Endoscopic therapy of stoma closure site strictures in ileal pouches is safe and effective.

Background: Strictures are a common complication after ileal pouch surgery with the most common locations being at the anastomosis, pouch inlet, and stoma closure site. No previous literature has described endoscopic therapy of stoma site stricture. This study aimed to assess the safety and efficacy of endoscopic therapy in the treatment of stoma closure site strictures. Method: Patients diagnosed with stoma closure site strictures following ileal pouch surgery who underwent endoscopic treatment at the Center for Colorectal Diseases, Inflammatory Bowel Disease (IBD), and Ileal Pouch between 2018 and 2022 were analysed. Primary outcomes (technical success and surgery-free survival) were compared between endoscopic balloon dilation (EBD) and stricturotomy and/or strictureplasty. Results: A total of 30 consecutive eligible patients were analysed. Most patients were female (66.7%) and most patients were diagnosed with IBD (93.3%). Twenty patients (66.7%) had end-to-end anastomosis. A total of 52 procedures were performed, with EBD in 16 (30.8%) and stricturotomy and/or strictureplasty in 36 (69.2%). The mean stricture length was 1.7 ± 1.0 cm. Immediate technical success was achieved in 47 of 52 interventions (90.4%). During a mean follow-up of 12.7 ± 9.9 months, none of the patients underwent surgical intervention for the stricture. Fourteen (46.7%) required endoscopic re-intervention for their strictures with an interval between index and re-interventional pouchoscopy of 8.8 ± 6.3 months. Post-procedural complications were reported in 2 (6.7%) with bleeding and none with perforation. Upon follow-up, 20 (66.7%) patients reported improvement in their symptoms. Conclusion: EBD and endoscopic stricturotomy and/or strictureplasty are safe and effective in treating stoma closure site strictures in patients with ileal pouches, providing symptomatic relief in most patients as well as avoiding surgery.

Efficacy and Safety of Upadacitinib in the Treatment of Chronic Pouchitis, Cuffitis, and Crohn's Disease of the Pouch.

Upadacitinib has shown efficacy in the treatment of moderate-to-severe ulcerative colitis and Crohn's disease (CD). The use of upadacitinib in the treatment of chronic antibiotics-refractory pouchitis (CARP), as well as CD of the pouch, has not been previously reported. We treated a series of 6 patients with CARP or CD of the pouch with a minimal 6 weeks of upadacitinib. The patients showed minimal or no significant improvement in clinical and endoscopic presentations. Our findings warrant further study to validate the efficacy and safety of upadacitinib in the treatment of CARP or CD of the pouch.

Sulfur vacancy rich MoS2/FeMoO4 composites derived from MIL-53(Fe) as PMS activator for efficient elimination of dye: Nonradical 1O2 dominated mechanism.

A novel MoS2/FeMoO4 composite was synthesized for the first time by introducing an inorganic promoter MoS2 into the MIL-53(Fe)-derived PMS-activator. The prepared MoS2/FeMoO4 could effectively activate peroxymonosulfate (PMS) toward 99.7% of rhodamine B (RhB) degradation in 20 min, and achieve a kinetic constant of 0.172 min-1, which is 10.8, 43.0 and 3.9 folds higher than MIL-53, MoS2 and FeMoO4 components, respectively. Both Fe(II) and sulfur vacancies are identified as the main active sites on catalyst surface, where sulfur vacancies can promote adsorption and electron migration between peroxymonosulfate and MoS2/FeMoO4 to accelerate peroxide bond activation. Besides, the Fe(III)/Fe(II) redox cycle was improved by reductive Fe0, S2- and Mo(IV) species to further boost PMS activation and RhB degradation. Comparative quenching experiment and in-situ electron paramagnetic resonance (EPR) spectra verified that SO4•-, •OH, 1O2 and O2•- were produced in the MoS2/FeMoO4/PMS system, while 1O2 dominates RhB elimination. In addition, the influences of various reaction parameters on RhB removal were examined and the MoS2/FeMoO4/PMS system exhibits good performance over a wide pH and temperature range, as well as coexistence with common inorganic ions and humic acid (HA). This study provides a new strategy for preparing MOF-derived composite with simultaneous introduction of MoS2 promotor and rich sulfur vacancies, and enables new insight into radical/nonradical pathway in PMS activation process.

