Severe Gastrointestinal Complications Research Articles

Tenascin-X deficiency causing classical-like Ehlers Danlos syndrome type 1 in humans is a significant risk factor for GI and tracheal ruptures.

Classical-like Ehlers Danlos Syndrome type 1 (clEDS1) is a very rare form of Ehlers Danlos Syndrome (EDS) caused by tenascin-X (TNX) deficiency, with only 56 individuals reported. TNX is an extracellular matrix protein needed for collagen stability. Previous publications propose that individuals with clEDS1 might be at risk for gastrointestinal (GI) tract perforations and/or tracheal ruptures. To characterize complications resulting from perforations of the GI tract and/or tracheal rupture in an international case series of individuals with clEDS1 due to disease-related tissue fragility. This case series includes individuals with confirmed clEDS1 and GI perforations and/or tracheal ruptures from participating centres. Researchers who previously reported such individuals were contacted for additional information. A retrospective assessment of clinical features was performed. Fifteen individuals were included. Ten had spontaneous GI perforations, seven of whom had multiple GI perforations. Almost all had severe diverticulosis. Three individuals experienced iatrogenic tracheal ruptures. Severe GI complications, such as perforation, and tracheal rupture were observed in a substantial number of individuals with clEDS1. As these features seem significantly more common in clEDS1 than in the average population, we advise vigilance during intubation and GI endoscopic interventions of individuals with clEDS1. Routine referrals to clinical geneticists are recommended for patients with symptoms indicative of clEDS1, especially with unexplained GI perforations and connective tissue symptoms. Our findings offer valuable insights for the clinical management of clEDS1 and underscore the importance of specialized care, providing a foundation for improved clinical guidelines and preventive strategies.

Comparison of clinical features of patients with or without severe gastrointestinal complications in aggressive gastrointestinal lymphomas.

Aggressive primary gastrointestinal non-Hodgkin lymphoma (PGINHL) is an uncommon and heterogeneous group of lymphoid malignancies, that differs from indolent lymphoma and has a high incidence of severe gastrointestinal complications (GICs). To investigate and compare the clinicopathological characteristics, treatments and outcomes in the GICs and No-GICs group with aggressive PGINHL. This retrospective analysis was performed on aggressive PGINHL patients between January 2013 and December 2021 at our hospital. The independent influence factors of GICs were obtained by univariate and multivariate Logistic regression analysis, the selected variables significantly related to GICs were selected as the final predictors to construct nomogram. Kaplan-Meier curves further analyzed the survival of patients in GICs and No-GICs groups. Survival analysis of GICs group was performed using Cox regression. We focused on 124 aggressive PGINHL cases, which had a relatively high incidence 48.4% (60/124 cases) of GICs, the most common histological type in GICs group was diffuse large B-cell lymphoma (DLBCL) (n = 49, 81.7%). In the GICs group, small intestine was the most common anatomic site of lesion (43.3%), followed by large intestine (31.7%), and then stomach and esophagus (25.0%). Multivariate Logistic regression analysis showed that the independent risk factors for GICs were the small intestine [odd ratio (OR) = 3.33; 95% confidence interval (CI): 1.47-9.41; P = 0.009), aggressive B-cell (OR = 0.09; 95%CI: 0.01-0.83; P = 0.033), maximum tumor diameter (OR = 1.25; 95%CI: 1.07-1.47; P = 0.005), invaded deep serous layer (OR = 3.38; 95%CI: 1.24-9.19; P = 0.017). We developed a nomogram to predict risk of GICs in aggressive PGINHL patients based on independent risk factors. The value of area under curve calculated by receiver operating characteristic curve was 0.815, and calibration curve and decision curve analysis further indicated that the prediction effect was superior. The majority of patients with GICs were given combination therapy (chemotherapy combined with surgery or radiation). Event-free survival and overall survival in GICs group were no worse than those in the No-GICs group. The complication rate of GICs in patients with aggressive PGINHL was relatively high, particularly in PGI-DLBCL. The independent risk factors for GICs were the small intestine, PGI-TNKL, bulky tumor, and depth of invasion. A combination treatment, involving surgery, improved survival in the GICs group.

Atomistic Insights into gp82 Binding: A Microsecond, Million-Atom Exploration of Trypanosoma cruzi Host-Cell Invasion.

