 000237015800002

  View details for PubMedID 16567167

• Repair and regeneration: opportunities for carcinogenesis from tissue stem cells JOURNAL OF CELLULAR AND MOLECULAR MEDICINE Perryman, S. V., Sylvester, K. G. 2006; 10 (2): 292-308

  Abstract

  This review will discuss the mechanisms of repair and regeneration in various tissue types and how dysregulation of these mechanisms may lead to cancer. Normal tissue homeostasis involves a careful balance between cell loss and cell renewal. Stem and progenitor cells perform these biologic processes as the functional units of regeneration during both tissue homeostasis and repair. The concept of tissue stem cells capable of giving rise to all differentiated cells within a given tissue led to the concept of a cellular hierarchy in tissues and in tumors. Thus, only a few cells may be necessary and sufficient for tissue repair or tumor regeneration. This is known as the hierarchical model of tumorigenesis. This report will compare this model with the stochastic model of tumorigenesis. Under normal circumstances, the processes of tissue regeneration or homeostasis are tightly regulated by several morphogen pathways to prevent excessive or inappropriate cell growth. This review presents the recent evidence that dysregulation of these processes may provide opportunities for carcinogenesis for the long-lived, highly proliferative tissue stem cell population. New findings of cancer initiating tissue stem cells identified in several solid and circulating cancers including breast, brain and hematopoietic tumors will also be reviewed. Finally, this report reviews the cellular biology of cancer and its relevance to the development of more effective cancer treatment protocols.

  View details for Web of Science ID 000239799000005

  View details for PubMedID 16796800

• In vivo selection of primary and bone-marrow-derived hepatocytes after allogeneic transplantation in mice 41st Annual Meeting of the European-Association-for-the-Study-of-the-Liver Streetz, K. L., Doyonnas, R., Jenkins, D., Perryman, S., Fuess, S., Lin, S., Shizuru, J., Blau, H., Trautwein, C., Sylvester, K., Kay, M. A. ELSEVIER SCIENCE BV. 2006: S33–S33

  View details for Web of Science ID 000237328100076

• Cell therapy for hepatocyte replacement through bone marrow derived myelomonocytic progenitors 91st Annual Clinical Congress of the American-College-of-Surgeons Sylvester, K. G., Jenkins, D., Streetz, K., Doyannis, R., Perryman, S., Kay, M., Blau, H. ELSEVIER SCIENCE INC. 2005: S47–S48

  View details for Web of Science ID 000231745800093

• The role of injury on the long-term expression of a hepatocyte transgene from bone marrow 91st Annual Clinical Congress of the American-College-of-Surgeons Perryman, S. V., Jenkins, D., Streetz, K., Doyonnas, R., Sylvester, K. ELSEVIER SCIENCE INC. 2005: S89–S89

  View details for Web of Science ID 000231745800198

• Multipotent progenitors from MSCs are regulated by Wnt/beta-catenin signaling 91st Annual Clinical Congress of the American-College-of-Surgeons Tataria, M., Ailles, L., Jenkins, D., Longaker, M. T., Weissman, I., Sylvester, K. ELSEVIER SCIENCE INC. 2005: S45–S45

  View details for Web of Science ID 000231745800087

• Donor-derived, liver-specific protein expression after bone marrow transplantation TRANSPLANTATION Jenkins, D. D., Streetz, K., Tataria, M., Sahar, D., Kurobe, M., Longaker, M. T., Kay, M. A., Sylvester, K. G. 2004; 78 (4): 530-536

  Abstract

  Bone marrow transplantation (BMT) may represent a novel mechanism to deliver a functional gene to a deficient liver. Bone marrow-derived hepatocytes are rare and without a defined contribution to liver function. Consequently, the clinical significance of BMT to treat liver disease is unclear. We sought to quantify bone marrow-derived hepatocyte protein expression after BMT and determine whether the process is inducible with liver injury.Mice transgenic for human alpha-1 antitrypsin (hAAT) under a hepatocyte-specific promoter were used as bone marrow donors. Adenoviral transduction of modified urokinase plasminogen activator (Ad-muPA) was used to induce liver injury. Eight weeks after lethal irradiation and BMT, recipients were stratified into two groups: BMT alone (n = 5) and BMT + Ad-muPA (n= 10). Both groups of animals were bled before (t = 0) and at 2, 4, 8, and 16 weeks after Ad-muPA administration, and the serum samples were assessed for hAAT by enzyme-linked immunosorbent assay.Transgenic donor mice expressed 5 to 10 mg/mL of hAAT. Recipients of BMT alone expressed less than 80 ng/mL of hAAT over all time periods. Animals receiving BMT + Ad-muPA showed sustained and stable hAAT expression of approximately 200 ng/mL. Differences were statistically significant at each time point.Serum protein levels from liver-specific transgene expression are detectable and persist after BMT. Expression is low, but inducible with liver injury. We are currently developing strategies to augment donor-derived, liver-specific protein expression after BMT.

  View details for DOI 10.1097/01.TP.0000130180.42573.BI

  View details for Web of Science ID 000223486500008

  View details for PubMedID 15446311

• Functional measurement of fusion in the liver after bone-marrow transplantation over time 39th Annual Meeting of the European-Association-for-the-Study-of-the-Liver Streetz, K. L., Jenkins, D., Longaker, G., Sylvester, K., Kay, M. A. ELSEVIER SCIENCE BV. 2004: 109–109

  View details for Web of Science ID 000220950800362

• Hepatocyte targeting for quantifiable and functional cellular transplantation 89th Annual Clinical Congress of the American-College-of-Surgeons Jenkins, D. D., Streetz, K., Kay, M., Longaker, M., Sylvester, K. ELSEVIER SCIENCE INC. 2003: S15–S15

  View details for Web of Science ID 000185248100026

• Bilateral cystic lung disease in a monoamnionic twin of an anencephalic: A case of glial heterotopia in the lungs. Western Regional Meeting of the American-Federation-for-Medical-Research Anderson, J. M., Adams, M. L., Morgan, T., Robinson, T., Enns, G. M., Keller, K. A., Sylvester, K. G., Hintz, S. R. LIPPINCOTT WILLIAMS & WILKINS. 2003: S119–S120

  View details for Web of Science ID 000180569600170