In vivo development of immune tissue in human intestinal organoids transplanted into humanized mice.

Human intestinal organoids (HIOs) derived from pluripotent stem cells provide a valuable model for investigating human intestinal organogenesis and physiology, but they lack the immune components required to fully recapitulate the complexity of human intestinal biology and diseases. To address this issue and to begin to decipher human intestinal-immune crosstalk during development, we generated HIOs containing immune cells by transplanting HIOs under the kidney capsule of mice with a humanized immune system. We found that human immune cells temporally migrate to the mucosa and form cellular aggregates that resemble human intestinal lymphoid follicles. Moreover, after microbial exposure, epithelial microfold cells are increased in number, leading to immune cell activation determined by the secretion of IgA antibodies in the HIO lumen. This in vivo HIO system with human immune cells provides a framework for future studies on infection- or allergen-driven intestinal diseases.

Body Composition of Infants With Congenital Gastroschisis.

ABSTRACT: Infants born with congenital gastroschisis are at risk for intrauterine growth restriction, small for gestational size at birth, and growth failure during the newborn period despite advanced care. Body composition provides a more complete picture of proportional growth than weight and length alone. Fat-free mass (FFM) represents organ growth, and in preterm infants without gastroschisis, improved FFM deposition is associated with improved neurodevelopmental outcomes. There is limited literature regarding the body composition of infants with gastroschisis. This case series describes the body composition of 10 infants with gastroschisis.

Effect of intraoperative fluid type on postoperative systemic inflammatory response and end organ dysfunction following total pancreatectomy with islet autotransplantation in children.

PURPOSE: To evaluate the effect of intraoperative fluid type [half normal saline (0.45NS) or lactated Ringer's solution (LR)] on the risk of systemic inflammatory response syndrome (SIRS) and acute kidney injury after total pancreatectomy with islet autotransplantation in children. METHODS: Retrospective review where demographics, operative details, systemic inflammatory response, and evaluation for end organ dysfunction over the first 5 postoperative days was obtained. Mixed effects Poisson regression compared risk of SIRS and acute kidney injury by intraoperative fluid type. RESULTS: Forty three patients were included with no difference in demographic characteristics between groups. SIRS was observed in 95, 77, and 71% over post operative days 1, 3, and 5. Intraoperative fluid type was found to not be associated with postoperative SIRS (RR: 0.91, p = 0.23). However, female sex (RR: 1.30, p < 0.01), increased BMI (RR: 1.08, p < 0.01), and longer operative time (RR: 1.07, p < 0.01) were found to be factors that are associated with increased risk of postoperative SIRS. Intraoperative 0.45NS use was associated with increased acute kidney injury compared to LR on postoperative day 1 (52% vs 0%, p < 0.01), but not on postoperative days 3 or 5. CONCLUSION: Intraoperative fluid type (0.45NS vs LR) does not increase the risk of postoperative SIRS in children after TPIAT. Predictive factors that are associated with an increased risk of eliciting postoperative SIRS includes female sex, increased BMI, and longer operative times. LEVEL OF EVIDENCE: III.

Primary mesenchymal stromal cells in co-culture with leukaemic HL-60 cells are sensitised to cytarabine-induced genotoxicity, while leukaemic cells are protected.

Tumour microenvironments are hallmarked in many cancer types. In haematological malignancies, bone marrow (BM) mesenchymal stromal cells (MSC) protect malignant cells from drug-induced cytotoxicity. However, less is known about malignant impact on supportive stroma. Notably, it is unknown whether these interactions alter long-term genotoxic damage in either direction. The nucleoside analogue cytarabine (ara-C), common in haematological therapies, remains the most effective agent for acute myeloid leukaemia, yet one-third of patients develop resistance. This study aimed to evaluate the bidirectional effect of MSC and malignant cell co-culture on ara-C genotoxicity modulation. Primary MSC, isolated from patient BM aspirates for haematological investigations, and malignant haematopoietic cells (leukaemic HL-60) were co-cultured using trans-well inserts, prior to treatment with physiological dose ara-C. Co-culture genotoxic effects were assessed by micronucleus and alkaline comet assays. Patient BM cells from chemotherapy-treated patients had reduced ex vivo survival (P = 0.0049) and increased genotoxicity (P = 0.3172) than untreated patients. It was shown for the first time that HL-60 were protected by MSC from ara-C-induced genotoxicity, with reduced MN incidence in co-culture as compared to mono-culture (P = 0.0068). Comet tail intensity also significantly increased in ara-C-treated MSC with HL-60 influence (P = 0.0308). MSC sensitisation to ara-C genotoxicity was also demonstrated following co-culture with HL60 (P = 0.0116), which showed significantly greater sensitisation when MSC-HL-60 co-cultures were exposed to ara-C (P = 0.0409). This study shows for the first time that malignant HSC and MSC bidirectionally modulate genotoxicity, providing grounding for future research identifying mechanisms of altered genotoxicity in leukaemic microenvironments. MSC retain long-term genotoxic and functional damage following chemotherapy exposure. Understanding the interactions perpetuating such damage may inform modifications to reduce therapy-related complications, such as secondary malignancies and BM failure.