Fecal Incontinence and Defecatory Disorders in Patients With Ileal Pouch-Anal Anastomosis.

Functional anorectal disorders are common in patients with ileal pouch-anal anastomosis (IPAA) and often have a debilitating impact on quality of life. The diagnosis of functional anorectal disorders, including fecal incontinence (FI) and defecatory disorders, requires a combination of clinical symptoms and functional testing. Symptoms are generally underdiagnosed and underreported. Commonly utilized tests include anorectal manometry, balloon expulsion test, defecography, electromyography, and pouchoscopy. The treatment for FI begins with lifestyle modifications and medications. Sacral nerve stimulation and tibial nerve stimulation have been trialed on patients with IPAA and FI, resulting in improvement in symptoms. Biofeedback therapy has also been used in patients with FI but is more commonly utilized in defecatory disorders. Early diagnosis of functional anorectal disorders is important because a response to treatment may significantly improve a patient's quality of life. To date, there is limited literature describing the diagnosis and treatment of functional anorectal disorders in patients with IPAA. This article focuses on the clinical presentation, diagnosis, and treatment of FI and defecatory disorders in patients with IPAA.

Stem cell therapy: light in the tunnel for penetrating Crohn's disease.

Patients with Crohn's disease frequently suffer from fistula resulting from adverse sequelae of persistent complicated active disease or surgical intervention. Fistula affects a patient's quality of life and is directly associated with the need for surgical intervention. Diagnosis of fistula can be made through CT enterography, MR enterography, gastrograffin-based imaging, and transanal ultrasound. Treatment for fistula mainly consists of medication, endoscopic procedures, and surgery. There are emerging approaches under current investigation, such as stem cell therapy. The results showed a decent response in patients with perianal and rectovaginal fistula with minimal side effects. Further investigation is still needed for other internal fistula.

Endoscopic Therapy for Fistulas and Abscesses in Crohn's Disease.

Crohn disease (CD) patients can develop fistula or abscess from persistent active disease or postsurgical complications. Penetrating CD is traditionally treated with medication and surgery. The role of medication alone in the treatment of fistula is limited, except perianal fistulas or enterocutaneous fistula. Surgery is the standard treatment in those with hollow-organ to hollow-organ fistula, like ileovesicular fistula. Surgery is invasive with a higher risk of postoperative complications. Endoscopic therapy has evolved as a valid option. Fistulotomy, surgical or endoscopic, should be considered first-line therapy when feasible. Incision and drainage of perianal abscesses with an endoscopic device may be attempted.

[Recurrent and Refractory Langerhans Cell Histiocytosis in Children Treated with the Combination of Cladribine and Cytarabine].

OBJECTIVE: To observe the efficacy and prognosis of cladribine (2-CdA) combined with cytarabine (Ara-C) regimen in the treatment of relapsed refractory Langerhans cell histiocytosis (LCH) in children. METHODS: Nine patients with relapsed refractory LCH treated with the 2-CdA combined with Ara-C regimen in the Department of Hematology and Oncology of Wuhan Children's Hospital from July 2014 to February 2020 were retrospectively analyzed, and the efficacy and disease status were evaluated according to the Histiocyte Society Evaluation and Treatment Guidelines (2009) and the Disease Activity Score (DAS), the drug toxicity were evaluated according to the World Health Organization（WHO） grading criteria for chemotherapy. All patients were followed up for survival status and disease-related sequelae. RESULTS: Before the treatment combining 2-CdA and Ara-C, 7 of 9 patients were evaluated as active disease worse (ADW), and 2 as active disease stable (ADS) with a median disease activity score of 8 (4-15). Of 9 patients, 6 cases achieved non active disease (NAD) and 3 achieved active disease better (ADB) with a median disease activity score of 0 (0 to 5) after 2-6 courses of therapy. All 9 patients experienced WHO grade IV hematologic toxicity and 3 patients had hepatobiliary adverse effects (WHO grade I～II) after treatment. The median follow-up time was 31(1 to 50) months with all 9 patients survived, 3 of the 9 patients experienced sequelae to the disease with 2 combined liver cirrhosis as well as cholestatic hepatitis and 1 with oral desmopressin acetate tablets for diabetes insipidus. CONCLUSION: 2-CdA combined with Ara-C is an effective regimen for the treatment of recurrent refractory LCH in children, and the main adverse effect is hematologic toxicity, which is mostly tolerated in children. Early treatment with this regimen may be considered for patients with multisystem LCH with risky organ involvement who have failed first-line therapy and for patients with relapse.

