Assessment of long-term quality of life, bowel and voiding function outcomes in patients with anorectal malformation at a single UK centre.

AIMS: Assess long-term quality of life (QoL), bowel and voiding function in anorectal malformation (ARM) paediatric patients. METHOD: Retrospective review of ARM patients between 2007 and 2020 was performed. QoL (all patients), bowel and voiding function (> 5 yo) were assessed using the paediatric quality of life inventory (PedsQL), paediatric incontinence and constipation score (PICS) and dysfunctional voiding scoring system (DVSS), respectively. RESULTS: There were 122 patients (49% female, 85 > 5 yo) with ARM. Two had died, four refused, twenty-two were non-contactable, leaving ninety-four patients (65 > 5 yo) included. Mean age was 89 months (19-183), and follow-up was 86 months (13-183). Patients had significantly poorer scores for QoL, bowel and voiding function compared to published healthy controls. 57% had poor bowel function, 32% had poor voiding function and 38% required 'ancillary aids' to facilitate function. Patients using 'ancillary aids' for voiding function had a significantly lower QoL (parent: 62 vs 77; p = 0.01, patient: 66 vs 79; p = 0.05). Bowel continence was worse in those with high vs low ARM (13 vs 20, p = 0.004) and timely vs delayed diagnosis (17 vs 24, p = 0.04). CONCLUSION: Patients with ARM have significantly worse QoL, bowel and voiding function than normal healthy controls. There is a need for long-term monitoring of function and further support for these children. LEVEL OF EVIDENCE: III.

Regulation Mechanism and Potential Value of Active Substances in Spices in Alcohol-Liver-Intestine Axis Health.

Excessive alcohol intake will aggravate the health risk between the liver and intestine and affect the multi-directional information exchange of metabolites between host cells and microbial communities. Because of the side effects of clinical drugs, people tend to explore the intervention value of natural drugs on diseases. As a flavor substance, spices have been proven to have medicinal value, but they are still rare in treating hepatointestinal diseases caused by alcohol. This paper summarized the metabolic transformation of alcohol in the liver and intestine and summarized the potential value of various perfume active substances in improving liver and intestine diseases caused by alcohol. It is also found that bioactive substances in spices can exert antioxidant activity in the liver and intestine environment and reduce the oxidative stress caused by diseases. These substances can interfere with fatty acid synthesis, promote sugar and lipid metabolism, and reduce liver injury caused by steatosis. They can effectively regulate the balance of intestinal flora, promote the production of SCFAs, and restore the intestinal microenvironment.

A generic pump-free organ-on-a-chip platform for assessment of intestinal drug absorption.

Organ-on-a-chip technology has shown great potential in disease modeling and drug evaluation. However, traditional organ-on-a-chip devices are mostly pump-dependent with low throughput, which makes it difficult to leverage their advantages. In this study, we have developed a generic, pump-free organ-on-a-chip platform consisting of a 32-unit chip and an adjustable rocker, facilitating high-throughput dynamic cell culture with straightforward operation. By utilizing the rocker to induce periodic fluid forces, we can achieve fluidic conditions similar to those obtained with traditional pump-based systems. Through constructing a gut-on-a-chip model, we observed remarkable enhancements in the expression of barrier-associated proteins and the spatial distribution of differentiated intestinal cells compared to static culture. Furthermore, RNA sequencing analysis unveiled enriched pathways associated with cell proliferation, lipid transport, and drug metabolism, indicating the ability of the platform to mimic critical physiological processes. Additionally, we tested seven drugs that represent a range of high, medium, and low in vivo permeability using this model and found a strong correlation between their Papp values and human Fa, demonstrating the capability of this model for drug absorption evaluation. Our findings highlight the potential of this pump-free organ-on-a-chip platform as a valuable tool for advancing drug development and enabling personalized medicine.

In vitro assessment of the bacterial stress response and resistance evolution during multidrug-resistant bacterial invasion of the Xenopus tropicalis intestinal tract under typical stresses.

