INTRODUCTION: Infants who have dysphagia (difficulty swallowing) are often recommended thickened oral liquids, which can be easier to swallow and allow infants to continue feeding orally. In the last decade, a xanthan gum thickener, SimplyThick®, was commonly used in preterm infants with dysphagia because of its ability to thicken breast milk. In 2011, the FDA cautioned against the use of SimplyThick in preterm infants, because of case reports of necrotizing enterocolitis (NEC), a condition where the bowel becomes inflamed and can lead to intestinal perforation or necrosis, systemic infection, the failure of multiple organs and death (Moore, 2016; Press Announcements, 2011). However, since the FDA warning, there have been no studies examining the prevalence of necrotizing enterocolitis in infants who consume SimplyThick. AIMS: Among infants at BCH who used SimplyThick and other thickeners at <1-year old between October 1st, 2012- December 31st, 2015 to 1) describe the patients’ clinical characteristics, including indications for SimplyThick and other thickeners and 2) determine the prevalence of necrotizing enterocolitis and adverse effects. METHODS: We performed a retrospective chart review in infants who had been seen at Boston Children’s Hospital, and prescribed or recommended SimplyThick thickener under the age of 1 (defined as from 0 up to and including 12 months) from October 1, 2012 to December 31, 2015. We collected information from electronic medical records and an existing quality improvement database of infants who had an abnormal modified barium swallow study. We collected information regarding clinical variables (e.g. patient age, patient sex, patient weight, gestational age at birth, clinical indications), nutritional information, and outcomes (presence of NEC or other adverse effects). These data were entered into a REDCap database and analyzed using SAS statistical software. RESULTS: We identified 20 cases of infants meeting our inclusion criteria. The duration of follow-up ranged from 6 months to 9.3 months. This follow up was either until the case turned 12 months of age or 6 months after the use of SimplyThick if the age started SimplyThick was greater than 6 months old. Mean corrected age at the time that SimplyThick was started was 6.2 months (range, 2.7 to 10.6 months), and 6 (30%) were born preterm at a gestational age ranging from 24.7 to 36.5 weeks. In cases that eventually stopped using SimplyThick (14 cases, 70%), SimplyThick was continued for a mean duration of 42.1 weeks (range 1.1 to 117.1 weeks). The most common indications for SimplyThick were aspiration documented on a modified barium swallow test, dysphagia and GERD. The most common reasons for discontinuation of SimplyThick were no longer requiring thickened feeds, or needing to stop oral feeding. No cases of necrotizing enterocolitis were reported among the 20 subjects. No adverse effects of SimplyThick were reported. CONCLUSION: Among 20 infants started on SimplyThick at 6.2 months and followed for up to 6 to 9.3 months, there were no cases of necrotizing enterocolitis. Further data collection is required to confirm these findings. / 2019-07-11T00:00:00Z

For most of human history, breastfeeding has been the optimal source of nutrition for infants. Human milk contains a variety of important nutritional sources including vitamins, fats, proteins, and immunological components. With the rise of artificial infant formulas, however, breastfeeding as a whole has decreased around the world. Preterm infants are especially susceptible to diseases such as necrotizing enterocolitis in the first few weeks of life. Therefore, they have the most to gain from the extra immunological and nutritional support that is present in human milk. Within the last few decades, donor human milk has been viewed as the next best option if mothers own milk is not available. Donor human milk contains many of the same beneficial milk properties as regular human milk including immunoglobulins and human milk oligosaccharides. Studies have shown decreases in preterm cases of NEC and fewer deaths in infants who received DHM. One argument against the use of DHM is that pasteurization can reduce the beneficial enzymes and immunoglobulins present in samples. However, the increased use of human milk fortifiers has been able to significantly decrease the nutrient gap between regular human milk and donor milk. Overall, DHM along with proper fortification serves as the best and most cost effective way to feed preterm infants if mother’s milk is unavailable.