Strongylocentrotus nudus Eggs Polysaccharide Enhances Macrophage Phagocytosis Against E.coli Infection by TLR4/STAT3 Axis.

Antibiotics resistance is one of the most significant public health threats globally. Strategies that strengthen host defenses to control pathogen infection has become a hot research field. Macrophages are part of early host defense mechanisms, and are activated via host pattern recognition receptors (PRRs), such as Toll-like receptor 4 (TLR4), which then facilitates phagocytosis and elimination of invading pathogens. However, few activators of PRRs have been approved for clinical use because of their toxic effects. This study aimed to investigate whether Strongylocentrotus nudus eggs polysaccharide (SEP), a non-toxic extract from seafood, contributes to host defense against bacterial infection. Results showed that SEP promoted bacterial clearance by enhancing phagocytosis by macrophages during E. coli infection in vitro, but was inhibited by TLR4 specific inhibitor TAK-242, STAT3 inhibitor Stattic or blockade of CD64. In addition, SEP protected mice from E. coli induced mortality, reduced pulmonary inflammation and inhibited dissemination of bacteria to organs, while TAK-242 retarded the protection of SEP. Overall, SEP strengthened innate host defense and improved the outcome in bacterial infection, suggesting that SEP could be used as a potential immunomodulator in host-directed therapies.

Recurrent and Refractory Langerhans Cell Histiocytosis in Children Treated with the Combination of Cladribine and Cytarabine / 中国实验血液学杂志

OBJECTIVE@#To observe the efficacy and prognosis of cladribine (2-CdA) combined with cytarabine (Ara-C) regimen in the treatment of relapsed refractory Langerhans cell histiocytosis (LCH) in children.@*METHODS@#Nine patients with relapsed refractory LCH treated with the 2-CdA combined with Ara-C regimen in the Department of Hematology and Oncology of Wuhan Children's Hospital from July 2014 to February 2020 were retrospectively analyzed, and the efficacy and disease status were evaluated according to the Histiocyte Society Evaluation and Treatment Guidelines (2009) and the Disease Activity Score (DAS), the drug toxicity were evaluated according to the World Health Organization（WHO） grading criteria for chemotherapy. All patients were followed up for survival status and disease-related sequelae.@*RESULTS@#Before the treatment combining 2-CdA and Ara-C, 7 of 9 patients were evaluated as active disease worse (ADW), and 2 as active disease stable (ADS) with a median disease activity score of 8 (4-15). Of 9 patients, 6 cases achieved non active disease (NAD) and 3 achieved active disease better (ADB) with a median disease activity score of 0 (0 to 5) after 2-6 courses of therapy. All 9 patients experienced WHO grade IV hematologic toxicity and 3 patients had hepatobiliary adverse effects (WHO grade I～II) after treatment. The median follow-up time was 31(1 to 50) months with all 9 patients survived, 3 of the 9 patients experienced sequelae to the disease with 2 combined liver cirrhosis as well as cholestatic hepatitis and 1 with oral desmopressin acetate tablets for diabetes insipidus.@*CONCLUSION@#2-CdA combined with Ara-C is an effective regimen for the treatment of recurrent refractory LCH in children, and the main adverse effect is hematologic toxicity, which is mostly tolerated in children. Early treatment with this regimen may be considered for patients with multisystem LCH with risky organ involvement who have failed first-line therapy and for patients with relapse.

Coordinated Regulation of Protoperithecium Development by MAP Kinases MAK-1 and MAK-2 in Neurospora crassa.