The intestinal microbiome might be both a sink and source of resistance genes (RGs). To investigate the impact of environmental stress on the disturbance of exogenous multidrug-resistant bacteria (mARB) within the indigenous microbiome and proliferation of RGs, an intestinal conjugative system was established to simulate the invasion of mARB into the intestinal microbiota in vitro. Oxytetracycline (OTC) and heavy metals (Zn, Cu, Pb), commonly encountered in aquaculture, were selected as typical stresses for investigation. Adenosine 5'-triphosphate (ATP), hydroxyl radical (OH·-) and extracellular polymeric substance (EPS) were measured to investigate their influence on the acceptance of RGs by intestinal bacteria. The results showed that the transfer and diffusion of RGs under typical combined stressors were greater than those under a single stressor. Combined effect of OTC and heavy metals (Zn, Cu) significantly increased the activity and extracellular EPS content of bacteria in the intestinal conjugative system, increasing intI3 and RG abundance. OTC induced a notable inhibitory response in Citrobacter and exerted the proportion of Citrobacter and Carnobacterium in microbiota. The introduction of stressors stimulates the proliferation and dissemination of RGs within the intestinal environment. These results enhance our comprehension of the typical stresses effect on the RGs dispersal in the intestine.

Impact of Bowel Coverage and Resuscitation Protocol on Gastroschisis Mortality in Low-Income Countries: Experience and Lessons From Uganda.

BACKGROUND: Gastroschisis causes near complete mortality in low-income countries (LICs). This study seeks to understand the impact of bedside bowel reduction and silo placement, and protocolized resuscitation on gastroschisis outcomes in LICs. METHODS: We conducted a retrospective cohort study of gastroschisis patients at a tertiary referral center in Kampala, Uganda. Multiple approaches for bedside application of bowel coverage devices and delayed closure were used: sutured urine bags (2017-2018), improvised silos using wound protectors (2020-2021), and spring-loaded silos (2022). Total parental nutrition (TPN) was not available; however, with the use of improvised silos, a protocol was implemented to include protocolized resuscitation and early enteral feeding. Risk ratios (RR) for mortality were calculated in comparison to historic controls from 2014. RESULTS: 368 patients were included: 42 historic controls, 7 primary closures, 81 sutured urine bags, 133 improvised silos and 105 spring-loaded silos. No differences were found in sex (p = 0.31), days to presentation (p = 0.84), and distance traveled to the tertiary hospital (p = 0.16). Following the introduction of bowel coverage methods, the proportion of infants that survived to discharge increased from 2% to 16-29%. In comparison to historic controls, the risk of mortality significantly decreased: sutured urine bags 0.65 (95%CI: 0.52-0.80), improvised silo 0.76 (0.66-0.87), and spring-loaded silo 0.65 (0.56-0.76). CONCLUSION: Bedside application of bowel coverage and protocolization decreases the risk of death for infants with gastroschisis, even in the absence of TPN. Further efforts to expand supply of low-cost silos in LICs would significantly decrease the mortality associated with gastroschisis in this setting. TYPE OF STUDY: Treatment Study. LEVEL OF EVIDENCE: III (Retrospective Comparative Study).

Toxicity assessment of organophosphate flame retardant triphenyl phosphate (TPHP) on intestines in mice.

Triphenyl phosphate (TPHP), one widely used organophosphate flame retardant, has attracted accumulating attention due to its high detection rate in human biological samples. Up to date, the effects of TPHP exposure on intestinal health remain unexplored. In this study, BALB/c mice were used as a model and exposed to TPHP at dose of 2, 10, or 50 mg/kg body weight for 28 days. We observed Crohn's disease-like features in ileum and ulcerative colitis disease-like features in colon, such as shorter colon length, ileum/colon structure impairment, intestinal epithelial cell apoptosis, enrichment of proinflammatory cytokines and immune cells, and disruption of tight junction. Furthermore, we found that TPHP induced production of reactive oxygen species and apoptosis in intestinal epithelial Caco-2 cells, accompanied by disruption of tight junction between cells. To understand the molecular mechanism underlying TPHP-induced changes in intestines, we build the adverse outcome pathway (AOP) framework based on Comparative Toxicogenomics and GeneCards database. The AOP framework revealed that PI3K/AKT and FoxO signaling pathway might be associated with cellular apoptosis, an increase in ROS production, and increased inflammation response in mouse ileum and colon tissues challenged with TPHP. These results identified that TPHP induced IBD-like features and provided new perspectives for toxicity evaluation of TPHP.