Infant body composition assessment in the neonatal intensive care unit (NICU) using air displacement plethysmography: Strategies for implementation into clinical workflow.

Nutritional management is integral to infant care in the neonatal intensive care unit (NICU). Recent research on body composition that specifically evaluated fat and fat-free mass has improved our understanding of infant growth and nutritional requirements. The need for body composition monitoring in infants is increasingly recognized as changes in fat mass and fat-free mass associated with early growth can impact clinical outcomes. With the availability of air displacement plethysmography (ADP) as a noninvasive method for assessing infant body composition and published normative gestational age- and sex-specific body composition curves, it is justifiable to integrate this innovation into routine clinical care. Here we describe our experiences in implementing body composition measurement using ADP in routine clinical care in different NICU settings.

Quality Improvement Efforts Reduce Incidence of Surgical Necrotizing Enterocolitis and Related Deaths.

OBJECTIVE: The aim of this study was to determine whether a regional quality improvement (QI) initiative decreased incidence and severity of surgical necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. STUDY DESIGN: A retrospective review of all VLBW infants who received care at one of the three hospitals involved in a NEC QI initiative from 2011 to 2016. Primary outcome was the number of surgical NEC cases per year. Secondary outcomes included associated outcomes and mortality. RESULTS: Sixty-three infants with either a diagnosis of Stage III NEC (n = 40) or spontaneous intestinal perforation (SIP) (n = 23) were included. The incidence of medical and surgical NEC and the mortality rate of infants with surgical NEC decreased over time. Incidence and mortality of SIP did not significantly change. CONCLUSION: A regional QI bundle to reduce the overall incidence of NEC also significantly decreased the incidence of surgical NEC and all-cause mortality of infants diagnosed with surgical NEC. KEY POINTS: · QI reduces surgical necrotizing enterocolitis.. · Reduction in NEC rate improves mortality.. · Human milk does not change SIP incidence..

Delay in achieving enteral autonomy and growth outcomes in very low birth weight infants with surgical necrotizing enterocolitis.

OBJECTIVE: To understand the nutritional intake and growth outcomes of very low birth weight infants with surgical necrotizing enterocolitis (NEC). STUDY DESIGN: In a retrospective cohort study, linear mixed models were used to compare growth outcomes from birth to 24 months corrected age for very low birth weight (VLBW) infants with surgical NEC to those with spontaneous intestinal perforation (SIP). Kaplan-Meier curves were developed to demonstrate the duration of parenteral nutrition (PN) use. RESULT: Height differed by surgical NEC and SIP over time (interaction p = 0.03). Surviving infants with surgical NEC had lower head circumference z-scores at 24 months. Of infants surviving surgical NEC, 71% received PN for >60 days after diagnosis. CONCLUSION: The majority of infants with surgical NEC have a delay in achieving enteral autonomy. There was a difference in linear catch-up growth over time between infants with SIP and surgical NEC at 24 months.

A child presents with perianal symptoms - how often is this Crohn's disease?

BACKGROUND: The cumulative incidence and predictors of future diagnosis of Crohn's disease (CD) following presentation with perianal symptoms, such as anorectal abscess, fistula or fissure, is unknown. METHODS: A 5-year retrospective review of children presenting with perianal symptoms without prior CD diagnosis was performed. Institutional cumulative incidence of CD was calculated to determine the risk of CD presenting with perianal symptoms. RESULTS: 1140 children presented for evaluation of an anorectal abscess (n = 232), fistula (n = 49), or fissure (n = 859). Thirty-five were later diagnosed with CD, resulting in an incidence of 3%. Prognostic indicators of future CD diagnosis included increased age per every additional year (RR 1.19, 95% CI: 1.14-1.25, p < 0.001), male sex (RR 2.12, 95% CI 1.07-4.22, p = 0.024), or perianal fistula (RR 4.67, 95% CI 2.26-9.67, p = 0.022). Among those diagnosed with CD, 57% experienced and had a documented history of a CD-associated symptom prior to perianal symptom onset. Absence of symptoms resulted in delayed diagnosis (43 vs 3 days, p < 0.02). CONCLUSION: Of children presenting with a perianal symptom, three percent will eventually be diagnosed with CD. At highest risk (35%) were males aged 10 years or older with a perianal fistula; which should prompt expeditious workup.

Natural Course of Pediatric Portal Hypertension.

