Interaction between the gut microbiota and colonic enteroendocrine cells regulates host metabolism.

Nutrient handling is an essential function of the gastrointestinal tract. Hormonal responses of small intestinal enteroendocrine cells (EECs) have been extensively studied but much less is known about the role of colonic EECs in metabolic regulation. To address this core question, we investigated a mouse model deficient in colonic EECs. Here we show that colonic EEC deficiency leads to hyperphagia and obesity. Furthermore, colonic EEC deficiency results in altered microbiota composition and metabolism, which we found through antibiotic treatment, germ-free rederivation and transfer to germ-free recipients, to be both necessary and sufficient for the development of obesity. Moreover, studying stool and blood metabolomes, we show that differential glutamate production by intestinal microbiota corresponds to increased appetite and that colonic glutamate administration can directly increase food intake. These observations shed light on an unanticipated host-microbiota axis in the colon, part of a larger gut-brain axis, that regulates host metabolism and body weight.

Evolution of filiform polyposis from classical pseudopolyposis in a pediatric ulcerative colitis patient.

Filiform polyposis (FP) is a morphologic variant of pseudopolyposis associated with inflammatory conditions of the gastrointestinal tract, namely, inflammatory bowel disease. Pediatric cases are uncommon in the literature. Here, we present a pediatric patient with FP arising from ulcerative colitis (UC). He initially presented at 7 years of age for an acute UC flare and was found to have classical pseudopolyposis. A follow-up colonoscopy at age 9 showed the evolution of classical pseudopolyposis to FP. The patient clinically improved with sulfasalazine monotherapy and remained in remission based on consistent pediatric ulcerative colitis activity index scores of zero and normal-range inflammatory markers. Repeat surveillance colonoscopy at age 14 showed persistent and diffuse FP in the background of healthy colonic mucosa. This case documents the development of FP from classical pseudopolyps in the setting of an asymptomatic patient in clinical remission.

An enteroendocrine-microbial axis in the large intestine controls host metabolism.

Nutrient handling is an essential function of the gastrointestinal tract. Most nutrient absorption occurs in the small intestine and is coordinated by hormone-producing intestinal epithelial cells known as enteroendocrine cells (EECs)1. In contrast, the colon mostly reclaims water and electrolytes, and handles the influx of microbially-derived metabolites, including short chain fatty acids (SCFA)2-4. Hormonal responses of small intestinal EECs have been extensively studied but much less in known about the role of colonic EECs in metabolic regulation. To address this core question, we investigated a mouse model deficient in colonic EECs. We found that colonic EEC deficiency leads to hyperphagia and obesity. Surprisingly, colonic EEC deficiency results in altered microbiota composition and metabolism, which we found through antibiotic treatment and transfer to germ free recipients, to be both necessary and sufficient for the development of obesity. Moreover, studying stool and blood metabolomes, we found that differential glutamate production by intestinal microbiota corresponds to increase appetite due to EEC loss. Finally, we show that colonic glutamate administration can directly increase food intake and activate appetite centers in the central nervous system. These observations shed light on an unanticipated host-microbiota axis in the colon, part of a larger gut-brain axis, that regulates host metabolism and body weight.

Bioavailability of the tumor necrosis factor alpha/regulated on activation, normal T cell expressed and secreted (RANTES) biosystem inside the gestational sac during the pre-immune stages of embryo development.

OBJECTIVES: In-vivo studies of the bioavailability of major components of the tumor necrosis factor alpha (TNFα) biosystem inside the gestational sac during embryogenesis have not been reported. We sought to determine the concentration of TNFα, soluble (s) TNFα receptors (sTNFR1, sTNFR2), and RANTES in the primate extraembryonic celomic fluid (ECF). METHODS: A validated timed-pregnant baboon animal model (N: 10) for experimental research in pregnancy was used to collect paired maternal blood and ECF samples in ongoing pregnancies. The concentrations (pg/dL) of TNFα, sTNFR1, sTNFR2, and RANTES were then determined by ELISA immunoassays. RESULTS: All animals delivered at term healthy newborns. The differential concentration of TNFα, sTNFR1, sTNFR2, and RANTES between the maternal plasma and the ECF could be determined with ratios for TNFα (5.4), sTNFR2 (1.85) and RANTES (3.59) that contrasted with that of sTNFR1 (0.07), which favored the gestational sac compartment. No significant correlations were noted between maternal plasma and ECF TNFR1, sTNFR2 and RANTES. There was a trend for a correlation between TNFα in maternal plasma and ECF (R=0.74; p=0.07). CONCLUSIONS: We report the physiological concentrations of TNFα, sTNFR1, sTNFR2, and RANTES in extraembryonic celomic fluid during embryogenesis in primates.