Evaluation of an in vitro experimental platform of human polarized intestinal epithelial monolayers for the hazard assessment of insecticidal proteins.

Previous work demonstrated the utility of using human-derived intestinal epithelial cell (IEC) lines cultured as polarized monolayers on Transwell® filters to differentiate between hazardous and non-hazardous proteins. The current study seeks to further resolve appropriate concentrations for evaluating proteins of unknown hazard potential using the IEC experimental platform and leverages these parameters for evaluating the potential toxicity of insecticidal proteins characteristic of those expressed in genetically modified (GM) agricultural biotechnology crops. To establish optimal test protein concentrations, effects of several known hazardous (C. perfringens epsilon toxin, Listeriolysin O, Phaseolus vulgaris erythroagglutinin, E. coli Shiga toxin 1, C. difficile Toxin B and wheat germ agglutinin) and non-hazardous (Ara-h2, ß-lactoglobulin, fibronectin and Rubisco) proteins on IEC barrier integrity and cell viability were evaluated at concentration ranges. Two insecticidal proteins (AfIP-1A and AfIP-1B) were evaluated for effects in the IEC assay, a seven-day insecticidal bioassay, and assessed in a high-dose 14-day acute oral toxicity study in mice. The results obtained from the human in vitro IEC assay were consistent with results obtained from an in vivo acute oral toxicity study, both demonstrating that the combination of AfIP-1A and AfIP-1B do not exhibit any identifiable harmful impacts on mammalian cells.

Improving Bowel Function Recovery and Quality of Life in Han Chinese Patients with Spinal Cord Injuries: A Quantitative Assessment-Based Nursing Intervention Study.

BACKGROUND Neurological bowel dysfunction (NBD) due to spinal cord injuries (SCIs) is common and significantly impacts patients' quality of life. This study evaluated the efficacy of quantitative assessment-based nursing interventions on bowel function recovery, quality of life, and caregivers' satisfaction with SCI patients with NBD. MATERIAL AND METHODS The study included 418 SCI patients with NBD. Patients were categorized into 3 cohorts: quantitative assessment-based nursing intervention (QN, n=114), conventional nursing intervention (CN, n=125), or no nursing intervention (DN, n=189). The 3 cohorts were followed over a 6-month period. RESULTS At 6 months post-intervention, patients in the QN and CN cohorts showed significant reductions in symptoms of fecal incontinence, constipation, and abdominal distension compared to the DN cohort. Additionally, defecation time decreased significantly in the QN and CN cohorts compared to both initial measures and the DN cohort. Notably, patients in the QN cohort demonstrated substantial improvement in overall quality of life scores compared to baseline, CN, and DN cohorts. The QN cohort also reported marked improvement in caregivers' satisfaction, surpassing that of caregivers in the CN and DN cohorts. CONCLUSIONS Six months of quantitative assessment-based nursing interventions significantly improved bowel function, quality of life, and caregiver satisfaction in SCI patients with NBD. This intervention appears beneficial for managing NBD in SCI patients and improving their quality of life and caregiver satisfaction.

[Radiation-induced intestinal fibrosis: pathological assessment and pharmacological prevention].

Although radiotherapy can improve the local control rate of tumors and prolong the survival period of patients, it can also lead to long-term adverse effects such as radiation-induced intestinal fibrosis. Radiation-induced intestinal fibrosis has a high incidence and poses significant challenges to treatment, severely impacting the quality of life of patients. Combining findings from domestic and international research, along with experiences of our center, this article mainly discusses the pathological changes of radiation-induced intestinal fibrosis, as well as the current status and challenges of pathological assessment and pharmacological prevention of this condition. At present, there is no definitive method to reverse the fibrotic pathological changes. Thus, the prevention of fibrosis is a crucial issue to be resolved. In the meantime, there is a lack of ideal assessment methods and effective preventive medications in clinical practice. It is necessary to enhance both basic and clinical research, thoroughly investigate the pathogenesis of the disease, and identify effective intervention targets to promote the diagnosis and treatment of radiation-induced intestinal fibrosis.

Histological assessment of intestinal injury by ionizing radiation.