Chagas disease, caused by the protozoan Trypanosoma cruzi , affects millions globally, leading to severe cardiac and gastrointestinal complications in its chronic phase. The invasion of host cells by T. cruzi is mediated by the interaction between the parasite's glycoprotein gp82 and the human receptor lysosome-associated membrane protein 2 (LAMP2). While experimental studies have identified a few residues involved in this interaction, a comprehensive molecular-level understanding has been lacking. In this study, we present a 1.44-million-atom computational model of the gp82 complex, including over 3,300 lipids, glycosylation sites, and full molecular representations of gp82 and LAMP2, making it the most complete model of a parasite-host interaction to date. Using microsecond-long molecular dynamics simulations and dynamic network analysis, we identified critical residue interactions, including novel regions of contact that were previously uncharacterized. Our findings also highlight the significance of the transmembrane domain of LAMP2 in stabilizing the complex. These insights extend beyond traditional hydrogen bond interactions, revealing a complex network of cooperative motions that facilitate T. cruzi invasion. This study not only confirms key experimental observations but also uncovers new molecular targets for therapeutic intervention, offering a potential pathway to disrupt T. cruzi infection and combat Chagas disease.

Necrotizing enterocolitis following spontaneous intestinal perforation in very low birth weight neonates.

Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are severe gastrointestinal complications of prematurity. The clinical presentation and treatment of NEC and SIP (peritoneal drain vs laparotomy) can overlap; however, the pathogenesis is distinct. Therefore, a patient initially treated for SIP can subsequently develop NEC. This phenomenon has only been described in case reports, and no risk factor evaluation exists. We evaluate clinical characteristics, risk factors, and outcomes of patients treated for a distinct episode of NEC after SIP. We performed a retrospective review of very low birth weight (<1500 g) neonates who presented with pneumoperitoneum between 07/2004 and 09/2022. Data was obtained from two separate neonatal intensive care units that were part of the same institution. Patients with an initial preoperative, intraoperative, or pathological diagnosis of NEC were excluded. Patients with an intraoperative diagnosis of SIP or preoperative diagnosis of SIP successfully treated with a peritoneal drain (PD) were evaluated. Patients subsequently treated (medically or surgically) for NEC after SIP were then compared to SIP-alone patients. Clinical characteristics included demographics, gestational age (GA), birth weight (BW), perinatal risk factors (chorioamnionitis, steroids, indomethacin), postoperative feeding regimen, and length of stay (LOS) were compared. Of the 278 patients included, 31 (11.2%) patients had NEC after SIP. There was no difference in GA (25 weeks vs 25 weeks, p = 0.933) or BW (760 g vs 735 g, p = 0.370) between NEC after SIP vs SIP alone cohorts, respectively. Twenty (64%) of NEC after-SIP patients were previously treated with LP. NEC after SIP occurred with a median onset of 56 days. Pneumatosis was the most frequent (81%) presenting symptom and 12 (39%) patients had hematochezia. Four (12.9%) patients required LP for NEC and all had NEC intraoperatively and on pathology. A majority (77.4%) of patients were on breast milk (BM) at time of NEC diagnosis. NEC after SIP patients had lower maternal age at delivery (29.0 vs 25.0, p = 0.055) and the incidence of NEC after LP (primary or failed drain) was higher than PD alone (16.7% vs 6.2%, p = 0.007). NEC after SIP patients had longer LOS (135 vs 81, p < 0.001). We report an 11.2% incidence of NEC at a median of 56 days following successful treatment of SIP, resulting in increased LOS. SIP patients are a high-risk cohort and protocols to prevent this phenomenon should be investigated.

Bifidobacterium and Lactobacillus Probiotics and Gut Dysbiosis in Preterm Infants

The effects of probiotic interventions on colonization with resistant bacteria and early microbiome development in preterm infants remain to be clarified. To examine the efficacy of Bifidobacterium longum subsp infantis, Bifidobacterium animalis subsp lactis (BB-12), and Lactobacillus acidophilus (La-5) probiotics to prevent colonization with multidrug-resistant organisms or highly epidemic bacteria (MDRO+) and to shape the microbiome of preterm infants toward the eubiotic state of healthy full-term infants. The multicenter, double-blinded, placebo-controlled, group sequential, phase 3 Priming Immunity at the Beginning of Life (PRIMAL) randomized clinical trial, conducted from April 2018 to June 2020, included infants with gestational age of 28 to 32 weeks at 18 German neonatal units. Data analyses were conducted from March 2020 to August 2023. A total of 28 days of multistrain probiotics diluted in human milk/formula starting within the first 72 hours of life. Colonization with MDRO+ at day 30 of life (primary end point), late-onset sepsis and severe gastrointestinal complication (safety end points), and gut dysbiosis, ie, deviations from the microbiome of healthy, term infants (eubiosis score) based on 16-subunit ribosomal RNA and metagenomic sequencing. Among the 643 infants randomized until the stop of recruitment based on interim results, 618 (median [IQR] gestational age, 31.0 [29.7-32.1] weeks; 333 male [53.9%]; mean [SD] birth weight, 1502 [369] g) had follow-up at day 30. The interim analysis with all available data from 219 infants revealed MDRO+ colonization in 43 of 115 infants (37.4%) in the probiotics group and in 39 of 104 infants (37.5%) in the control group (adjusted risk ratio, 0.99; 95% CI, 0.54-1.81; P = .97). Safety outcomes were similar in both groups, ie, late-onset sepsis (probiotics group: 8 of 316 infants [2.5%]; control group: 12 of 322 infants [3.7%]) and severe gastrointestinal complications (probiotics group: 6 of 316 infants [1.9%]; control group: 7 of 322 infants [2.2%]). The probiotics group had higher eubiosis scores than the control group at the genus level (254 vs 258 infants; median scores, 0.47 vs 0.41; odds ratio [OR], 1.07; 95% CI, 1.02-1.13) and species level (96 vs 83 infants; median scores, 0.87 vs 0.59; OR, 1.28; 95% CI, 1.19-1.38). Environmental uptake of the B infantis probiotic strain in the control group was common (41 of 84 [49%]), which was highly variable across sites and particularly occurred in infants with a sibling who was treated with probiotics. Multistrain probiotics did not reduce the incidence of MDRO+ colonization at day 30 of life in preterm infants but modulated their microbiome toward eubiosis. German Clinical Trials Register: DRKS00013197.

