Digestive Diseases and Sciences

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PRISMA flow diagram for new systematic reviews
Adopted from Page et al. [31]
Risk of bias in included randomized controlled trials studies
Alkaline phosphatase levels (A), total serum bilirubin levels (B), Gamma-glutamyltransferase levels (C), Immunoglobulin M levels (D) in primary biliary cholangitis patients treated with combination therapy versus monotherapy. IV inverse-variance, CI confidence interval, df degrees of freedom, UDCA ursodeoxycholic acid
Background Bezafibrate (BZF) alone or in combination with ursodeoxycholic acid (UDCA) has been used to slow disease progression in patients with primary biliary cholangitis (PBC). We performed a systematic review and meta-analysis to assess the efficacy and harms of BZF monotherapy or combination therapy. Methods We performed a systematic search of PubMed, EMBASE, Cochrane Library, Scopus, ClinicalTrials.gov, and WHO ICTRP from inception until January 2020, for randomized controlled clinical trials assessing BZF + UDCA versus UDCA monotherapy or BZF monotherapy versus UDCA monotherapy in PBC patients. Additionally, we systematically evaluated data on harms using seven observational studies. Pooled effect estimates were calculated for the outcomes of interest. The certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). Results We identified 7 randomized controlled trials with a total of 279 participants. Comparing BZF + UDCA to UDCA alone, a clinically significant improvement was observed in serum ALP with a mean difference (MD) of − 159.04 U/L (95% CI − 186.45 to − 131.62) and a reduction in gamma-glutamyltransferase (GGT) (MD − 106.94 IU/L; 95% CI − 151.99 to − 61.89), but not in total bilirubin (TB) or IgM levels. A statistically significant reduction in ALP levels was also noticed with BZF monotherapy compared to UDCA monotherapy. The effect of BZF + UDCA versus UDCA on mortality remains unclear. Across 5 observational studies including 106 patients, one death was reported due to advanced liver disease in an incomplete responder getting treatment with BZF + UDCA. Analysis of observational studies demonstrated improvement in pruritus intensity with BZF. Conclusions Use of BZF alone or in combination with UDCA improved liver biochemistries in patients with PBC, but its effect on mortality, liver-related complications or quality of life remains unknown.
 
The perceptions, practice patterns, and preferences of NAFLD management among PCPs
Background Primary care providers (PCPs) face increasing numbers of patients at risk for NAFLD and are responsible for the detection of NAFLD and the decision on referral to specialists. We conducted a PCP needs assessment to ascertain the barriers and desired supports for NAFLD in primary care. Methods We designed a cross-sectional study of PCPs at a large diverse health system and surveyed faculty, residents, and nurse practitioners. Questions assessed NAFLD knowledge, approach to diagnosis and fibrosis testing including use of FIB-4, and attitudes toward support tools. Results The survey was sent to 115 PCPs with an 80% (n = 92) response rate. Respondents were 52% faculty and 48% residents. Over 40% were unsure of which diagnostic tests to order and which data constituted a diagnosis. PCPs were aware of the importance of fibrosis, yet few knew the components of FIB-4, few used FIB-4 in practice, and yet the most common reason for referral was to obtain fibrosis staging. The majority showed high levels of interest toward possible tools to improve NAFLD management, and only 5% perceived lack of time to be a barrier. Discussion Our survey revealed PCPs need and want strategic approaches to NAFLD. We found PCPs lack confidence in diagnosing NAFLD and are inconsistent in management strategies. PCPs had high awareness of the importance of fibrosis, but not of the FIB-4. It was encouraging that PCPs reported that time was not a major barrier and had positive attitudes toward potential practice support tools, indicating that practice guidelines designed for primary care should be created.
 
The number of participants who received their first, second, and third doses of the COVID-19 vaccine
The number of participants who experienced any local or systemic side effects following COVID-19 vaccination
Association of COVID-19 vaccine side effects with sex differences among patients with IBD
Background Patients with inflammatory bowel disease (IBD) are recommended to receive the coronavirus disease 2019 (COVID-19) vaccine. However, a recent survey showed that patients with IBD are more hesitant to receive the vaccine than the general population. Detailed information on the side effects of the COVID-19 vaccine is necessary to encourage vaccination among patients with IBD. Aim To investigate the frequency of side effects following COVID-19 vaccination in patients with IBD in Japan. Study design: a cross-sectional survey was conducted using a questionnaire administered to adult patients with IBD in a tertiary medical facility. Results Among the participants who answered the questionnaire, 92.6%, 91.5%, and 41.5% of the participants had received their first, second, and third doses of the COVID-19 vaccine, respectively. Of the vaccinated participants, 88.3%, 86.3%, and 89.0% experienced side effects after receiving the first, second, and third doses of the vaccine, respectively. The incidences of fever, chills, and headaches were significantly higher among female participants than among male participants (p < 0.05). However, the frequencies of most side effects were comparable between the BNT162b2 mRNA and mRNA-1273 vaccines. Conclusion The findings of our survey can help encourage patients with IBD to receive the COVID-19 vaccine.
 