Given the potential risk of radiological terrorism and disasters, it is essential to develop plans to prepare for such events. In these hazardous scenarios, radiation-induced gastrointestinal (GI) syndrome is one of the many manifestations that may happen after the organism is exposed to a lethal dose of ionizing radiation. Therefore, it is critical to better understand how the intestinal tissues initiate and orchestrate regeneration following severe radiation injury. In this chapter, we aimed to provide several key considerations for researchers who utilize histological assessment to study radiation-induced intestinal injury. Rigor and reproducibility are critical in experimental design and can be achieved by maintaining proper radiation administration, maintaining consistency in sample collection, and selecting and using appropriate controls. We also provided technical details of histological preparation of the intestines with tips on dissecting, cleaning, fixing, and preserving. Step-by-step descriptions of both bundling and Swiss rolling are provided with discussion on how to choose between the two approaches. In the following section, we detailed several histological assessment methods and then provided suggestions on how to use histological assessment to study cellular dynamics in the small intestines. Finally, we touched on some non-histological assessments. We hope that the information provided in this chapter will contribute to the research society of radiation-induced intestinal injury with an ultimate goal of promoting the development of radiation countermeasures against the GI acute radiation syndrome.

Reply to comment on "Ultrasonographic scores for ileal Crohn's disease assessment: better, worse or the same as contrast­enhanced ultrasound?

We read the comments by Nylund K et al. regarding our paper "Ultrasonographic scores for ileal Crohn's disease assessment: Better, worse or the same as contrast­enhanced ultrasound?". Intestinal ultrasound has become one of the most valuable developments in the past decade, a non-invasive, well-tolerated exam, with an easy repeatability, and absence of sedation, ionizing radiation, or preparation. Particularly for inflammatory bowel disease, where there is a lack of agreement of patient's symptoms with disease activity, in an era where the paradigm of mucosal healing is changing to transmural healing, and with the emergence of several therapies leading to repeated imaging surveillance, it is essential to highlight the role of intestinal ultrasound. Although intestinal ultrasound is an increasingly used tool to monitor inflammatory bowel disease activity, there is no widely accepted reproducible activity index, since the methodology for the development of the scores was shown to be insufficient in most studies and none have been adequately validated (Bots et al., J Crohns Colitis 12:920-9, 2018). In our study, we showed that the contrast-enhanced ultrasound (CEUS) peak enhancement derived from the time-intensity curve (TIC) is a promising non-invasive emerging method with a good accuracy to correlate clinical and endoscopic activity in the terminal ileum, superior to intestinal ultrasound scores relying on bowel wall thickness and colour Doppler.

Does intestinal obstruction influence hypo-albuminemia: assessment of the physio-pathogenesis of protein-losing enteropathy with literature review.

BACKGROUND: Non-steroidal anti-inflammatory drug (NSAID) use may cause diaphragm-like lesions in the bowel. Although NSAID-enteropathy is among the causes of protein-losing enteropathy (PLE), intractable hypoalbuminemia is rare. CASE REPORT: Here, we discuss a case of NSAID-enteropathy with a diaphragm-like disease that presented with Protein Losing Enteropathy (PLE) rather than obstruction. The hypoalbuminemia recovered immediately after resection of the obstructive segment, despite ongoing annular ulcerations in the early postoperative period. Thus, it was not clear whether obstructive mechanisms influenced resistant hypoalbuminemia besides the ulcers. We also reviewed the English-written literature for "diaphragm-type lesion, NSAID-enteropathy, obstruction, and protein-losing enteropathy". We noted that the role of obstruction in the pathophysiology of PLE was not clear. CONCLUSIONS: As our case and a couple of cases reported in literature, slow-onset obstructive pathology seems to contribute to well-known factors: inflammatory response, exudation, tight-junction dysfunction, and increase in permeability in the physiopathology of NSAID-induced PLE. Factors such as distention-induced low-flow ischemia and reperfusion, cholecystectomy-related continuous bile flow, bacterial overgrowth-related bile deconjugation and concomitant inflammation are among other potential influencers. The possible role of a slow-onset obstructive pathology in the physiopathology of NSAID-induced and other PLE needs to be further elucidated.

In Vitro Characterization and Real-Time Label-Free Assessment of the Interaction of Chitosan-Coated Niosomes with Intestinal Cellular Monolayers.