Mitochondrial neurogastrointestinal encephalopathy: a case report

BackgroundMitochondrial neurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive disease associated with alterations in mitochondrial DNA (mtDNA). The typical age of onset of MNGIE is between the first and second decade of life. Diagnosis requires the presence of several key clinical features: sensorimotor neuropathy, external ophthalmoplegia, ocular ptosis, leukoencephalopathy, and gastrointestinal (GI) dysmotility. Unfortunately, MNGIE diagnosis is very challenging, and patients often undergo multiple diagnostic and surgical operations that are unnecessary.Case presentationThis case is of a 51-year-old male presenting with a 2-year history of limb weakness, GI problems and cachexia. There was also a 1-year history of progressive ptosis and ophthalmoplegia. The patient’s uncle and brother had both died from GI-related issues prior to the age of 40. On physical examination, ocular motility was impaired in all directions and there was atrophy and reduction in power in both lower and upper extremities. FLAIR and T2-weighted sequences of brain MRI demonstrated diffuse cerebral white matter hyperintensity (leukoencephalopathy). On discharge, the patient was referred for genetic consultation for bone marrow transplantation and had regular follow-up with a gastroenterology specialist.ConclusionIn patients presenting with chronic progressive ophthalmoplegia, severe gastrointestinal complications, sensorimotor neuropathy and white matter lesions on MRI, it is important to consider investigating for MNGIE.

Recent Progress in Innate Immune Responses to Enterovirus A71 and Viral Evasion Strategies.

Enterovirus A71 (EV-A71) is a major pathogen causing hand, foot, and mouth disease (HFMD) in children worldwide. It can lead to severe gastrointestinal, pulmonary, and neurological complications. The innate immune system, which rapidly detects pathogens via pathogen-associated molecular patterns or pathogen-encoded effectors, serves as the first defensive line against EV-A71 infection. Concurrently, the virus has developed various sophisticated strategies to evade host antiviral responses and establish productive infection. Thus, the virus-host interactions and conflicts, as well as the ability to govern biological events at this first line of defense, contribute significantly to the pathogenesis and outcomes of EV-A71 infection. In this review, we update recent progress on host innate immune responses to EV-A71 infection. In addition, we discuss the underlying strategies employed by EV-A71 to escape host innate immune responses. A better understanding of the interplay between EV-A71 and host innate immunity may unravel potential antiviral targets, as well as strategies that can improve patient outcomes.

Severe Gastrointestinal Complications After IVIG Infusion in Newborns: A Two-Center Study and Literature Review

Background: There are several studies regarding perforations after intravenous immunoglobulin (IVIG) infusion; however, the risk factors are not defined yet. Objectives: The present study aimed to investigate gastrointestinal complications in newborns regarding the reported immunoglobulin A (IgA) levels in IVIG preparations. Methods: This retrospective chart review was conducted on term newborns who received IVIG therapy in two centers in Istanbul. The study included patients with IVIG-associated gastrointestinal bleedings, necrotizing enterocolitis (NEC), and intra-abdominal perforations without any underlying diseases and recorded demographic data (gestational age, birth weight, and gender) and the IgA levels in the IVIG preparations. Infants born below 35 gestational weeks were excluded as they were more likely to have NEC. Results: A total of 71 patients received IVIG therapy, and 15.5% (n = 11) developed major gastrointestinal system (GIS) complications. A total of 36 patients were born ≥ 35 gestational weeks, and gastrointestinal perforation or bleeding occurred in 22.2% (n = 8) of these patients. Two patients died before surgery due to aggressive disease progression. None of these patients had any gastrointestinal symptoms before IVIG therapy or any predisposing factors for gastrointestinal perforation. All patients were on spontaneous breathing and enteral feeding without intolerance. The IgA level content of the IVIG preparations was related to the major GIS complications with strong evidence, and the safe threshold resulted in 14 mg/dL in receiver operating characteristic (ROC) analysis in the present study group. Conclusions: Higher IgA levels in IVIG preparations might be a risk factor for gastrointestinal perforation and bleeding in term newborns. Clinicians should be aware of this potential complication when using IVIG therapy in term newborns and closely monitor for signs and symptoms of major gastrointestinal complications.