Prevalence of fatty liver disease and fibrosis by sex and race-ethnicity among participants 20 + years in the National Health and Nutrition Examination Survey, United States, 2017–March 2020 prepandemic data (N = 7923). NH, non-Hispanic
Prevalence of fatty liver disease and fibrosis among participants 20 + years in the National Health and Nutrition Examination Survey, United States, 2017–March 2020 prepandemic data (N = 7923). A By lifestyle factors. B By physical activity and sedentary time
Background and Aims Fatty liver disease is a growing public health burden. We estimated prepandemic fatty liver disease prevalence determined by transient elastography-assessed hepatic steatosis and fibrosis, and examined associations with lifestyle and other factors in a United States population sample. Methods Liver stiffness and controlled attenuation parameter (CAP) were assessed on 7923 non-Hispanic white, non-Hispanic black, non-Hispanic Asian, and Hispanic men and women aged 20 years and over in the National Health and Nutrition Examination Survey (NHANES) 2017–March 2020 prepandemic data. Results The prevalence of fatty liver disease (CAP > 300 dB/m) was 28.8% and of fibrosis (liver stiffness > 8 kPa) was 10.4%. Only 7.2% of participants with fatty liver disease and 10.9% with fibrosis reported being told by a health care provider that they had liver disease. In addition to known risk factors such as metabolic factors and ALT, persons with fatty liver disease were less likely to meet physical activity guidelines, more likely to be sedentary for ≥ 12 h a day, and reported a less healthy diet. Persons with fibrosis were less likely to have a college degree and reported a less healthy diet. Conclusions In the U.S. population, most persons with fatty liver disease are unaware of their condition. Physical activity and dietary modifications might reduce the fatty liver disease burden. There is an urgent need for fatty liver disease management in high-risk individuals using transient elastography or other noninvasive methods to intervene in disease progression.
 
Age- and gender-stratified cohort of constipated patients that completed anorectal function testing
Anorectal function testing characteristics in patients with chronic constipation
Anorectal function testing in younger vs. older patients with chronic constipation
Anorectal function testing in male vs. female patients with chronic constipation
Background The effect of age and gender differences on anorectal function, symptoms severity, and quality of life (QoL) in patients with chronic constipation (CC) is not well studied. This study examines the impact of age and gender on anorectal function testing (AFT) characteristics, symptoms burden, and QoL in patients with CC. Methods This is a retrospective analysis of prospectively collected data from 2550 adults with CC who completed AFT. Collected data include demographics, sphincter response to simulated defecation during anorectal manometry (ARM), balloon expulsion testing (BET), and validated surveys assessing constipation symptoms and QoL. DD was defined as both the inability to relax the anal sphincter during simulated defecation and an abnormal BET. Results 2550 subjects were included in the analysis (mean age = 48.6 years). Most patients were female (81.6%) and Caucasian (82%). 73% were < 60 years old (mean = 41) vs. 27% ≥ 60 years old (mean = 69). The prevalence of impaired anal sphincter relaxation on ARM, abnormal BET, and DD in patients with CC was 48%, 42.1%, and 22.9%, respectively. Patients who were older and male were significantly more frequently diagnosed with DD and more frequently had impaired anal sphincter relaxation on ARM, compared to patients who were younger and female (p < 0.05). Conversely, CC patients who were younger and female reported greater constipation symptoms severity and more impaired QoL (p ≤ 0.004). Conclusion Among patients with CC referred for anorectal function testing, men and those older than 60 are more likely to have dyssynergic defecation, but women and patients younger than 60 experience worse constipation symptoms and QoL.
 
Mean daily after-hours time completing electronic health record tasks among subspecialties
Mean number of electronic health record patient messages received per day by subspecialty
Background and Aims There is a paucity of research on the use of the electronic health record (EHR) by gastroenterology and hepatology providers and its effect on work–life balance. Our aim was to study the after-hour EHR work completed among providers within a multispecialty academic practice. Methods Time spent completing EHR tasks during evening hours (7p-7a) and days off was prospectively recorded for 35 providers over six consecutive months at a single center. Type and time of EHR tasks completed were compared based on subspecialty, academic degree, academic track category, identified gender, and number of weekly assigned clinical days worked. Prior to the data collection, providers filled out a survey regarding EHR use, work hours, and work–life balance. Results All providers used EHR during evening hours and during days off. The total mean after-hours time spent completing EHR tasks was 18.4 m (± 13.0) per day and 45.0 m (± 25.8) during days off. There was significant variation in the daily mean after-hours time spent completing EHR tasks among subspecialties, range 45.3 m (± 27.1) (advanced endoscopy)-28.7 m (± 22.7) (hepatology), and among providers who work clinically > 7.5 days per week versus those who do not, 42.1 m (± 25.7) vs 30.0 m (± 14.0). The most common after-hours EHR task was note completion. 83% providers reported being unable to complete EHR tasks during allotted workday time and 87% report that EHR tasks interfered with family life; 74% with social life. Conclusion Gastroenterology and hepatology providers spend a significant amount of after-hour time completing EHR tasks which is perceived to interfere with family/social life.
 