BACKGROUND: Adequate feeding is a significant challenge for premature infants in the neonatal intensive care unit. These patients are often treated with glycerin suppositories to stimulate the passage of meconium and prevent feeding intolerance. Unfortunately, the evidence for this practice is limited and inconclusive. METHODS: We conducted a systematic review on the use of glycerin suppositories and enemas in premature infants. Following this, we conducted a pilot study for a multicenter randomized controlled trial of premature infants randomized to glycerin suppositories or a placebo procedure once daily. Outcomes included rate of recruitment, rate of reaching the primary endpoint of full enteral feeds, treatment-related adverse events, and cost. RESULTS: Twenty-two infants were recruited and randomized active treatment or the placebo procedure. Gestational age was 24-32 weeks and birth weight was 500-1500 grams. During the study period, 61 infants were screened, 46 (75%) were eligible and approached for consent, 25 (54%) consented to participate, 22 (48%) were randomized, and 19 reached the primary endpoint of full enteral feeds. Three infants (14%) experienced rectal bleeding 5 to 43 days after completing study treatments. An anal fissure was also noted in two of these patients (9%). There were no cases of rectal perforation or necrotizing enterocolitis. Protocol violations occurred during 14 of 130 (11%) treatment days. The total cost for running this pilot study was estimated to be $16,000. A revised sample size calculation for the multicenter study indicated that 72 infants would be required to detect a treatment effect of 2 days faster to full enteral feeds. CONCLUSIONS: This external pilot study suggested that conducting a multicenter randomized controlled trial of glycerin suppositories in premature infants is feasible and safe. In the multicenter trial, we recommend tolerating a lower platelet count in the exclusion criteria, using a fixed rather than variable treatment duration, conducting follow-up assessments at predefined time points, and conducting an interim analysis to ensure that treatment is not associated with increased risk of necrotizing enterocolitis. / Thesis / Master of Science (MSc) / Feeding is a significant challenge for premature babies in the neonatal intensive care unit. These infants have immature digestive tracts and may not have normal bowel movements until a week or more after birth. One way to help premature babies is by giving them a medication called glycerin suppositories. This treatment is already used in many hospitals around the world. Unfortunately, previous studies have not shown for sure that this medication is actually helpful. In fact, there are some signs that using glycerin suppositories in premature infants may be harmful. We conducted a small study involving 22 premature infants randomized to either glycerin suppositories or a placebo. We found that it is safe and practical to do a larger study on this treatment involving multiple hospitals and hundreds of premature babies. The larger study will have enough participants to full show the risks and benefits of using glycerin suppositories to treat these infants.