Human Milk Supports Robust Intestinal Organoid Growth, Differentiation, and Homeostatic Cytokine Production

Background and AimsNecrotizing enterocolitis (NEC) is a severe gastrointestinal complication of prematurity. Using small intestinal organoids derived from fetal tissue of a gestational age similar to an extremely preterm infant, this study aims to assess the effect of diet on intestinal epithelial growth and differentiation to elucidate the role nutrition type plays in intestinal development and modifies the risk for NEC. MethodsOrganoids were cultured for 5 days in growth media and 5 days in differentiation media supplemented 1:40 with four different diets: parental milk (PM), donor human milk (DHM), standard formula, or extensively hydrolyzed formula. Images were captured daily and organoids were quantified. Organoids were preserved for RNA sequencing and immunofluorescence staining with Ki67, cleaved caspase 3, and chromogranin-A. Media was saved for cytokine/chemokine and growth factor analysis. ResultsHuman milk supplementation improved growth and differentiation of intestinal organoids generating larger organoids during the growth phase and organoids with longer and wider buds during differentiation compared to formula. Ki67 staining confirmed the proliferative nature of milk-supplemented organoids and chromogranin A staining proved that MM-supplemented organoids induced highest enteroendocrine differentiation. Human milk supplementation also upregulated genes involved in Wnt signaling and fatty acid metabolism pathways and promoted a homeostatic immune landscape, including via increased secretion of TNF-related apoptosis inducing ligand (TRAIL) among other cytokines. Conversely, organoids supplemented with formula had a downregulation of cell-cycle-promoting genes and a more inflammatory immune signature, including a reduced levels of leukemia inhibitory factor (LIF). ConclusionsOur results demonstrate that PM, and to a lesser extent DHM, support robust intestinal epithelial proliferation, differentiation, and homeostatic cytokine production, suggesting a critical role for factors enriched in human milk in intestinal epithelial health.

High-dimensional mass cytometry reveals systemic and local immune signatures in necrotizing enterocolitis.

Patients with necrotizing enterocolitis display severe gastrointestinal complications of prematurity, but the mechanism driving this clinical profile remains unknown. We used mass cytometry time-of-flight to characterize and compare immune cell populations in the blood and intestine tissue from patients with and without (controls) necrotizing enterocolitis at single-cell resolution. We completed a deep mapping of the immune system of the peripheral blood mononuclear cells and intestinal mucosa tissue using mass cytometry to evaluate immune cell types, which revealed global immune dysregulation characteristics underlying necrotizing enterocolitis. Compared with controls, natural killer cells display signs of heightened activation and increased cytotoxic potential in the peripheral blood and mucosa of patients with necrotizing enterocolitis. Furthermore, CD4+ T effector memory cells, non-classical monocytes, active dendritic cells, and neutrophils were specifically enriched in the mucosa, suggesting trafficking from the periphery to areas of inflammation. Moreover, we mapped the systemic and local distinct immune signatures suggesting patterns of cell localization in necrotizing enterocolitis. We used mass cytometry time-of-flight technology to identify immune cell populations specific to the peripheral blood and intestinal mucosa tissue from patients with necrotizing enterocolitis and controls. This information might be used to develop precise diagnosis and therapies that target specific cell populations in patients with necrotizing enterocolitis.

Intermittent feeding with an overnight fast versus 24-h feeding in critically ill neonates, infants, and children: An open-label, single-centre, randomised controlled trial