Cumulative colonoscopy completion in a national sample of US Veterans with red flag signs and symptoms of CRC pre- vs. intra-COVID-19 pandemic. Survival curves, estimated via Kaplan–Meier approach for the outcome of time to colonoscopy completion, are shown for individuals with red flag signs or symptoms pre- vs. intra-COVID-19 pandemic. The curves demonstrate a similar cumulative proportion with colonoscopy completion for individuals with red flag signs/symptoms post vs. pre-COVID-19 pandemic. Red flags included abnormal FIT/gFOBT, iron deficiency anemia, and hematochezia
Time to colonoscopy pre- and intra-COVID-19 pandemic, stratified by red flag sign/symptom of CRC, in a national sample of 45,012 individuals receiving VHA care. Median time to colonoscopy among colonoscopy completers with red flag signs and symptoms of CRC was shorter in the pre- vs. intra-COVID-19 pandemic period overall. In analyses stratified by red flag, individuals with iron deficiency anemia had significantly shorter time to colonoscopy in the intra- vs. pre-COVID-19 pandemic period. Abbreviation: Fecal immunochemical test/guaiac fecal occult blood test, FIT/gFOBT
Background Delays in colonoscopy work-up for red flag signs or symptoms of colorectal cancer (CRC) during the COVID-19 pandemic are not well characterized. Aims To examine colonoscopy uptake and time to colonoscopy after red flag diagnosis, before and during the COVID-19 pandemic. Methods Cohort study of adults ages 50–75 with iron deficiency anemia (IDA), hematochezia, or abnormal stool blood test receiving Veterans Health Administration (VHA) care from April 2019 to December 2020. Index date was first red flag diagnosis date, categorized into “pre” (April–December 2019) and “intra” (April–December 2020) policy implementation prioritizing diagnostic procedures, allowing for a 3-month “washout” (January–March 2020) period. Outcomes were colonoscopy completion and time to colonoscopy pre- vs. intra-COVID-19, examined using multivariable Cox models with hazard ratios (aHRs) and 95% confidence intervals (CIs). Results There were 52,539 adults with red flag signs or symptoms (pre-COVID: 25,154; washout: 7527; intra-COVID: 19,858). Proportion completing colonoscopy was similar pre- vs. intra-COVID-19 (27.0% vs. 26.5%; p = 0.24). Median time to colonoscopy among colonoscopy completers was similar for pre- vs. intra-COVID-19 (46 vs. 42 days), but longer for individuals with IDA (60 vs. 49 days). There was no association between time period and colonoscopy completion (aHR: 0.99, 95% CI 0.95–1.03). Conclusions Colonoscopy work-up of CRC red flag signs and symptoms was not delayed within VHA during the COVID-19 pandemic, possibly due to VHA policies supporting prioritization and completion. Further work is needed to understand how COVID-19 policies on screening and surveillance impact CRC-related outcomes, and how to optimize colonoscopy completion after a red flag diagnosis. Graphical Abstract
 
Age-specific death rates of ulcerative colitis (UC), Crohn’s disease (CD), Hodgkin lymphoma (HL), and multiple sclerosis (MS) in England & Wales from 1951 to 2020, plotted as period-age contours on a logarithmic scale. Individual age groups and time periods are indicated by their respective mid-years, for instance, 30 instead of 25–34 and 1955 instead of 1951–1960
Age-specific death rates of ulcerative colitis (UC), Crohn’s disease (CD), Hodgkin lymphoma (HL), and multiple sclerosis (MS) in England & Wales from 1951 to 2020, plotted as cohort-age contours on a logarithmic scale. Individual age groups and time periods are indicated by their respective mid-years, for instance, 30 instead of 25–34 and 1865 instead of 1856–1875
Standardized cohort-mortality ratios (SCMR) of ulcerative colitis (UC), Crohn’s disease (CD), Hodgkin lymphoma (HL), and multiple sclerosis (MS) in England & Wales from 1865–1985, with males (M) and females (F) being plotted separately. Birth-cohorts are indicated by their respective mid-years
Superimposed standardized cohort-mortality ratios (SCMR) of ulcerative colitis (UC), Crohn’s disease (CD), Hodgkin lymphoma (HL), and multiple sclerosis (MS) in 6 different countries between 1865 and 1985. Birth-cohorts are indicated by their respective mid-years
Background The Epstein-Barr virus (EBV) plays a role in the causation of Hodgkin lymphoma (HL) and multiple sclerosis (MS). A previous study showed that the time trends of mortality from Crohn’s disease (CD) and MS shared striking similarities. It was hypothesized that such similarities would also involve the time trends of ulcerative colitis and HL. Aims To compare the time trends of CD and UC with those of HL and MS in 6 different countries. Methods Using the vital statistics of England, Canada, Netherlands, Scotland, Switzerland, and United States from 1951 to 2020, the time trends of mortality from these 4 diseases were compared. The time-dependent changes of death rates were subjected to a birth-cohort analysis. Results Similar trends were observed in all 6 countries. UC mortality rose among generations born during the nineteenth century and decreased among all generations born subsequently during the twentieth century. CD mortality was similarly characterized by a birth-cohort pattern with a rise and fall that were shifted by 20–30 years towards more recent generations when compared to UC. The birth-cohort pattern of UC was matched by a similar pattern of HL, whereas the birth-cohort pattern of CD was matched by a similar pattern of MS. Conclusions The similarities in the ubiquitous birth-cohort patterns of UC, CD, HL, and MS suggest that these 4 diseases share a common environmental risk factor. Such risk factor may be linked to EBV or its acquisition during an early period of a patient’s lifetime.
 