In vitro cell-based characterization methods of nanoparticles are generally static and require the use of secondary analysis techniques and labeling agents. In this study, bare niosomes and chitosan-coated niosomes (chitosomes) and their interactions with intestinal cells are studied under dynamic conditions and without fluorescent probes, using surface plasmon resonance (SPR)-based cell sensing. Niosomes and chitosomes were synthesized by using Tween 20 and cholesterol in a 15 mM:15 mM ratio and then characterized by dynamic light scattering (DLS). DLS analysis demonstrated that bare niosomes had average sizes of ∼125 nm, polydispersity index (PDI) below 0.2, and a negative zeta (ζ)-potential of -35.6 mV. In turn, chitosomes had increased sizes up to ∼180 nm, with a PDI of 0.2-0.3 and a highly positive ζ-potential of +57.9 mV. The viability of HT29-MTX, Caco-2, and Caco-2/HT29-MTX cocultured cells showed that both niosomes and chitosomes are cytocompatible up to concentrations of 31.6 µg/mL for at least 240 min. SPR analysis demonstrated that chitosomes interact more efficiently with HT29-MTX, Caco-2, and Caco-2/HT29-MTX cocultures compared to bare niosomes. The resulting SPR measurements were further supported by confocal microscopy and flow cytometry studies, which demonstrated that this method is a useful complementary or even alternative tool to directly characterize the interactions between niosomes and in vitro cell models in label-free and real-time conditions.

Production performance and economic analysis of broiler chickens after vaccination with a live attenuated vaccine against avian coccidiosis.

The objective of this study was to evaluate the effectiveness of live attenuated commercial vaccine LIVACOX® T against avian coccidiosis upon parasite exposure through its correlation with productive and economic performance, clinical observation, and oocyst excretion of broiler chickens. For this purpose, 420 1-day-old Cobb chicks were divided into five groups of 84 birds: (G1) unvaccinated and unchallenged control; (G2) vaccinated on day 0; (G3) challenged on day 1; (G4) vaccinated on day 0 and challenged on day 14; and (G5) challenged on day 14. For 28 days, the clinical signs of infection, weight and feed conversion of the birds, and excretion of oocysts in the feces were evaluated. Macroscopic analysis of intestinal lesions in birds was also performed. After vaccination in G2, G3, and G4 as well as after challenge in G3, G4, and G5, there was an increase in oocyst excretion. In the analysis of weight gain, the difference in final weight between groups G3 and G4 is - 105.74 g per bird. Therefore, if we multiply this value by the average number of birds slaughtered per day in a medium/large slaughterhouse (250,000), we have 26,435 kg of chicken meat per day of slaughter, representing 581,570 kg of monthly losses (22 days of slaughter/month), or approximately R$3,489,420.00 (US$872,355.00), considering the commercial value at R$6.00/kg (US$ 1.5/kg). Thus, the productive and economic impact of coccidiosis in broiler chickens is evident, and the importance of vaccination to prevent the occurrence of the disease and reduce subsequent loss is highlighted.

Reconstructed human intestinal comet assay, a possible alternative in vitro model for genotoxicity assessment.

The aim of the present study was to evaluate the compatibility of reconstructed 3D human small intestinal microtissues to perform the in vitro comet assay. The comet assay is a common follow-up genotoxicity test to confirm or supplement other genotoxicity data. Technically, it can be performed utilizing a range of in vitro and in vivo assay systems. Here, we have developed a new reconstructed human intestinal comet (RICom) assay protocol for the assessment of orally ingested materials. The human intestine is a major site of food digestion and adsorption, first-pass metabolism as well as an early site of toxicant first contact and thus is a key site for evaluation. Reconstructed intestinal tissues were dosed with eight test chemicals: ethyl methanesulfonate (EMS), ethyl nitrosourea (ENU), phenformin hydrochloride (Phen HCl), benzo[a]pyrene (BaP), 1,2-dimethylhydrazine hydrochloride (DMH), potassium bromate (KBr), glycidamide (GA), and etoposide (Etop) over a span of 48 h. The RICom assay correctly identified the genotoxicity of EMS, ENU, KBr, and GA. Phen HCl, a known non-genotoxin, did not induce DNA damage in the 3D reconstructed intestinal tissues whilst showing high cytotoxicity as assessed by the assay. The 3D reconstructed intestinal tissues possess sufficient metabolic competency for the successful detection of genotoxicity elicited by BaP, without the use of an exogenous metabolic system. In contrast, DMH, a chemical that requires liver metabolism to exert genotoxicity, did not induce detectable DNA damage in the 3D reconstructed intestinal tissue system. The genotoxicity of Etop, which is dependent on cellular proliferation, was also undetectable. These results suggest the RICom assay protocol is a promising tool for further investigation and safety assessment of novel ingested materials. We recommend that further work will broaden the scope of the 3D reconstructed intestinal tissue comet assay and facilitate broader analyses of genotoxic compounds having more varied modes of actions.