Critically ill children are fed day and night, assuming this improves enteral tolerance and the probability of achieving nutritional goals. It was previously shown that a fasting response, reflected by increased ketosis, at least partly explained the beneficial outcome of delayed initiation of supplemental parenteral nutrition. This study aims to investigate whether an overnight fast increases ketosis and is feasible and safe in critically ill children. The Continuousversus Intermittent Nutrition in Paediatric Intensive Care (ContInNuPIC) study is a randomised controlled trial in a tertiary referral Paediatric Intensive Care Unit (PICU) in the Netherlands. Critically ill children (term newborn-18 years) with an expected PICU stay ≥48h, dependent on artificial nutrition, were eligible. Participants were randomly assigned (1:1, stratified for age group) to intermittent feeding, with interruption of feedings during an age-dependent overnight period of eight to 12h, or to continuous feeding, with the administration of feedings day and night. In both groups, similar daily caloric targets were pursued. For children younger than one year, mandatory minor glucose infusions were provided during fasting. The primary outcome was the feasibility, defined as two conditions (1): a significant difference in the patients' highest daily ketone (3-β-hydroxybutyrate, BHB) levels during each overnight period, and (2): non-inferiority regarding daily caloric intake, examined using a two-part mixed-effects model with a predefined non-inferiority margin of 33%, in an intention-to-treat analysis. The study is registered in the Netherlands Trial Register (NL7877). Between May 19, 2020, and July 13, 2022, 140 critically ill children, median (first quartile; third quartile) age 0.3 (0.1; 2.7) years, were randomised to intermittent (n=67) or continuous feeding (n=73). In the intermittent feeding group, BHB levels were significantly higher (median 0.4 (0.2; 1.0) vs. 0.3 (0.1; 0.7) mmol/L, p<0.001). The ratio of total caloric intake in the intermittent feeding group to the intake in the continuous feeding group was not consistently significantly more than 0.67, thus not proving non-inferiority. No severe, resistant hypoglycaemic events, nor severe gastrointestinal complications related to the intervention occurred, and feeding intolerance did not occur more often in the intermittent than in the continuous feeding group. Compared with day and night feeding, intermittent feeding with an overnight fast and mandatory glucose infusion for children younger than one year marginally increased ketosis and did not lead to more hypoglycaemic incidents in critically ill children. Because non-inferiority regarding daily caloric intake was not proven, the feasibility of an overnight fast could not be shown in the current study. However, as feeding intolerance did not increase during the condensed feeding periods, the nutritional intake was probably limited by the prescription of nutrition and interruptions. More research is needed to determine the optimal level and duration of clinically relevant ketosis and the best method to achieve this.

Clinical features, treatment and outcome of pediatric patients with severe cutaneous manifestations in IgA vasculitis: Multicenter international study

ObjectiveIgA vasculitis (IgAV) (formerly Henoch-Schönlein Purpura, HSP) rarely causes severe skin lesions in children. The purpose of the research was to determine whether severe skin manifestations were associated with a more severe disease course. MethodsSevere cutaneous manifestations were defined as presence of hemorrhagic vesicles, bullae, ulcerations and/or necroses. Data were collected retrospectively from 12 international tertiary university medical centers. ResultsA total of 64 patients with the most severe skin changes in IgAV/HSP and median (Q1, Q3) age of 8.08 (5.08, 11.92) years at the disease onset were compared with 596 IgAV/HSP patients without these manfiestations and median (Q1, Q3) age of 6.33 (4.50, 8.92) years. The patients with severe cutaneous manifestations were older in comparison to other patients with IgAV/HSP (p<0.001), they developed nephritis more frequently (40.6% vs. 20.6%, p = 0.001) with worse outcome of renal disease (p = 0.001). This group of patients also had higher frequencies of severe gastrointestinal complications like hematochezia, massive bleeding and/or intussusception (29.3% vs. 14.8%, p<0.001). d-dimer concentrations were significantly higher in these patients (4.60 mg/L vs. 2.72 mg/L, p = 0.003) and they had more frequent need for treatment with systemic glucocorticoids (84.4% vs. 37.2%, p<0.001) in comparison with the control group. Further multivariate analysis showed that severe cutaneous changes were associated with higher risk of developing nephritis [OR=3.1 (95%CI 1.04–9.21), p = 0.042] and severe gastrointestinal complications [OR=3.65 (95%CI 1.08–12.37), p = 0.038]. ConclusionPatients with IgAV/HSP and severe skin manifestations had a more severe clinical course and more frequently required glucocorticoids compared to classic IgAV/HSP patients.

Evaluation of gastrointestinal complications in Egyptian patients after autologous stem cell transplantation using melphalan-based regimens

BackgroundAutologous stem cell transplantation (ASCT) is a curative treatment for patients with hematological malignancies. Melphalan either alone or in combination with other chemotherapeutic agents is a widely used pre-transplant conditioning regimen with known gastrointestinal (GI) complications. We retrospectively evaluate the incidence and severity of GI toxicities, the possible risk factors, and their impact on transplant outcomes in 47 patients who received ASCT using melphalan-based conditioning.ResultsMedian age was 50 years. Among our patients, 48.9% received melphalan at 200 mg/m2. Mucositis was developed in 93.6% of patients, nausea in 87.2% and grade 2 vomiting in 36.2% of patients. Grade 3 diarrhea was detected in 42.6%. Severe GI toxicities were associated with significantly delayed engraftment, longer hospital stay, and increased transfusion requirements but overall survival (OS) and transplant-related mortality (TRM) were not affected by the severity of GI symptoms.ConclusionDespite using prophylactic and supportive care, some patients developed severe GI complications following different doses of melphalan with a negative effect on some transplant outcomes. Melphalan dose or disease type was not identified as a risk factor for severe GI toxicity. Additional larger prospective studies with higher doses, different formulations, and better prophylactic measures are warranted to evaluate potential risk factors and their impact on GI toxicities.