Flow diagram of study
Scatter diagram showing correlation of antibody signal/cut-off ratio with Child-Turcotte-Pugh score (A) and model for end-stage liver disease (MELD) score (B)
Introduction Patients with cirrhosis have a higher risk of severe COVID-19 and mortality and are high-priority patients for vaccination. However, cirrhotics were excluded from the phase 2/3 vaccine trials. Hence, we aimed to assess the antibody response and safety of Covishield (ChAdOx1nCoV-19) among patients with cirrhosis. Methods Patients who attended the tele-hepatology services at our institute from March 2020 to June 2021 and diagnosed with cirrhosis as per their medical records were telephonically interviewed in July 2021 using a pre-specified questionnaire. Patients who had completed 2 doses of ChAdOx1-nCOV (with the 2nd dose administered at least 2 weeks back) and without history of documented COVID-19 infection (pre- or post-vaccination) were tested for antibodies against the spike protein. Seropositive patients were divided into high, moderate, and low antibody responses based on the signal/cut-off. Results We interviewed 784 patients with cirrhosis. At least 1 dose of ChAdOx1-nCOV was received by 231 patients among whom 134 (58%) had received 2 doses. Documented COVID-19 was reported in 3.9% patients who received at least 1 dose of ChAdOx1-nCOV including breakthrough infections in 3.7% patients vaccinated with 2 doses. Local and systemic adverse events were reported by 42% and 22.1% patients. None developed anaphylaxis, acute decompensation, acute-on-chronic liver failure, or other serious adverse events requiring hospitalization. Seroconversion was documented in 81 (92%) out of 88 patients. No difference was observed in level of antibody response between patients with compensated and decompensated cirrhosis (p = 0.12). Conclusion Our preliminary data suggest that ChAdOx1-nCOV is safe with high seroconversion rates in patients with cirrhosis.
 
Background Patients with Barrett’s esophagus (BE) and esophageal varices present a unique management dilemma. Endoscopic ablation and endoscopic resection are not suitable treatment options due to bleeding risk. Data are limited on successful eradication of BE and esophageal varices utilizing band ligation. Aims To assess the outcomes of patients with BE and esophageal varices treated with banding. Methods Retrospective analysis of patients with BE and esophageal varices who were treated with band ligation. Results A total of eight patients were included in the case series. In all eight cases, BE and esophageal varices were successfully treated with band ligation alone. There were no bleeding, perforation or infectious complications in any patients undergoing banding for treatment of BE. Four patients had biopsy-proven dysplasia prior to treatment with band ligation. After band ligation, the 2 of 4 dysplastic cases that had repeat biopsies showed histologic resolution of the dysplasia. All patients who received banding for BE were followed at least yearly except for one patient lost to follow up. No interval esophageal cancers were reported in any patients with BE that were banded. Conclusions Band ligation was used to treat BE pathology in eight patients with esophageal varices. Treatment of dysplasia through this method yielded negative biopsies both for dysplasia and BE on repeat endoscopy. This case series highlights the value of utilizing band ligation to address the management dilemma of BE in the context of esophageal varices.
 
The cumulative rates of the development of significant findings in patients with pancreatic cysts based on the three risk groups
Background Predicting the risk of malignant transformation in pancreatic cyst patients is challenging. Aim We retrospectively investigated the risk factors for malignant transformation in pancreatic cyst patients. Methods Patients with pancreatic cysts diagnosed using imaging tests were followed from November 2008 to December 2021. A significant change was defined as the additional development of high-risk stigmata (HRS), worrisome features (WFs), or pancreatic cancer during monitoring. Results In total, 479 patients were analyzed, with a median observation period of 50 months. Forty-four patients (9.2%) showed significant changes, and eight (1.7%) developed pancreatic cancer. The univariate analysis showed that the cyst diameter at diagnosis (≥ 14 mm), main pancreatic duct (MPD) diameter at diagnosis (≥ 3 mm), presence of multilocular cysts, and an inconsistent MPD caliber were significant predictive factors for a significant change. One point was assigned for each significant factor. We grouped the patients into three groups: the low-risk group (total score 0), medium-risk group (score 1–2), and high-risk group (score 3–4). The high-risk group had a higher risk of a significant change than the medium- and low-risk groups (age-adjusted HRs for the medium-risk and high-risk groups were 3.0 and 5.2 compared with the low-risk group). Conclusion Stratification based on risk factors may help predict the development of significant changes in pancreatic cyst patients.
 