Mitogen-activated protein (MAP) kinase pathways function as signaling hubs that are integral for many essential cellular processes, including sexual development. The molecular mechanisms and cross-talk between PR and CWI MAP kinase pathways have been extensively studied during asexual development. However, if these can be extended to sexual development remains elusive. By analyzing genome-wide transcriptional responses to deletion of each of two MAP kinase coding genes mak-2 (PR-MAP kinase pathway) and mak-1 (CWI-MAP kinase pathway) in Neurospora crassa during protoperithecium formation, 430 genes co-regulated by the MAK-1 and MAK-2 proteins were found, functionally enriched at integral components of membrane and oxidoreductase. These genes include 13 functionally known genes participating in sexual development (app, poi-2, stk-17, fsd-1, vsd-8, and NCU03863) and melanin synthesis (per-1, pkh-1, pkh-2, mld-1, scy-1, trn-2, and trn-1), as well as a set of functionally unknown genes. Phenotypic analysis of deletion mutants for the functionally unknown genes revealed that 12 genes were essential for female fertility. Among them, single-gene deletion mutants for NCU07743 (named as pfd-1), NCU02250 (oli), and NCU05948 (named as pfd-2) displayed similar protoperithecium development defects as the Δmak-1 and Δmak-2 mutants, failing to form protoperithecium. Western blotting analysis showed that both phosphorylated and total MAK-1 proteins were virtually abolished in the Δnrc-1, Δmek-2, and Δmak-2 mutants, suggesting that the posttranscriptional regulation of MAK-1 is dependent on the PR-MAP kinase pathway during the protoperithecium development. Taken together, this study revealed the regulatory roles and cross-talk between PR and CWI-MAP kinase pathways during protoperithecium development.

Effects of Empirical Glucocorticoid Use on Severe Acute Exacerbation of COPD During Hospitalization.

Background: Clinicians' selection of glucocorticoids during hospitalization of COPD patients is often based on the medical staff's judgment of the patient's condition, and there is no objective judgment standard. The purpose of this study was to investigate the outcome of severe COPD deterioration in patients treated with glucocorticoid and without glucocorticoid during hospitalization. Methods: This study was an observational cohort study. Data on hospitalization with severe COPD deterioration were collected and followed up for 1 year. One year after discharge, the re-hospitalization due to COPD was collected retrospectively. The patients were divided into glucocorticoid group and control group according to whether the patients were given glucocorticoid therapy or not when they were admitted to hospital for the first time. The primary outcome was rate of future COPD exacerbations, while the secondary outcome was hospital stay, treatment cost and COPD-related readmission time. These results are analyzed by using Poisson model and Cox regression model. Results: A total of 91 patients were enrolled in the study, including 39 in the control group and 52 in the glucocorticoid group. The annual rate of future COPD exacerbations in the glucocorticoid group was significantly lower than that in the control group (RR,0.50 [95% CI, 0.26-0.98]; P = 0.045). The risk of COPD recurrence in the glucocorticoid group was lower than that in the control group, as assessed in a time-to-first-event analysis (HR,0.46[95% CI 0.22-0.97]; P = 0.042). Subgroup analysis found that in patients with blood eosinophil <100 cells/µ l, the future annual severe exacerbation rate of glucocorticoid group was significantly lower than that in the control group (adjusted RR,0.37 [95% CI 0.17-0.83]; P = 0.016). Conclusion: The use of glucocorticoids during hospitalization in COPD can more effectively reduce the severe deterioration of COPD than without glucocorticoids.

Esculetin protects against early sepsis via attenuating inflammation by inhibiting NF-κB and STAT1/STAT3 signaling.

Esculetin, a natural derivative from the traditional and widely-used Chinese medicinal herb Cortex Fraxini, has a variety of pharmacological effects, especially in anti-inflammation. However, it is not clear whether esculetin has a therapeutic effect on sepsis. This study aimed to investigate the anti-inflammatory and protective effects of esculetin on early sepsis. The results showed that the lung injury was significantly relieved with the treatment of esculetin, accompanied with the restrained production of inflammatory factors including IL-1ß, IL-6, TNF-α, CCL2 and iNOS during the early phase of E.coli-induced sepsis. Of note, activation of NF-κB and STAT1/STAT3 signals, the main upstream signals of many inflammatory factors, were attenuated by esculetin in both lung tissues from septic mice and LPS-stimulated macrophage. These findings suggested that the protection of esculetin against early sepsis should be related to its anti-inflammatory effect, which was at least partly due to its inhibition on NF-κB and STAT1/STAT3 signaling pathway in macrophage. Thus, esculetin could serve as a potential therapeutic agent by rebalancing innate immune response in macrophage for the treatment of early sepsis.