Leung, Wan Lun Fiona. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 179-204). / Abstracts in English and Chinese. / Abstract --- p.i / 中文摘要 --- p.v / Acknowledgement --- p.viii / List of Abbreviations and Symbols x --- p.vi / List of Tables --- p.xx / List of Figures --- p.xxi / Chapter CHAPTER ONE --- Introduction --- p.1 / Chapter 1.1 --- General Overview --- p.1 / Chapter 1.2 --- Necrotizing Enterocolitis (NEC) --- p.3 / Chapter 1.2.1 --- Epidemiology of NEC --- p.3 / Chapter 1.2.2 --- "Clinical Presentation, Diagnosis and Management of NEC" --- p.5 / Chapter 1.2.3 --- Pathophysiology of NEC --- p.9 / Chapter 1.2.3.1 --- Prematurity --- p.9 / Chapter 1.2.3.2 --- Bacterial Colonization --- p.12 / Chapter 1.2.3.3 --- Enteral Feeding --- p.15 / Chapter 1.2.3.4 --- Hypoxia and Ischemia --- p.16 / Chapter 1.2.3.5 --- Genetic Polymorphism --- p.17 / Chapter 1.2.3.6 --- Inflammatory Mediators --- p.20 / Chapter 1.3 --- Spontaneous Intestinal Perforation (SIP) --- p.24 / Chapter 1.3.1 --- Epidemiology of SIP --- p.24 / Chapter 1.3.2 --- "Clinical Presentation, Diagnosis and Management of SIP" --- p.26 / Chapter 1.3.3 --- Risk Factors of SIP --- p.28 / Chapter 1.3.3.1 --- Prematurity --- p.29 / Chapter 1.3.3.2 --- Use of Drugs --- p.30 / Chapter 1.4 --- Comparison between NEC and SIP --- p.32 / Chapter 1.5 --- Role of Cytokines in Pathogenesis of NEC and SIP --- p.38 / Chapter 1.6 --- Immunoregulatory Molecules of Interest in This Study --- p.46 / Chapter 1.6.1 --- Angiopoietin-2 (Ang-2) --- p.46 / Chapter 1.6.2 --- v-erb-b2 Erythroblastic Leukemia Viral Oncogene Homolog 2 (avian) (ErbB3) --- p.48 / Chapter 1.6.3 --- Type II Interleukin-1 Receptor (IL-1RII) --- p.52 / Chapter 1.6.4 --- Urokinase Plasminogen Activator Receptor (uPAR) --- p.54 / Chapter CHAPTER TWO --- Objectives --- p.57 / Chapter CHAPTER THREE --- Materials and Methodology --- p.58 / Chapter 3.1 --- Overview of the Experimental Procedures --- p.58 / Chapter 3.1.1 --- Investigation on the Profile of Circulatory Immunoregulatory Proteins in Plasma of NEC and SIP High Risk Neonates --- p.58 / Chapter 3.1.2 --- Investigation on the mRNA Expression Level of Targeted Immunoregulatory Molecules on Resected Intestinal Tissues in NEC and SIP Neonates --- p.58 / Chapter 3.1.3 --- Investigation on the mRNA and Protein Expression Levels of Targeted Immunoregulatory Molecules in Human Intestinal Cell Lines --- p.60 / Chapter 3.2 --- Reagents and Lab-wares with Their Sources --- p.61 / Chapter 3.3 --- Study Population --- p.63 / Chapter 3.4 --- Collection of Neonatal Whole Blood Samples --- p.65 / Chapter 3.5 --- Cytokine Antibody Array Analyses --- p.67 / Chapter 3.6 --- Enzyme-linked Immunosorbant Assays (ELISA) --- p.69 / Chapter 3.6.1 --- Angiopoietin-2 --- p.69 / Chapter 3.6.2 --- sErbB3 --- p.71 / Chapter 3.6.3 --- sIL-lRII --- p.72 / Chapter 3.6.4 --- suPAR --- p.74 / Chapter 3.7 --- Collection of Neonatal Resected Intestinal Tissues --- p.76 / Chapter 3.8 --- Resected Intestinal Tissue RNA Isolation --- p.78 / Chapter 3.9 --- Purity Assessment of the Purified Tissue RNA Samples --- p.80 / Chapter 3.10 --- Integrity Assessment of the Purified Tissue RNA Samples --- p.81 / Chapter 3.11 --- In vitro Stimulation of Human Enterocytes by Lipopolysaccharides (LPS) and/or Platelet Activating Factor (PAF) --- p.84 / Chapter 3.12 --- mRNA Expression Level Assessment of Selected Target Genes in Resected Intestinal Tissues and Human Intestinal Cell Lines --- p.86 / Chapter 3.12.1 --- Synthesis of First Strand cDNA --- p.86 / Chapter 3.12.2 --- Quantitative Polymerase Chain Reaction (qPCR) --- p.87 / Chapter 3.13 --- Statistical Analysis --- p.89 / Chapter CHAPTER FOUR --- Screening of Immunoregulatory Target Protein Molecules in Plasma of NEC and SIP Patients by Cytokine Array Analyses --- p.104 / Chapter 4.1 --- Results --- p.104 / Chapter 4.1.1 --- Screening of Detectable Immunoregulatory Target Molecules --- p.104 / Chapter 4.1.2 --- Selection of Target Molecules Based on the Fold Change in NEC or SIP Compared with Control Samples --- p.105 / Chapter 4.1.2.1 --- Similar Regulation of Target Molecules in Both NEC and SIP patients --- p.105 / Chapter 4.1.2.2 --- Differential regulation of Target Molecules in NEC and SIP Patients --- p.106 / Chapter 4.1.2.3 --- "Relative Normalized Expressions of Selected Circulatory Immunoregulatory Protein Molecules in NEC, SIP and Control Neonates" --- p.108 / Chapter 4.1.2.3.1 --- Anti-inflammation --- p.108 / Chapter 4.1.2.3.2 --- Pro-inflammation --- p.109 / Chapter 4.1.2.3.3 --- Cell Growth --- p.110 / Chapter 4.1.2.3.4 --- Wound Healing --- p.110 / Chapter 4.1.2.3.5 --- Angiogenesis --- p.111 / Chapter 4.1.2.3.6 --- "Anti-apoptosis, Cell Adhesion and Extracellular Matrix Organization" --- p.112 / Chapter 4.1.3 --- Further Selection of Novel Target Molecules Based on Statistical Significance and Fold Change of NEC versus SIP --- p.113 / Chapter 4.2 --- Discussion --- p.115 / Chapter CHAPTER FIVE --- Validation of Target Proteins in Plasma of NEC and SIP Patients by Enzyme-linked Immunosorbant Assay --- p.132 / Chapter 5.1 --- Results --- p.133 / Chapter 5.1.1 --- Demographic Data of the Study Group --- p.133 / Chapter 5.1.2 --- "Comparison of Plasma Levels of Target Proteins between NEC, SIP and Respective Controls" --- p.134 / Chapter 5.1.3 --- Longitudinal Study of the Pre- and Post-operative Target Proteins Levels in Plasma --- p.136 / Chapter 5.2 --- Discussion --- p.138 / Chapter CHAPTER SIX --- Investigation on mRNA Expression Levels of Target Immunoregulatory Protein Molecules in Intestinal Tissue and Intestinal Cell Lines --- p.151 / Chapter 6.1 --- Results --- p.152 / Chapter 6.1.1 --- mRNA Expression Levels of Target Molecules in the Diseased Margin of Resected Intestinal Tissues of NEC and SIP patients --- p.152 / Chapter 6.1.2 --- mRNA Expression Levels of Target Molecules in the Macroscopically Normal and Diseased Margin of Resected Intestinal Tissues of NEC and SIP patients --- p.154 / Chapter 6.1.3 --- mRNA Expression Levels of Target Molecules in Human Intestinal Cell Lines upon LPS and PAF Challenge --- p.156 / Chapter 6.1.3.1 --- FHs-74 Int Cell Line --- p.156 / Chapter 6.1.3.2 --- Caco-2 Cell Line --- p.157 / Chapter 6.2 --- Discussion --- p.158 / Chapter CHAPTER SEVEN --- General Discussion --- p.171 / Chapter 7.1 --- Overall Findings --- p.171 / Chapter 7.2 --- Limitations of Study --- p.174 / Chapter 7.3 --- Future Investigations --- p.177 / References --- p.179