Z value for univariate cox proportional hazard analyses of association between complication and laboratory variable (albumin, CRP, MCV, and platelet count), using varying statistical methods to represent the laboratory variable. The event horizon decreases from 720 to 0 days from left to right in each graph. For variables that tend to rise with illness (CRP, platelet count), minimum value during window period was the representative statistic most strongly associated with complication. For variables that tend to fall with illness (albumin, hemoglobin, mean cell volume), maximum value was most strongly associated with complication
Z value for univariate cox proportional hazard analyses of association between complication, and the selected statistical method to represent laboratory variables (albumin, CRP, MCV, and platelet count), with a varying window period. The event horizon decreases from 720 to 0 days from left to right. 365 days is the window period that is most consistently correlated with complication
Z scores for univariate cox proportional hazard analyses of each pathology test, each modeled independently using minimum (white cell count, neutrophil count, platelet count, ALT, CRP, ESR, fecal calprotectin) or maximum (albumin, hemoglobin, ferritin, MCV) of values from a 365-day window period prior to each time point. The event horizon decreases from 720 to 0 days from left to right. Values above the dashed line survive Bonferroni correction
Z score for univariate cox regression of laboratory variables categorized above or below a cut-off. The cut-off used varies along the x axis, and the vertical dotted line represents the cut-off value which gives the strongest association with complication
Receiver Operating Characteristic (ROC) curve for the Longitudinal Laboratory Scoring Tool in predicting a subsequent complication
Background Stenosis, fistulization, and perforation of the bowel are severe outcomes which can occur in patients with Crohn’s disease. Accurate prediction of these events may enable clinicians to alter treatment strategies and avoid these outcomes. Aims To study the correlation between longitudinal laboratory testing and subsequent intestinal complications in patients with Crohn’s disease. Methods An observational cohort of patients with Crohn’s disease at a single center were analyzed between 01/01/1994 and 06/30/2016. A complication was defined as the development of an intestinal fistula, stenosis, or perforation. Exploratory analysis using Cox regression was performed to select the best statistical method to represent longitudinal laboratory data. Cox regression was used to identify laboratory variables independently associated with the development of a subsequent complication. A clinical scoring tool was designed. Results In 246 patients observed over a median of 5.72 years, 134 complications occurred. Minimum or maximum value in a preceding window period of one year was most strongly associated with subsequent complication. A Longitudinal Laboratory score of ≥ 2 (maximum albumin level < 39 g/L = 1, maximum mean cell volume < 88 fL = 1, minimum platelet count > 355 × 10⁹/L = 1, minimum C reactive protein > 5 mg/L = 1) was 62% sensitive and 91% specific in identifying patients who develop a subsequent complication. Conclusion A consistent reduction in serum albumin and mean cell volume, and a consistent increase in platelet count and C reactive protein were associated with a subsequent complication in patients with Crohn’s disease. Longitudinal laboratory tests may be used as described in this paper to provide a rational for earlier escalation of therapy.
 
Anal canal transition zone stem cell isolation. A Anal canal with distal rectum was removed “en bloc.” B The specimen was further dissected on a back table using surgical loop to remove anoderm, sphincters, and remaining rectum. C Standard hematoxylin–eosin staining of a slide demonstrating that only the upper anal canal mucosa was isolated (anoderm was absent). We observed the rectal columnar single-layer epithelium, the transition epithelium [anal transition zone (AZT)], and the multilayer epithelium of the anal canal with numerous glands
Differentiation assay of pig anal canal transition zone stem cells. Representative pictures of differentiation assay. Isolated cells were incubated for 3 weeks with either adipogenic differentiation medium, chondrogenic differentiation medium, or osteogenic differentiation medium. A In contact with adipogenic differentiation medium, isolated cells transformed into adipocytes, as demonstrated by cell morphology and the presence of cytoplasm lipid inclusion after Oil-red-O staining (A2). This differentiation did not occur when control medium was used (A1). B Following incubation of isolated cells with osteogenic medium, we detected the presence of calcium deposits after Alizarin Red S staining, indicating the presence of osteoblasts (B2). Calcium deposits were not shown after control plate staining (B2). C Cell cultured in pellet for chondrocyte differentiation assay. In this Masson’s trichrome staining we observed in the control group (C1) a poor production of collagen type I, whereas cells incubated with chondrogenic differentiation medium (C2) exhibited type I collagen deposit (blue)
Background Utilization of autologous stem cells has been proposed for the treatment of anal incontinence despite a lack of understanding of their mechanism of action and of the physiological healing process of anal sphincters after injury.AimsWe aim to develop a technique allowing isolation and further study of local mesenchymal stem cells, directly from anal canal transition zone in pig.Methods Anal canal was resected “en bloc” from two young pigs and further microdissected. The anal canal transition zone was washed and digested with 0.1% type I collagenase for 45 min at 37 °C. The isolated cells were plated on dishes in mesenchymal stem cell medium and trypsinized when confluent. Cells were further used for flow cytometry analysis and differentiation assays.ResultsThe anal canal transition zone localization was confirmed with H&E staining. Following culture, cells exhibited a typical “fibroblast-like” morphology typical of stem cells. Isolated cells were positive for CD90 and CD44 but negative for CD14, CD34, CD45, CD105, CD106, and SLA-DR. Following incubation with specific differentiation medium, isolated cells differentiated into adipocytes, osteoblasts, and chondrocytes, confirming in vitro multipotency.Conclusions Herein, we report for the first time the presence of mesenchymal stem cells in the anal canal transition zone in pigs and the feasibility of their isolation. This preliminary study opens the path to the isolation of human anal canal transition zone mesenchymal stem cells that might be used to study sphincters healing and to treat anal incontinence.
 