Prognosis and complications of patients with primary gastrointestinal diffuse large B-cell lymphoma: Development and validation of the systemic inflammation response index-covered score.

This study aimed to evaluate the predictive value of systemic inflammation response index (SIRI) in primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) patients and establish a highly discriminating risk prediction model. This retrospective analysis included 153 PGI-DCBCL patients diagnosed between 2011 and 2021. These patients were divided into a training set (n=102) and a validation set (n=51). Univariate and multivariate Cox regression analyses were conducted to examine the significance of variables on overall survival (OS) and progression-free survival (PFS). An inflammation-covered score system was established according to the multivariate results. The presence of high pretreatment SIRI (≥1.34, p < 0.001) was significantly associated with poorer survival and identified as an independent prognostic factor. Compared with NCCN-IPI, the prognostic and discriminatory capability of the novel model SIRI-PI showed a more precise high-risk assessment with ahigher area under the curve (AUC) (0.916 vs 0.835) and C-index (0.912 vs 0.836) for OS in the training cohort, and similar results were obtained in the validation cohort. Moreover, SIRI-PI also showed good discriminative power for efficacy assessment. This new model identified patients at risk of developing severe gastrointestinal complications following chemotherapy. The results of this analysis suggested that the pretreatment SIRI may be a potential candidate for identifying patients with apoor prognosis. And we established and validated a better-performing clinical model, which facilitated the prognostic stratification of PGI-DLBCL patients and can serve as a reference for clinical decision-making.

Single cell analysis via mass cytometry of spontaneous intestinal perforation reveals alterations in small intestinal innate and adaptive mucosal immunity.

Spontaneous intestinal perforation (SIP) is a poorly understood severe gastrointestinal complications of prematurity which is poorly understood. Extremely premature infants born prior to 28 weeks' gestation develop a localized perforation of the terminal ileum during the first week of life and therapy involves surgery and cessation of enteral feeds. Little is known regardj g the impact of mucosal immune dysfunction on disease pathogenesis. We performed mass cytometry time of flight (CyTOF) of small intestinal mucosa of patients with SIP (Gestational age (GA) 24 - 27 weeks, n=8) compared to patients who had surgery for non-SIP conditions (neonatal (GA >36 weeks, n=5 ) and fetal intestine from elective terminations (GA 18-21 weeks, n=4). CyTOF analysis after stimulation of T cells with PMA/Ionomycin was also performed. We noted changes in innate and adaptive mucosal immunity in SIP. SIP mucosa had an expansion of ckit+ neutrophils, an influx of naïve CD4 and CD8 T cells and a reduction of effector memory T cells. SIP T cells were characterized by reduced CCR6 and CXCR3 expression and increased interferon gamma expression after stimulation. These findings suggest that previously unrecognized immune dysregulation is associated with SIP and should be explored in future studies.

P677 Combination of vedolizumab and exclusive enteral nutrition in patients with moderate to severe Crohn’s Disease

Abstract Background Crohn’s disease (CD) is an incurable chronic inflammatory condition of the gut. It causes severe gastrointestinal and extraintestinal complications and is associated with high morbidity, poor quality of life and increased health expenditure. Although increasing randomized controlled tests (RCT) studies demonstrated the premise of efficacy of biologics including vedolizumab in adult patients with active CD, there’re still 60% of patients hard to achieve clinical and endoscopic remission in real-world studies. Here, we investigated the efficacy of combination strategy of vedolizumab and exclusive enteral nutrition (EEN) in moderate to severe active CD treatment. Methods Twenty-eight patients with moderately to severely active CD patients treated with vedolizumab in IBD medical center of Renmin Hospital of Wuhan University in Hubei Province were retrospectively enrolled in this cohort. All patients received EEN for 16 weeks with concomitant vedolizumab standard induction. The clinical response, clinical remission, and fecal calprotectin (FC) normalization was evaluated in short- (week 16) and moderate-term (week 32 and 48). Endoscopic response and mucosal healing were assessed at week 16 and 48 (Figure 1). Figure 1: Study design Results Following vedolizumab intravenous induction and 16-weeks EEN treatment, patients achieved 71.4% (20/28) of clinical remission, 73.1% (19/26) of endoscopic response and 71.4% (20/28) FC normalization at week 16. For moderate-term assessment at week 32, sustainable efficacy of current treatment induced 19/24 (79.2%) of clinical response, 15/24 (62.5%) of clinical remission and 16/24 (66.7%) of FC normalization. Clinical response (15/22, 68.2%) and mucosa healing (14/22, 63.6%) were also observed in over 60% of patients at week 48 since treatment induction (Figure 2,3). Figure 2. Clinical and biochemical endpoints Figure 3. Endoscopic endpoint Conclusion Combination of Vedolizumab and 16-weeks EEN increased clinical and endoscopic outcomes in short and moderate term for patients with moderate to severe Crohn’s Disease.