The etiology of portal hypertension (pHTN) in children differs from that of adults and may require different management strategies. We set out to review the etiology, management, and natural history of pHTN at a pediatric liver center. From 2008 to 2018, 151 children and adolescents with pHTN were identified at a free-standing children's hospital. Patients were stratified by etiology of pHTN (intrahepatic disease [IH], defined as cholestatic disease and fibrotic or hepatocellular disease; extrahepatic disease [EH], defined as hepatic vein obstruction and prehepatic pHTN). Patients with EH were more likely to undergo an esophagoduodenscopy for a suspected gastrointestinal bleed (77% vs. 41%; P < 0.01). Surgical interventions differed based on etiology (P < 0.01), with IH more likely resulting in a transplant only (65%) and EH more likely to result in a shunt only (43%); 30% of patients with IH and 47% of patients with EH did not undergo an intervention for pHTN. Kaplan-Meier analysis revealed a significant increase in mortality in the group that received no intervention compared to shunt, transplant, or both and lower mortality in patients with prehepatic pHTN compared to other etiologies (P < 0.01 each). Multivariate analysis revealed increased odds of mortality in patients with refractory ascites (odds ratio [OR], 4.34; 95% confidence interval [CI], 1.00, 18.88; P = 0.05) and growth failure (OR, 13.49; 95% CI, 3.07, 58.99; P < 0.01). Conclusion: In this single institution study, patients with prehepatic pHTN had better survival and those who received no intervention had higher mortality than those who received an intervention. Early referral to specialized centers with experience managing these complex disease processes may allow for improved risk stratification and early intervention to improve outcomes.

Primary Placement of a Low-Profile Gastrostomy Button Is Safe and Associated With Improved Outcomes in Children.

BACKGROUND: This study evaluates tube-specific outcomes after primary placement of low-profile buttons (LPBs) compared with long gastrostomy tubes (LGTs). MATERIALS AND METHODS: All surgically placed gastrostomy tubes from 2015 to 2017 from a single institution were reviewed. Primary outcomes were tube dislodgement and tube-related readmissions within 30 d. Secondary outcomes were resource utilization and minor complications within 6 mo. RESULTS: 53% (n = 253) of patients received an LGT and 47% (n = 228) received an LPB. Groups were similar with regard to operative indication and approach, but LPB patients were slightly older (9 versus 6 mo, P = 0.02). Tube dislodgement occurred overall in 6% of patients, with 23% and 41% experiencing leakage and granulation tissue, respectively. LGT patients experienced higher rates of tube dislodgement (9% versus 3%, P = 0.006), but no difference in tube-related readmissions (P = 0.38). LGT patients were also more likely to visit the ER for a tube-related concern (43.9% versus 31.6%, P = 0.01) and report problems of leakage around the tube (27.7% versus 17.5%, P = 0.01). No difference was found for issues of peristomal granulation tissue or in tube-related readmissions. CONCLUSIONS: Primary placement of low-profile gastrostomy buttons is safe and demonstrated superior tube-related outcomes compared with LGTs.

Weight loss after sleeve gastrectomy in developmentally delayed adolescents and young adults.

BACKGROUND: Adolescent obesity is a significant factor in caring for patients with developmental delay (DD). Sleeve gastrectomy provides durable weight loss for teens with obesity but requires behavioral change that may not occur in patients with DD. OBJECTIVES: To determine whether patients with DD had similar weight loss and adverse outcomes to patients without a diagnosis of DD after sleeve gastrectomy. SETTING: Academic children's hospital, United States. METHODS: Patients with DD undergoing sleeve gastrectomy were matched to adolescents without DD. Chart review was performed to determine etiology and severity of DD, weight, and body mass index (BMI) change in each group at 3, 6, 9, and 12 months postoperatively. One-year emergency department visits, readmissions, and reoperations were reviewed. RESULTS: Ten patients with DD and 44 patients without DD underwent sleeve gastrectomy between 2008 and 2017. Six patients with DD (60%) had mild cognitive impairment, 3 patients (30%) had moderate cognitive impairment, and 1 patient (10%) had severe cognitive impairment. Patients were 81.5% female, had a mean age of 17.3 years, and had a preoperative BMI of 48.6 kg/m2. Preoperative BMI was similar in the 2 groups, and percent BMI reduction at 1 year was -29% (95% confidence interval: -35 to -23) and -26% (95% confidence interval: -29 to -23) in groups with and without DD respectively (group by time interaction, P = .27). CONCLUSION: Adolescents with DD experience similar 1-year weight loss and adverse events following sleeve gastrectomy to adolescents without DD. Understanding the long-term outcomes for this population is crucial to ensure appropriate implementation of surgical weight loss programs.

MIFEPRISTONE TREATMENT FOR MILD AUTONOMOUS CORTISOL SECRETION DUE TO ADRENAL ADENOMAS: A PILOT STUDY.