PRISMA flow diagram
Rates of empty stomach using network meta-analysis: A Network diagram (the line represents a direct comparison in studies and width of line represents no. of studies, RR relative risk, CI confidence interval), B Forest plot with Placebo as comparison group (CI confidence interval, NG nasogastric lavage, RR relative risk)
Need for second look endoscopy using network meta-analysis: A Network diagram (the line represents a direct comparison in studies and width of line represents no. of studies, RR relative risk, CI confidence interval), B forest plot with Placebo as comparison group (CI confidence interval, NG Nasogastric lavage, RR relative risk)
Ranking using frequentist approach and graded using P-score 1–100. Note: Higher P-score represented higher rates of empty stomach allowing mucosal visualization. Higher P-score for second look EGD and mortality represent lower rates of these outcomes, respectively. Higher P-score demonstrate lower EGD duration and PRBC requirement (EGD esophagogastroduodenoscopy, NG nasogastric lavage, PRBC packed red blood cell)
Background/Aim Upper gastrointestinal bleeding (UGIB) usually requires esophagogastroduodenoscopy (EGD) for diagnostic and—potentially—therapeutic purposes. However, blood within the gastric lumen may hinder the procedure. Administration of prokinetics like erythromycin has shown efficacy. This network meta-analysis investigates the efficacy of this intervention prior to EGD. Methods We performed a systematic literature search of Embase, PubMed/Medline, and other databases through March 8, 2022 to include randomized controlled trials (RCTs) comparing prokinetic use in EGD for UGIB. We used the DerSimonian-Laird approach to pool data and compare outcomes including need for repeat endoscopy and blood transfusion. Pooled prevalence of proportional outcomes, 95% confidence interval (CI), and p-values were calculated. Results We included eight RCTs with four distinct intervention groups (erythromycin, placebo to erythromycin, nasogastric (NG) lavage and NG lavage + erythromycin) published between 2002 and 2020 with a total of 721 patients (mean age 60.0 ± 3.1 years; 73.2% male). The need for second look endoscopy was significantly lower with erythromycin than placebo (relative risk: 0.42, CI 0.22–0.83, p = 0.01). Using the frequentist approach, the combination of NG lavage and erythromycin (92.2) was rated highest, followed by erythromycin alone (73.1) for higher rates of empty stomach. Erythromycin was rated highest for lower need for packed red blood cell transfusion (72.8) as well as mean endoscopy duration (66.0). Conclusion Erythromycin improved visualization at EGD, reduced requirements for blood transfusion and repeat EGD, and shortened hospital stay. The combination of erythromycin and NG lavage showed reduced mortality.
 
Background Motorized Spiral Enteroscopy (MSE) reduces procedure time and increases insertion depth into the small bowel; however, there is scarce evidence on factors affecting MSE efficacy. Aims To evaluate diagnostic yield and adverse events of MSE including patients with prior major abdominal surgery. Methods A prospective observational study was conducted on patients undergoing MSE from June 2019 to December 2021. Demographic characteristics, procedure time, depth of maximum insertion (DMI), technical success, diagnostic yield, and adverse events were collected. Results Seventy-four anterograde (54.4%) and 62 retrograde (45.6%) enteroscopies were performed in 117 patients (64 males, median age 67 years). Fifty patients (42.7%) had prior major abdominal surgery. Technical success was 91.9% for anterograde and 90.3% for retrograde route. Diagnostic yield was 71.6% and 61.3%, respectively. The median DMI was 415 cm (264–585) for anterograde and 120 cm (37–225) for retrograde enteroscopy. In patients with prior major abdominal surgery, MSE showed significantly longer small bowel insertion time (38 vs 29 min, p = 0.004), with similar diagnostic yield (61 vs 71.4%, p = 0.201) and DMI (315 vs 204 cm, p = 0.226). The overall adverse event rate was 10.3% (SAE 1.5%), with no differences related to prior abdominal surgery (p = 0.598). Patients with prior surgeries directly involving the gastrointestinal tract showed lower DMI (189 vs 374 cm, p = 0.019) with equal exploration time (37.5 vs 38 min, p = 0.642) compared to those with other abdominal surgeries. Conclusions MSE is effective and safe in patients with major abdominal surgery, although longer procedure times were observed. A lower depth of insertion was detected in patients with gastrointestinal surgery.
 