Severe Gastro-Intestinal Complications of Radiation Therapy in Rectal Cancer: Modeling the Influence of Age Based upon Population Level Data

<h3>Purpose/Objective(s)</h3> Gastro-intestinal (GI) side effects are dose limiting for pelvic & abdominal radiation therapy (RT). Advanced-age is hypothesized to be an aggravating factor in severe radiation toxicity, but this has not been well defined. We sought to quantify the effect of age on grade IV / V gastro-intestinal complications of RT by combining information from two US population-based databases. <h3>Materials/Methods</h3> The absolute number of complications was obtained by querying the National Inpatient Database (NIS) of the Healthcare Cost and Utilization Project, which contains discharge data from a 20% stratified sample of all US non-federal hospitals. Inclusion criteria were inpatient episodes between 2015-18, with listed diagnoses of both ‘Malignant neoplasm of rectum' (ICD-10-CM Code C20), and ‘Gastroenteritis and colitis due to radiation' (ICD-10-CM Code K52.0). A grade IV complication was defined as a hospitalization, alive on discharge; whereas grade V was defined as a hospitalization culminating in death. The relative age-distribution of patients with rectal cancer treated with RT was obtained from the SEER database. Relative toxicity incidence by age group was obtained by normalizing the absolute number of toxic events obtained from NIS with the age-distribution treatment data from SEER. Statistical techniques included best-fit linear regression and multivariate logistic regression. <h3>Results</h3> Within the NIS database there were 31,878 hospitalizations with a listed diagnosis of rectal cancer (median age 63 years), of whom 290 had grade IV (median age 66) and 10 grade V (median age 76.5) radiation gastroenteritis / colitis. There were no grade 4 toxicities under the age of 20, and no grade 5 toxicities under the age of 70. After adjusting for the baseline age distribution of rectal cancer patients receiving radiation derived from SEER data, the relative risk (RR) of grade IV toxicity was 0.44 for subjects aged 20-39, and 0.53 for subjects aged 40-59 and 1.0 for 60-79 (the comparator). The RR for grade V toxicity was zero for <60, 1.0 for 60-79 (the comparator), and 1.26 for subjects aged 80-99. Best-fit linear regression line for grade IV toxicity was defined by [0.0084* age(yrs)* + 0.2], and for grade V toxicity by [0.024* age(yrs)* - 0.87]. On multivariate logistic regression, amongst all those with grade 4-5 radiation gastroenteritis / colitis, age was the only clinical predictor of death (dosimetric factors were not available). <h3>Conclusion</h3> We demonstrate that the risk of acute severe radiation-induced bowel toxicity in rectal cancer patients rises linearly with age. Modelling demonstrates that the gradient is far steeper for grade V toxicity than grade IV toxicity. Importantly, our results facilitate the incorporated of age into existing NTCP models of bowel toxicity. Age-adjusted radiation dose constraints for the bowel should be adopted.

Continuous Versus Intermittent Nutrition in Pediatric Intensive Care Patients: Protocol for a Randomized Controlled Trial.