Anti-cryptococcal activity of preussolides A and B, phosphoethanolamine-substituted 24-membered macrolides, and leptosin C from coprophilous isolates of Preussia typharum.

Cryptococcus neoformans is a serious human pathogen with limited options for treatment. We have interrogated extracts from fungal fermentations to find Cryptococcus-inhibiting natural products using assays for growth inhibition and differential thermosensitivity. Extracts from fermentations of four fungal strains from wild and domestic animal dung from Arkansas and West Virginia, USA were identified as Preussia typharum. The extracts exhibited two antifungal regions. Purification of one region yielded new 24-carbon macrolides incorporating both a phosphoethanolamine unit and a bridging tetrahydrofuran ring. The structures of these metabolites were established mainly by analysis of high-resolution mass spectrometry and 2D NMR data. Relative configurations were assigned using NOESY data, and the structure assignments were supported by NMR comparison with similar compounds. These new metabolites are designated preussolides A and B. The second active region was caused by the cytotoxin, leptosin C. Genome sequencing of the four strains revealed biosynthetic gene clusters consistent with those known to encode phosphoethanolamine-bearing polyketide macrolides and the biosynthesis of dimeric epipolythiodioxopiperazines. All three compounds showed moderate to potent and selective antifungal activity toward the pathogenic yeast C. neoformans.

Experience of Hospital Admission and Surgery During the COVID-19 Pandemic: a Survey of IBD Patients.

BACKGROUND: The aim of this study was to evaluate the experience of surgery in IBD patients during the COVID pandemic. METHODS: A survey was distributed among patients undergoing IBD-related surgeries from January 2020 to March 2020 via an online platform. The response was submitted anonymously. RESULTS: A total of 78 patients responded to the survey. COVID-19 testing was conducted in 60 (76.9%) patients, and they were all tested negative. Emergent surgery was performed in 12 (15.4%) patients and postponed surgery in 18 (23.1%) patients. The surgical indications were mainly bowel obstruction (N = 21, 26.9%) and perianal abscess (N = 18, 23.1%). Postoperative complications were noted in 5.1% of cases, but no re-operation was required. Due to the ongoing COVID pandemic, 58 (74.4%) patients reported various levels of concern and anxiety for surgery. CONCLUSIONS: Common surgical indications were for bowel obstruction and perianal abscess. Surgery can be postponed, but disease progression should be monitored closely and surgically intervened as needed. Most patients expressed anxiety resulting from the pandemic. The overall experience was satisfactory.

Endoscopic treatment of pouch inlet and afferent limb strictures: stricturotomy vs. balloon dilation.

BACKGROUND: Strictures are common complications after ileal pouch surgery. The aim of this study is to evaluate the efficacy and safety of endoscopic stricturotomy vs. endoscopic balloon dilation (EBD) in the treatment of pouch inlet strictures. METHODS: All consecutive ulcerative colitis patients with the diagnosis of pouch inlet or afferent limb strictures treated in our Interventional Inflammatory Bowel Disease Unit (i-IBD) from 2008 to 2017 were extracted. The primary outcomes were surgery-free survival and post-procedural complications. RESULTS: A total of 200 eligible patients were included in this study, with 40 (20.0%) patients treated with endoscopic stricturotomy and 160 (80.0%) patients treated with EBD. Symptom improvement was recorded in 11 (42.3%) patients treated with endoscopic stricturotomy and 16 (13.2%) treated with EBD. Subsequent surgery rate was comparable between the two groups (9 [22.5%] vs. 33 [20.6%], P = 0.80) during a median follow-up of 0.6 years (interquartile range [IQR] 0.4-0.8) vs. 3.6 years (IQR 1.1-6.2) in patients receiving endoscopic stricturotomy and EBD, respectively. The overall surgery-free survival seems to be comparable as well (P = 0.12). None of the patients in the stricturotomy group developed pouch failure, while 9 patients (5.6%) had pouch failure in the balloon dilation group (P = 0.17). Procedural bleeding was seen in three occasions (4.7% per procedure) in patients receiving endoscopic stricturotomy and perforation was seen in three occasions (0.8% per procedure) in patients receiving EBD (P = 0.02). In multivariable analysis, an increased length of the stricture (hazard ratio [HR] 1.4, 95% confidence interval [CI] 1.0-1.8) and concurrent pouchitis (HR 2.5, 95% CI 1.0-5.7) were found to be risk factors for the requirement of surgery. CONCLUSION: Endoscopic stricturotomy and EBD were both effective in treating patients with pouch inlet or afferent limb strictures, EBD had a higher perforation risk while endoscopic stricturotomy had a higher bleeding risk.