Objective: Adrenal incidentalomas are increasingly detected with the widespread use of thoracic and abdominal imaging. The most common secretory syndrome in adrenal nodules is autonomous cortisol secretion (ACS). Recent data show that even mild cortisol excess is associated with adverse outcomes. The glucocorticoid receptor antagonist mifepristone has been used in patients with overt Cushing syndrome and hyperglycemia. The purpose of our study was to determine the effect of mifepristone on metabolic parameters in patients with ACS and concomitant prediabetes or diabetes. Methods: Eight patients with either unilateral or bilateral adrenal nodules with ACS were included in the study. Fasting laboratory tests including glucose and insulin levels to calculate homeostatic model assessment for insulin resistance (HOMA-IR) were performed at baseline and again after either 3 months (3 patients) or 6 months (5 patients) on mifepristone 300 mg daily treatment. Patients also completed several validated surveys on mood and quality of life at baseline and follow-up. Results: There were significant reductions in fasting glucose measurements and insulin resistance as measured by HOMA-IR in the 6 of 8 study patients in whom these measurements were available (P = .03). Conclusion: This pilot study demonstrates that mifepristone treatment of ACS is associated with a significant decrease in fasting glucose and insulin resistance as measured by HOMA-IR scores. Mifepristone treatment of ACS may be considered as a medical option for patients with ACS due to adrenal adenomas with concomitant abnormal glucose parameters in whom surgical removal is not being considered. Abbreviations: ACS = autonomous cortisol secretion; ACTH = adrenocorticotropic hormone; AI = adrenal incidentaloma; DHEAS = dehydroepiandrosterone sulfate; GR = glucocorticoid receptor; HbA1c = hemoglobin A1c; HOMA-IR = homeostatic model assessment for insulin resistance; ODT = overnight dexamethasone suppression test; QoL = quality of life; STAI = state trait anxiety inventory; TSH = thyroid stimulating hormone; UFC = urinary free cortisol.

A comparison of surgical complications after appendicostomy and neoappendicostomy in pediatric patients.

PURPOSE: There are limited data on neoappendicostomy complications owing to small patient populations. This study compares appendicostomy and neoappendicostomy procedures with an emphasis on major postoperative complications requiring either a surgical or interventional radiology procedure. METHOD: A single-institution retrospective review included all patients with complete medical charts in the Cincinnati Children's Colorectal Database who underwent either an appendicostomy or neoappendicostomy from August 2005 through December 2016. Demographics, details of the procedure, and major postoperative complications were evaluated. RESULTS: 261 patients (appendicostomy n = 208, neoappendicostomy n = 53) with a median follow up time of 2.5 years resulted in 84 patients (appendicostomy n = 60, neoappendicostomy n = 24) experiencing a total of 118 complications requiring surgical or radiologic intervention with a significant difference between the groups (29% vs 45%, RR = 1.79 (95% CI: 1.24-2.60), p < 0.01). Skin level stricture was the most common complication (20% appendicostomies vs 30% neoappendicostomies, p = 0.13). CONCLUSIONS: Appendicostomies and neoappendicostomies can be an effective way to manage fecal incontinence; however, 32% of our patients experienced a complication that required either a surgical or interventional radiology procedure. Patients need to be informed of the possible complications that are associated with appendicostomy and neoappendicostomy construction. TYPE OF STUDY: Single institution retrospective review. LEVEL OF EVIDENCE: IV.

Host-Gut Microbiota Crosstalk in Intestinal Adaptation.

Short-bowel syndrome represents the most common cause of intestinal failure and occurs when the remaining intestine cannot support fluid and nutrient needs to sustain adequate physiology and development without the use of supplemental parenteral nutrition. After intestinal loss or damage, the remnant bowel undergoes multifactorial compensatory processes, termed adaptation, which are largely driven by intraluminal nutrient exposure. Previous studies have provided insight into the biological processes and mediators after resection, however, there still remains a gap in the knowledge of more comprehensive mechanisms that drive the adaptive responses in these patients. Recent data support the microbiota as a key mediator of gut homeostasis and a potential driver of metabolism and immunomodulation after intestinal loss. In this review, we summarize the emerging ideas related to host-microbiota interactions in the intestinal adaptation processes.

Adrenal mild hypercortisolism.

Adrenal incidentalomas have become detected more often as the use of abdominal imaging has increased. Up to one-third of these may be secreting low levels of cortisol, known as mild hypercortisolism or subclinical Cushing syndrome. These low levels of cortisol have been found to be associated with an increased in the metabolic syndrome, osteoporosis, cardiovascular events, and mortality. This article discusses in detail the epidemiology, diagnosis, clinical associations, and treatment options of mild hypercortisolism.