Background The incidence of extrahepatic malignancies (EHMs) after hepatitis C virus (HCV) eradication by interferon (IFN)-based and IFN-free direct-acting antivirals (DAAs) treatment remains unclear. Aims The aim was to evaluate the cumulative incidence of EHMs diagnosed for the first time after the antiviral treatments. Methods We analyzed a total 527 patients with chronic HCV infection and without prior history of any malignancies who achieved sustained virological response by antiviral treatments, including IFN-based (n = 242) or IFN-free DAAs (n = 285). The baseline predictors for EHM occurrence were analyzed using Cox regression analysis. Results Thirty-two patients were diagnosed with EHMs, 14 in IFN-based and 18 in IFN-free DAAs, respectively. The total duration of follow-up was 1,796 person-years in IFN-based and 823 person-years in IFN-free DAAs. The incidence of EHMs in IFN-based and IFN-free DAAs was 7.8 and 21.9 per 1,000 person-years, respectively. The cumulative incidence of EHMs was significantly higher in IFN-free DAAs than IFN-based (p = 0.002). IFN-free DAAs was a single independent predictor for incidence of EHMs (p = 0.012). As for gender, the incidence of EHMs was significantly higher in IFN-free DAAs only in the female cohort (p = 0.002). After propensity score matching, IFN-free DAAs was a single independent predictor for incidence of EHMs in the female patients (p = 0.045). Conclusions The incidence of EHMs after HCV eradication is higher in IFN-free DAAs than IFN-based regimens, especially in female patients. We should carefully follow-up not only HCC but also EHMs after IFN-free DAAs regimens.
 
MLN4924 inhibited PSCs’ growth and the secretion of collagen and CXCL-1 a Representative microphotographs of activated human PSCs. PSCs were stellate-like or spindle-shaped in light microscopy, and lack of lipid droplets in the Oil Red O staining (original magnification: ×200). b Representative microphotographs of immunofluorescence staining of α-SMA and vimentin in PSCs. Activated human PSCs were confirmed by the positive staining of α-SMA and vimentin (original magnification: ×200). c MTT assay showed that MLN4924 inhibited the growth of PSCs in a dose-dependent manner. d–e The effects of MLN4924 and/or GANT61 on the secretion of collagen, CXCL-1 and MCP-1 of PSCs. PSCs were treated with MLN4924 (300 nM) and/or GANT61 (10 μM) for 48 h, then the concentration of soluble collagen in the supernatant of PSCs was measured using the Sircol Collagen Assay, and the concentrations of CXCL-1 and MCP-1 were measured using ELISA
The transcription factor Gli1 was decreased and was related with the collagen and CXCL-1 secretion inhibition of MLN4924 a RT-qPCR (left) and western blot (right) showed that the transcription and expression levels of Gli1 in PSCs were both inhibited after 48 h treatment of MLN4924. b RT-qPCR (left) and western blot (right) confirmed the effective overexpression of Gli1 in PSCs. c MTT assay showed that there were significant difference between the growth of Gli1 overexpressed cells and cells treated with MLN4924 (P < 0.05). d–e The effects of MLN4924 on the secretion of collagen, CXCL-1 and MCP-1 of control PSCs and Gli1 overexpressed PSCs. PSCs were treated with MLN4924 (300 nM) for 48 h, then the concentration of soluble collagen in the supernatant of PSCs was measured using the Sircol Collagen Assay, and the concentrations of CXCL-1 and MCP-1 were measured using ELISA
MLN4924 inhibited the angiogenesis of HMEC-1 cells in a dose-dependent manner. After cells were treated with MLN4924 at indicated concentrations for 48 h, Capillary-like tube formation assay was performed. a Representative microphotographs of the vascular network-like structure formed by HMEC-1 cells (original magnification: × 10). b–e The area, skeleton length, number of branching points and number of branches of the vascular network-like structure formed by HMEC-1 cells after MLN4924 treatment
MLN4924 inhibited the growth and migration of HMEC-1 cells and induced apoptosis in HMEC-1 cells a MTT assay showed that MLN4924 inhibited the growth of HMEC-1 cells significantly. b BrdU assay showed that MLN4924 inhibited the proliferation of HMEC-1 cells significantly. c FACS analysis showed that the percentage of apoptotic cells (Annexin V + and PI ±) was increased in HMEC-1 cells treated with MLN4924. d Migration assay showed that MLN4924 inhibited the migration of HMEC-1 cells significantly
REDD1 was increased by MLN4924 and REDD1 knockdown promoted the angiogenesis of HMEC-1 cells The mTOR agonist 3BDO partially relieved the inhibition of MLN4924 on HEMC-1 cells. a RT-qPCR (left) and western blot (right) showed that the transcription and expression levels of REDD1 in HMEC-1 cells were both promoted after 48 h treatment of MLN4924. b RT-qPCR (left) and western blot (right) confirmed the effective knockdown of REDD1 in HMEC-1 cells. c Representative microphotographs of the vascular network-like structure formed by HMEC-1 cells (original magnification: × 10). d–g Cells were treated with MLN4924 and/or 3BDO (20 μM) for 48 h, and capillary-like tube formation assay was performed. The area, skeleton length, number of branching points and number of branches of the vascular network-like structure formed by HMEC-1 cells treated as indicated
PurposePancreatic cancer is characterized by a dense desmoplasia stroma, which hinders efficient drug delivery and plays a critical role in tumor progression and metastasis. MLN4924 is a first-in-class NEDD8-activating enzyme inhibitor that exhibits anti-tumor activities toward pancreatic cancer, and given the comprehensive effects that MLN4924 could have, we ask what impact MLN4924 would have on the stroma of pancreatic cancer and its underlying mechanisms.Methods Primary pancreatic stellate cells (PSCs) and human HMEC-1 cells were treated with MLN4924 in vitro. The proliferation and extracellular matrix protein levels of PSCs were tested, and their relationship with transcription factor Gli1 in PSCs was investigated. The angiogenic phenotypes of HMEC-1 cells were evaluated using capillary-like tube formation assay, and their relationship with REDD1 in HMEC-1 cells was investigated.ResultsIn this study, we found that MLN4924 inhibited the proliferation of pancreatic stellate cells and their secretion of collagen and CXCL-1, and the collagen secretion inhibiting effect of MLN4924 was related with transcription factor Gli1. MLN4924 inhibited multiple angiogenic phenotypes of HMEC-1 cells, and mTOR agonist partially relieved the inhibition of MLN4924 on HEMCs. MLN4924 increased the expression of REDD1 and REDD1 knockdown promoted the angiogenic phenotypes of HMEC-1 cells.Conclusions Our study suggests that MLN4924 inhibits both the tumor stroma and angiogenesis in pancreatic cancer, and the inhibition effect is related with Gli1 in pancreatic stellate cells and REDD1 in vascular endothelial cells, respectively.
 