Association between anti-acid therapies and advanced fibrosis in type 2 diabetics with biopsy-proven non-alcoholic fatty liver disease.

BACKGROUNDS AND AIMS: Data on associations of antacid therapies with advanced fibrosis (AF) in patients with non-alcoholic fatty liver disease (NAFLD) are limited. We aimed to assess the association of histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) with AF in NAFLD patients with underlying type 2 diabetes (T2D). METHODS: We retrospectively reviewed patient's charts with T2D who had a liver biopsy for suspected NAFLD. Fibrosis stages were determined as F0-F4, AF being F3-4. Laboratory data and use of various medications within 24 months of liver biopsies were used for the analysis. Univariable and multivariable logistic regression analyses were performed to assess any association. RESULTS: Our cohort consisted of 1008 T2D patients with biopsy-proven NAFLD. Sixty-six percent were female, 86.2% were Caucasian, and median HbA1C was 6.4%. AF was present in 32% of the patients. Thirty-four percent were on H2RAs and 60.6% were on PPI therapy (p < 0.001) for a median duration of 3.6 [0.10, 3.8] (p = 0.20) and 45.6 [0.80, 15.4] (p = 0.17) months, respectively. On multivariable logistic regression analysis being on H2RAs was associated with a 68% lower risk of AF (odds ratio [OR] [95%CI]: 0.32 [0.24, 0.44]) (p < 0.001), but use of PPIs showed a trend towards higher risk of AF (OR [95%CI]: 1.4 [1.00, 1.8]) (p = 0.053). CONCLUSION: Our study suggests that H2RAs are associated with lower risk of AF in NAFLD patients with underlying diabetes and should be considered as the first-line antacid therapy in these patients. Risk stratification should be done if PPIs are indicated in high-risk diabetics with NAFLD.

Identification of the Antifungal Metabolite Chaetoglobosin P From Discosia rubi Using a Cryptococcus neoformans Inhibition Assay: Insights Into Mode of Action and Biosynthesis.

Cryptococcus neoformans is an important human pathogen with limited options for treatments. We have interrogated extracts from fungal fermentations to find Cryptococcus-inhibiting natural products using assays for growth inhibition, differential thermosensitivity, and synergy with existing antifungal drugs. Extracts from fermentations of strains of Discosia rubi from eastern Texas showed anticryptococcal bioactivity with preferential activity in agar zone of inhibition assays against C. neoformans at 37°C versus 25°C. Assay-guided fractionation led to the purification and identification of chaetoglobosin P as the active component of these extracts. Genome sequencing of these strains revealed a biosynthetic gene cluster consistent with chaetoglobosin biosynthesis and ß-methylation of the tryptophan residue. Proximity of genes of the actin-binding protein twinfilin-1 to the chaetoglobosin P and K gene clusters suggested a possible self-resistance mechanism involving twinfilin-1 which is consistent with the predicted mechanism of action involving interference with the polymerization of the capping process of filamentous actin. A C. neoformans mutant lacking twinfilin-1 was hypersensitive to chaetoglobosin P. Chaetoglobosins also potentiated the effects of amphotericin B and caspofungin on C. neoformans.