BackgroundIntermittent fasting is a time-restricted feeding strategy with proven health benefits, which is based on multiple metabolic and endocrine changes, in several patient populations and healthy participants. In the pediatric intensive care unit (PICU), artificial feeding is usually administered 24 hours a day, although solid evidence supporting this practice is lacking. This discards the potential benefits of fasting in this population. We hypothesize that intermittent nutrition with a focus on an overnight feeding interruption (intermittent fasting), as compared with 24-hour continuous nutrition, is a feasible and safe strategy, with potential benefits, for critically ill children.ObjectiveThe aim of the Continuous versus Intermittent Nutrition in Pediatric Intensive Care randomized controlled trial (RCT) is to investigate a strategy of intermittent nutrition with a focus on an overnight feeding interruption period versus 24-hour nutrition during the first 14 days in the PICU.MethodsThe Continuous versus Intermittent Nutrition in Pediatric Intensive Care study is an investigator-initiated RCT in a tertiary referral PICU. Critically ill children (term newborn to 18 years), expected to stay in the PICU for ≥48 hours, and dependent on artificial nutrition, are eligible for inclusion. This study will randomize critically ill children (n=140) to a continuous versus intermittent nutrition strategy. In both groups, similar daily caloric targets will be prescribed. In the continuous group (control), nutrition will be administered 24 hours a day, with a maximum interruption period of 2 hours. In the intermittent group (intervention), nutrition will be interrupted during an age-dependent overnight fasting period. The study intervention will last until admission day 14, initiation of oral intake, or discharge from the PICU, whichever comes first. The primary outcome is the difference in ketosis between the groups under the condition of noninferiority regarding caloric intake. Secondary outcomes are feeding intolerance; the proportion of severe and resistant hypoglycemic events and severe gastrointestinal complications; and additional observed effects on nutritional intake, circadian rhythm, and clinically relevant outcome measures of the intermittent feeding strategy compared with continuous nutrition.ResultsThe study was approved by the Dutch national ethical review board in February 2020. The first patient was enrolled on May 19, 2020. By May 2022, a total of 132 patients had been included in the study. Recruitment of the last patient is expected in Q3 2022.ConclusionsAlthough intermittent fasting has been proven to have many health benefits in both animal and human studies, the feasibility and safety of this strategy in a PICU setting must be investigated. This RCT will help physicians gain more insight into the feasibility, safety, and potential clinical effects of intermittent feeding with overnight fasting in critically ill children.Trial RegistrationNetherlands Trial Register NL7877; https://trialsearch.who.int/Trial2.aspx?TrialID=NL7877International Registered Report Identifier (IRRID)DERR1-10.2196/36229

Development of the Gastrointestinal Tract in Newborns as a Challenge for an Appropriate Nutrition: A Narrative Review.

The second and third trimesters of pregnancy are crucial for the anatomical and functional development of the gastrointestinal (GI) tract. If premature birth occurs, the immaturity of the digestive and absorptive processes and of GI motility represent a critical challenge to meet adequate nutritional needs, leading to poor extrauterine growth and to other critical complications. Knowledge of the main developmental stages of the processes involved in the digestion and absorption of proteins, carbohydrates, and lipids, as well as of the maturational phases underlying the development of GI motility, may aid clinicians to optimize the nutritional management of preterm infants. The immaturity of these GI systems and functions may negatively influence the patterns of gut colonization, predisposing to an abnormal microbiome. This, in turn, further contributes to alter the functional, immune, and neural development of the GI tract and, especially in preterm infants, has been associated with an increased risk of severe GI complications, such as necrotizing enterocolitis. Deeper understanding of the physiological colonization patterns in term and preterm infants may support the promotion of these patterns and the avoidance of microbial perturbations associated with the development of several diseases throughout life. This review aims to provide a global overview on the maturational features of the main GI functions and on their implications following preterm birth. We will particularly focus on the developmental differences in intestinal digestion and absorption functionality, motility, gut–brain axis interaction, and microbiomes.

Relationship Between Gastrointestinal Transit, Medsger Gastrointestinal Severity, and University of California-Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 Symptoms in Patients With Systemic Sclerosis.

Systemic sclerosis (SSc)-associated gastrointestinal (GI) complications are attributed to a variety of factors, including diet, microbiota dysbiosis, or GI transit abnormalities. Our objective was to examine the contribution of abnormal GI transit to SSc Medsger GI severity scores and/or University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA GIT) 2.0 symptoms. Patients with SSc and GI symptoms (n = 71) and healthy controls (n = 18) underwent whole gut transit (WGT) scintigraphy to assess transit from the esophagus to the colon. The presence of delayed transit and percent emptying in each GI region were measured. We compared the WGT measurements between categories of the Medsger GI severity score (0-4) and across UCLA GIT 2.0 domains and total score (0-3). A total of 88% of patients had >1 abnormal region of the gut on WGT scintigraphy. All patients requiring total parenteral nutrition had delayed small bowel transit, compared to only approximately 11% of patients in other Medsger GI severity groups (P ≤ 0.01). Severe colonic transit delays were more likely in patients with Medsger GI scores of 3 (pseudo-obstruction and/or malabsorption) compared to other Medsger GI groups (P = 0.02). Seventy-percent of these patients had ≤30% colonic emptying at 72 hours. Modest associations were noted between gastroesophageal reflux disease symptoms and delayed esophageal (r = -0.31, P = 0.05) and gastric emptying (r = -0.32, P = 0.05). These data are important in providing evidence that SSc bowel disease affects transit of GI content and that delay in transit accounts in part for both bowel symptoms and Medsger GI severity. Prospective studies examining the benefit of early therapeutic intervention targeting GI transit abnormalities in patients at high risk for severe GI complications are needed.