Dissertation (Ph.D.)--University of South Florida, 2008. / Title from PDF of title page. Document formatted into pages; contains 106, 1 pages. Includes vita. Includes bibliographical references.

Necrotizing enterocolitis (NEC) is a costly and deadly disease in neonates. Composite risk for NEC is poorly understood and consensus has not been established on the relevance of risk factors. This two-phase study attempted to validate and test a neonatal NEC risk index, GutCheck(NEC). Phase I used an E-Delphi methodology in which experts (n=35) rated the relevance of 64 potential NEC risk factors. Items were retained if they achieved predefined levels of expert consensus or stability. After three rounds, 43 items were retained (CVI=.77). Qualitative analysis revealed two broad themes: individual characteristics of vulnerability and the impact of contextual variation within the NICU on NEC risk. In Phase II, the predictive validity of GutCheck(NEC) was evaluated using a sample from the Pediatrix BabySteps Clinical Data Warehouse (CDW). The sample included infants born<1500 grams, before 36 weeks, and without congenital anomalies or spontaneous intestinal perforation (N=58,818, of which n=35,005 for empiric derivation and n=23,813 for empiric validation). Backward stepwise likelihood-ratio method regression was used to reduce the number of predictive factors in GutCheck(NEC) to 11 and derive empiric weights. Items in the final GutCheck(NEC) were gestational age, history of a transfusion, NICU-specific NEC risk, late onset sepsis, multiple infections, hypotension treated with Inotropic medications, Black or Hispanic race, outborn status, metabolic acidosis, human milk feeding on both day 7 and day 14 (reduces risk) and probiotics (reduces risk).Discrimination was fair in the case-control sample (AUC=.67, 95% CI .61-.73) but better in the validation set (AUC=.76, 95% CI .75-.78) and best for surgical NEC (AUC=.84, 95% CI .82-.84) and infants who died from NEC (AUC=.83, 95% CI .81-.85). A GutCheck(NEC) score of 33 (range 0-58) yielded a sensitivity of .78 and a specificity of .74 in the validation set. Intra-individual reliability was acceptable (ICC (19) =.97, p<.001). Future research is needed to repeat this procedure in infants between 1500 and 2500 grams, complete psychometric testing, and explore unit variation in NEC rates using a comprehensive approach.

Microarray experiments generate vast amounts of data that evidently reflect many aspects of the underlying biological processes. A major challenge in computational biology is to extract, from such data, significant information and knowledge about the complex interplay between genes/proteins. An analytical approach that has recently gained much interest is reverse engineering of genetic networks. This is a very challenging approach, primarily due to the dimensionality of the gene expression data (many genes, few time points) and the potentially low information content of the data. Bayesian networks (BNs) and its extension, dynamic Bayesian networks (DBNs) are statistical machine learning approaches that have become popular for reverse engineering. In the present study, a DBN learning algorithm was applied to gene expression data produced from experiments that aimed to study the etiology of necrotizing enterocolitis (NEC), a gastrointestinal inflammatory (GI) disease that is the most common GI emergency in neonates. The data sets were particularly challenging for the DBN learning algorithm in that they contain gene expression measurements for relatively few time points, between which the sampling intervals are long. The aim of this study was, therefore, to evaluate the applicability of DBNs when learning genetic networks for the NEC disease, i.e. from the above-mentioned data sets, and use biological knowledge to assess the hypothesized gene interactions. From the results, it was concluded that the NEC gene expression data sets were not informative enough for effective derivation of genetic networks for the NEC disease with DBNs and Bayesian learning.