Enhancing Residents' Warmth in Greeting Caregivers: An Inpatient Intervention to Improve Family-Centered Communication.

ABSTRACT: Hospitals are increasingly motivated to improve the patient and family experience and increase patient satisfaction scores. The manner by which a provider greets patients and their families sets the tone for the hospital stay. This study aimed to improve residents' greetings of caregivers in the inpatient pediatric setting to improve family-centered communication. The study was conducted from October 2017 to April 2018 at a single, urban children's hospital on a unit with patients primarily <5 years old. The intervention consisted of posting a prominent board outside of patients' rooms that (1) listed caregivers' preferred names (e.g., Mom/Dad, first names), (2) instructed residents to greet caregivers warmly by their preferred names, and (3) identified residents for families by name and photograph. During implementation, we conducted 5 Plan-Do-Study-Act cycles and surveyed 114 caregivers. Improvement was assessed using run charts. The primary outcome was the percentage of caregivers who rated residents' warmth of greetings as "excellent." This measure increased from a baseline median of 62.5%-84.4% with ≥6 consecutive postintervention points above the baseline median. The intervention improved caregiver-perceived quality of residents' greetings and could serve as a model for other hospitals to enhance provider-family rapport and improve communication.

Pediatric Residents' Sense of Meaning in Their Work: Is This Value Related to Higher Specialty Satisfaction and Reduced Burnout?

OBJECTIVE: Physician wellness is frequently measured as the absence of burnout, rather than the perception of meaningful work. This study of pediatric residents aimed to test the hypothesis that their sense of meaning at work is associated positively with specialty satisfaction and negatively with burnout. METHODS: In June 2018, we surveyed residents at a large urban pediatrics program, using the Work and Meaning Inventory (WAMI), the Global Specialty Satisfaction measure, and a single-item burnout measure. Residents were surveyed at the end of their intern, second or third/fourth year. We compared resident responses to outcome measures by year, gender, race, and type of program (pediatrics and medicine-pediatrics). We assessed the associations between WAMI scores and specialty satisfaction using linear regression and between WAMI scores and burnout using logistic regression, both adjusted for residency year and characteristics. RESULTS: The survey was completed by 119/154 (77.3%) residents. Mean WAMI score was 40.6 ± 5.6 (standard deviation), mean specialty satisfaction score was 11.9 ± 2.4, and 48.7% (58/119) of residents reported burnout with no significant differences in scores by residency year, gender, race, or type of program (all P > .05). Residents' WAMI scores were positively associated with specialty satisfaction (r = +0.57, P < .001) and negatively associated with burnout (adjusted odds ratio  = 0.80, 95% confidence interval 0.73-0.89). CONCLUSIONS: Pediatric residents' sense of meaning at work was significantly positively associated with specialty satisfaction and negatively associated with burnout. We recommend that efforts to improve resident wellness focus on interventions to foster meaning in work, such as supporting team cohesion and autonomy in job design.

Should We Call You Mom and Dad? Caregiver Preferences and Pediatric Physician and Nurse Manner in Greetings.

OBJECTIVES: In this study, we evaluated whether caregivers preferred to be called "Mom" and "Dad" or by name in the inpatient pediatric setting and how often caregivers reported that residents, attending physicians, and nurses greeted them as they preferred. METHODS: We measured caregivers' greeting preferences and perceptions of how residents, attending physicians, and nurses greeted them by surveying caregivers on 1 unit at a large urban children's hospital from October 2017 to April 2018. The 27-item survey consisted of multiple choice, Likert scale, and demographic measures. A member of the study team enrolled caregivers at the patient's bedside to complete the written survey anonymously. RESULTS: A total of 114 caregivers completed the survey (51% of 223 enrolled caregivers); 63% (95% confidence interval [CI] 53%-74%) of mothers and 57% (95% CI 36%-77%) of fathers preferred to be greeted as Mom and Dad, respectively; the rest preferred greetings by name. Caregiver preferences did not significantly vary on the basis of relationship to the child (mother or father), age, race, or education level (P > .05). Caregivers reported that 48% (95% CI 35%-62%) of residents, 43% (95% CI 29%-57%) of attending physicians, and 63% (95% CI 49%-75%) of nurses always or usually addressed them as they preferred. CONCLUSIONS: Approximately half of mothers and fathers preferred to be called Mom and Dad, respectively, whereas the rest preferred to be greeted by name. Caregiver preferences did not differ on the basis of demographics. Caregivers reported that residents, attending physicians, and nurses were inconsistent in following their greeting preferences.