Drug cytotoxicity screening using human intestinal organoids propagated with extensive cost-reduction strategies.

Organoids are regarded as physiologically relevant cell models and useful for compound screening for drug development; however, their applications are currently limited because of the high cost of their culture. We previously succeeded in reducing the cost of human intestinal organoid culture using conditioned medium (CM) of L cells co-expressing Wnt3a, R-spondin1, and Noggin. Here, we further reduced the cost by replacing recombinant hepatocyte growth factor with CM. Moreover, we showed that embedding organoids in collagen gel, a more inexpensive matrix than Matrigel, maintains organoid proliferation and marker gene expression similarly when using Matrigel. The combination of these replacements also enabled the organoid-oriented monolayer cell culture. Furthermore, screening thousands of compounds using organoids expanded with the refined method identified several compounds with more selective cytotoxicity against organoid-derived cells than Caco-2 cells. The mechanism of action of one of these compounds, YC-1, was further elucidated. We showed that YC-1 induces apoptosis through the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway, the mechanism of which was distinct from cell death caused by other hit compounds. Our cost-cutting methodology enables large-scale intestinal organoid culture and subsequent compound screening, which could expand the application of intestinal organoids in various research fields.

Toward Inclusivity in Preclinical Drug Development: A Proposition to Start with Intestinal Organoids.

Representation of humans from diverse backgrounds in the drug development process is key to advancing health equity, and while clinical trial design has recently made strides toward greater inclusivity, preclinical drug development has struggled to make those same gains. One barrier to inclusion is the current lack of robust and established in vitro model systems that simultaneously capture the complexity of human tissues while representing patient diversity. Here, the use of primary human intestinal organoids as a mechanism to advance inclusive preclinical research is proposed. This in vitro model system not only recapitulates tissue functions and disease states, but also retains the genetic identity and epigenetic signatures of the donors from which they are derived. Thus, intestinal organoids are an ideal in vitro prototype for capturing human diversity. In this perspective, the authors call for an industry-wide effort to leverage intestinal organoids as a starting point to actively and intentionally incorporate diversity into preclinical drug programs.

Pediatric intestine transplant cost: Analysis of the Pediatric Health Information System database.

BACKGROUND: We aimed to evaluate costs from transplant to discharge in children who had undergone intestine transplant. METHODS: We performed a cross-sectional observational study of pediatric intestine transplant recipients from 2004 through 2020, utilizing the Pediatric Health Information System database. Standardized costs were applied to all charges and converted to 2021 US dollars. We analyzed the association of cost from transplant to discharge with age, sex, race and ethnicity, length of stay, insurance type, transplant year, short bowel syndrome diagnosis, liver-containing graft, hospitalization status, and immunosuppressive regimen. Predictors with a P value <0.20 in univariable analysis were included in a multivariable model, which was reduced using backwards selection with a P value of 0.05. RESULTS: We identified 376 intestinal transplant recipients across nine centers (median age, 2 years; 44% female). Most patients had short bowel syndrome (294; 78%). The liver was included in 218 transplants (58%). Median posttransplant cost was $263,724 (interquartile range [IQR], $179,564-$384,147), and length of stay was 51.5 days (IQR, 34-77). In the final model, increased cost from transplant to hospital discharge was associated with liver-containing graft (+$31,805; P = 0.028), T-cell-depleting antibody use (+$77,004; P < 0.001), and mycophenolate mofetil use (+$50,514; P = 0.012) while controlling for insurance type and length of stay. A 60-day posttransplant hospital stay would cost an estimated $272,533. CONCLUSIONS: Intestine transplant has high immediate cost and long length of stay that varies by center, graft type, and immunosuppression regimen. Future work will examine the cost-effectiveness of various management strategies before and after transplant.