<p>Microarray experiments generate vast amounts of data that evidently reflect many aspects of the underlying biological processes. A major challenge in computational biology is to extract, from such data, significant information and knowledge about the complex interplay between genes/proteins. An analytical approach that has recently gained much interest is reverse engineering of genetic networks. This is a very challenging approach, primarily due to the dimensionality of the gene expression data (many genes, few time points) and the potentially low information content of the data. Bayesian networks (BNs) and its extension, dynamic Bayesian networks (DBNs) are statistical machine learning approaches that have become popular for reverse engineering. In the present study, a DBN learning algorithm was applied to gene expression data produced from experiments that aimed to study the etiology of necrotizing enterocolitis (NEC), a gastrointestinal inflammatory (GI) disease that is the most common GI emergency in neonates. The data sets were particularly challenging for the DBN learning algorithm in that they contain gene expression measurements for relatively few time points, between which the sampling intervals are long. The aim of this study was, therefore, to evaluate the applicability of DBNs when learning genetic networks for the NEC disease, i.e. from the above-mentioned data sets, and use biological knowledge to assess the hypothesized gene interactions. From the results, it was concluded that the NEC gene expression data sets were not informative enough for effective derivation of genetic networks for the NEC disease with DBNs and Bayesian learning.</p>

In extremely preterm infants, acute abdominal emergencies are fortunately less common with improving care. Spontaneous intestinal perforation and necrotizing enterocolitis are conditions where emergency surgery is most often needed. Conservative medical management and placement of temporary drain are often used in the initial management. Internal hernia (IH) is an uncommon cause of bowel obstruction in neonates, is difficult to diagnose and unfortunately are found only at autopsy. The presentation in preterm infants, distinction between these conditions, and the need for early diagnosis of IH are discussed.

Problem: Necrotizing Enerocolitis (NEC) is one of the leading causes of morbidity and mortality in neonatal intensive care units (NICU), affecting 7% to 14% of premature neonates weighing less than 1500g (Lin et al., 2008). Healthcare costs for the treatment of NEC account for roughly 20% of the 5 billion dollars spent on infants in the NICU annually (Gephart, McGrath, Effken & Halpern, 2012). Nutritional supplements, such as probiotics, may be used prophylactically to prevent NEC in this high-risk population. Objective: A literature review was performed to examine which strains of probiotics show the most potential in reducing the incidence of necrotizing enterocolitis. Method: A literature review was performed using CINAHL, Science Citation Index, Science Direct, Medline, Academic One file, PsychINFO, and PUBMED databases. Key words included enterocolitis, Necrotizing*/PC OR NEC* AND probiotics*. After applying exclusion criteria, 9 articles remained for this review. Results: A variety of probiotic strains used to reduce the incidence of NEC were identified, along with inconsistent times of initiation, number of colony forming units and length of treatment. The most commonly studied probiotic strains include Lactobacillus species, Bifidobacterium species, and Saccharomyces species. After detailed analysis, it appears that a combination of Bifidobacterium species and Lactobacillus species reduce the incidence of NEC from an 8% (Fernández-Carrocera et. al, 2013) reduction up to 100% reduction in the incidence of NEC (Braga, Pontes da Silva, Cabral de Lira, & Lima, 2011). These two species, when combined, were more successful when compared to Saccharomyces species or Lactobacillus species alone. Conclusion: Although there is positive support for the proactive use of probiotics for the reduction of the incidence of NEC in premature neonates, the inconsistencies between studies are a barrier for determination of a specific treatment recommendation. Although the combination of Bifidobacterium species and Lactobacillus species has been shown to have an impact on the reduction of NEC incidence, the research inconsistencies provide a barrier to generalizations for treatment. Additional research that focus on Bifidobactrium species in combination with Lactobacillus species is needed. Furthermore, the use of probiotics as a preventative treatment for NEC has not been thoroughly researched in extremely premature infant populations (gestation). Therefore, although the results are promising, further research is needed before this can be determined as a safe preventative method. The current questions remaining include: when prophylactic treatment should be initiated, how long prophylactic treatment should last, the number of colony forming units to be administered, and what is the long-term impact of probiotic administration on the normal gut flora, if any.