Association of histological chorioamnionitis and magnesium sulfate treatment in singleton and dichorionic twin pregnancies with preterm premature rupture of membranes: preliminary observations.

Objective To evaluate the possible association between antenatal magnesium sulfate treatment with histological chorioamnionitis in patients with singleton or dichorionic twins that had preterm premature rupture of the membranes. Methods This was an observational study performed in patients admitted to the hospital with rupture of membranes before 34 weeks' gestation. The primary outcome was histological chorioamnionitis and the primary predictor was antenatal magnesium sulfate treatment. A logistic regression model was used without consideration of other antenatal medical treatments. Results Among 107 patients with preterm deliveries, 57 were admitted to the hospital before 34 weeks' gestation with preterm premature rupture of membranes. Fifty-cases were excluded from the analysis because they were admitted after 34 weeks' gestation, delivered before 24 weeks' gestation or had intrauterine fetal demise or monochorionic twins. The logistic regression analysis adjusting for maternal age, gravidity, parity, multiple gestation, gestational age at delivery, and birthweight, indicated that patients with singleton pregnancies and histological chorioamnionitis had received magnesium sulfate antenatally more frequently (χ2=6.46; P=0.01). The association between histological chorioamnionitis and magnesium sulfate treatment was not found among patients with dichorionic twin pregnancies with one intact gestational sac. Conclusions In this cohort of patients with preterm premature rupture of membranes admitted to the hospital before 34 week's gestation, those with singleton pregnancies treated antenatally with magnesium sulfate for neonatal neuroprotection had a greater rate of histological chorioamnionitis.

The Microbiota and Transgenomic Networks: Potential Implications for Maternal-Fetal Medicine.

The maternal microbiota has long been considered a potential cause for adverse perinatal outcomes. Gene expression regulators in prokaryotic and eukaryotic cells are influenced by changes in their microenvironments. We propose the novel idea that during in utero development, an adaptive and dynamic gene-regulatory cross talk might exist between the host genome and the maternal microbiota. Understanding these cross talks could increase the appreciation for the discovery of new diagnostics and therapeutics in maternal-fetal medicine.

Risk factors for perinatal mortality in patients admitted to the hospital with the diagnosis of placental abruption.

OBJECTIVE: Placental abruption is a clinical term used when premature separation of the placenta from the uterine wall occurs prior to delivery of the fetus. Hypertension, substance abuse, smoking, intrauterine infection and recent trauma are risk factors for placental abruption. In this study, we sought for clinical factors that increase the risk for perinatal mortality in patients admitted to the hospital with the clinical diagnosis of placental abruption. MATERIALS AND METHODS: We identified all placental abruption cases managed over the past 6 years at our Center. Those with singleton pregnancies and a diagnosis of abruption based on strict clinical criteria were selected. Eleven clinical variables that had potential for increasing the risk for perinatal mortality were selected, logistic regression analysis was used to identify variables associated with perinatal death. RESULTS: Sixty-one patients were included in the study with 16 ending in perinatal death (26.2%). Ethnicity, maternal age, gravidity, parity, use of tobacco, use of cocaine, hypertension, asthma, diabetes, hepatitis C, sickle cell disease and abnormalities of amniotic fluid volume were not the main factors for perinatal mortality. Gestational age at delivery, birthweight and history of recent trauma were significantly associated with perinatal mortality. The perinatal mortality rate was 42% in patients who delivered prior to 30 weeks of gestation compared to 15% in patients who delivered after 30 weeks of gestation (p < 0.05). A three-fold increase in severe trauma was reported in the group of patients with perinatal mortality than in the group with perinatal survivors (25% versus 7%, respectively, p < 0.05). CONCLUSIONS: In patients admitted to hospital for placental abruption delivery prior to 30 weeks of gestation and a history of abdominal trauma are independent risk factors for perinatal death.

Screening for Down syndrome in dichorionic twin pregnancies conceived by in vitro fertilization (IVF): a clinical pilot study to confirm the laboratory methods.

PURPOSE: The corrections necessary to estimate the risk for Down syndrome in twin pregnancies have been pointed out. We performed a nested controlled study to evaluate the validity of these corrections in dichorionic twins conceived by IVF. METHODS: Detailed clinical data was collected from the medical records. Twins were matched with a contemporaneous cohort of spontaneously conceived singleton pregnancies that serve as reference in a 1 to 4 ratio. All patients had their entire obstetrical care at our Hospital. The Student t-test was used for group comparisons and a p-value <0.05 was considered significant. RESULTS: Nineteen sets of normal twins concordant in size and with appropriate weight for gestational age were matched with 80 normal and mature newborns. Significant differences between groups were found for maternal age, gestational age at delivery and newborn weight (all p < 0.01). No statistical differences were noted for the levels of the biochemical markers expressed as multiples of the median. However, a 15 % closer approximation to the laboratory median for PAPP-A and a 10 % closer approximation to the laboratory median for free ß-hCG was evident in twins when compared to the reference group. CONCLUSIONS: These findings support the methods used to estimate the risk for Down syndrome in dichorionic twin pregnancies conceived after IVF. A future study with a larger sample size could confirm if the laboratory corrections done on the combined screening test improve the predictability of Down syndrome in dichorionic twin pregnancy conceived by IVF when compared to singleton pregnancies.

Baseline TNFα operational capacity in fetal and maternal circulation prior to the onset of labor: "tuned for different purposes".

OBJECTIVE: In this study, we sought to characterize the tumor necrosis factor α (TNFα) baseline operational capacity in mature fetuses and their mothers prior to the onset of labor. MATERIALS AND METHODS: We used an experimental pregnant nonhuman primate model to measure the plasma concentration of TNFα, TNF transmembrane receptor I (TNFRI), and TNFRII with validated enzyme-linked immunosorbent assays. Coefficients of correlations between the maternal and the fetal values and the soluble TNFα, TNFRI, or TNFRII concentrations and ratios were calculated. RESULTS: The TNFα/TNFRI ratio was 3 times lower in fetal circulation than in maternal circulation. No correlations were noted between the maternal and the fetal TNFα, TNFRI, or TNFRII plasma concentrations. CONCLUSIONS: These findings suggest that the fetal and maternal baseline circulatory operational capacities of TNFα are independent of each other and tuned differently. This differential regulation of TNFα in fetal and maternal circulation at the end of pregnancy may be guided to protect the fetus from the systemic inflammatory response that is essential for the mechanisms of labor to proceed in the mother.

Candidate biomarkers for acute rejection of pregnancy after in-utero cell-based therapy in pre-immune embryos via ultrasound-guided celocentesis.

PROBLEM: A maternal serum biomarker profile analysis was performed to determine potential indicators of acute rejection of pregnancy following in-utero cell-based treatments in pre-immune embryos. METHOD OF STUDY: We used an established non-human primate model for in-utero stem cell therapy at 38-42 days from fertilization. The maternal serum concentrations of nine candidate biomarkers for acute rejection of pregnancy were determined before and after the injection of different cocktails of human umbilical cord blood stem cells into the gestational sac. All animals were then followed until delivery. RESULTS: Twenty-four hours after celocentesis, two of the animals aborted. These two animals received a cocktail of haemopoietic stem cells with the highest concentration of human CD3(+) cells and showed a twofold increase in maternal serum IL-6 and a threefold increase in prolactin after the procedure. The remaining six animals delivered at term live and normal newborns and only demonstrated an increase in prolactin after the celocentesis procedure. CONCLUSION: IL-6 and prolactin are master immunoregulators with pleiotropic biological functions that have different maternal serum concentrations depending on pregnancy outcome. These findings suggest that increases in maternal serum prolactin and IL-6 concentration may be associated with acute rejection of pregnancy after in-utero stem cell therapy.