Construction and selection of the IRF5 shRNA lentiviral vector. Map of PL6.3-shRNA-BSD vector. BsmBI is the digestion site for the restriction enzyme (A). Sequencing identified the positive recombinant plasmid DNA (B). The lentiviral vector constructed with shRNA oligo IRF5-1198 was found to have the maximal efficiency (C and D). Efficiency of shRNA IRF5 lentiviral vectors derived from the three oligos determined using Western blot (C) and qPCR (D). C, D: n = 6 per group. The data are presented as the mean ± SD. ***p < 0.001, ****p < 0.0001 by one-way ANOVA. BC blank control, NC negative control
Establishment of the depressive-like behavior model and effect of depression on colitis. Depressive-like behavior exacerbated DSS-induced colitis (A–H). Weight change (A) and sucrose preference test (B) validated the depressive-like behavior model. Shorter colon length (C, D), higher DAI score (E), and higher macroscopic (F) and hematoxylin and eosin (H&E)-stained colon sections (G) and histologic score (H) were observed in depressed versus non-depressed colitis rats. A and B: n = 6 rats per group; C–H: n = 8 rats per group. Magnification: ×50, ×100, ×200, ×400. Scale bar: 200 μm, 100 μm, 50 μm, 20 μm correspondingly. Representative transmission electron microscope images delineating the ultrastructural alteration of the colonic epithelial barrier (white triangle) and subepithelial macrophage (white arrow) in colonic section (I). I: n = 5 rats per group. Magnification: Images at the left side, ×25,000 , scale bar = 500 nm; Images at the right side, ×20,000 , scale bar = 1 µm. The data are presented as the mean ± SD. For all panels: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 by one-way ANOVA. DSS dextran sulfate sodium-induced colitis, depr depressive-like behavior, DSS + depr DSS-colitis rats with depressive-like behavior, DAI disease activity index
Effect of depression on macrophage polarization of DSS-colitis rats and expression of IRF5 and IRF5/CD86 co-expression separately. Macrophage polarization toward the M1 phenotype was enhanced in the depressive state. Panels are representative images of colonic specimens stained by immunohistochemistry for CD68 as a pan-macrophage marker, CD86 as M1 macrophage marker, and CD163 as M2 macrophage marker. Magnification 400x, scale bar = 20 µm. Positive cells appear in dark brown (A). Panels summarize the average positive cells in ten randomly selected nonoverlapping high-power fields (B). Representative blots and densitometric analysis for IRF5 expression in colonic specimens of DSS-colitis rats with or without depressive-like behavior (C, D). Representative immunofluorescence images of colonic specimens for dual staining of IRF5 and CD86 (E). Magnification 400x, scale bar = 20 µm. The bar charts show the number ratios of IRF5⁺ and CD86⁺ co-expression cells, and positive cells were averaged in ten randomly selected nonoverlapping high-power fields (F). A-F: n = 6 rats per group. The data are presented as the mean ± SD. For all panels: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 by one-way ANOVA. DSS dextran sulfate sodium-induced colitis, depr depressive-like behavior, DSS + depr DSS-colitis rats with depressive-like behavior
Effect of lentivirus-mediated shRNA-IRF5 interference on colitis with depression, peritoneal macrophage polarization in vitro, macrophage polarization in vivo, and colonic inflammatory cytokine expression. IRF5 silencing switched peritoneal macrophage polarization in vitro from the M1 to the M2 phenotype. Representative images of gating strategy and macrophage subsets in control, IRF5-shRNA treated, and NC-shRNA treated groups (A). Percentage of M1 macrophages was decreased while percentage of M2 macrophages increased in the IRF5 silencing group (B). A-B: n = 5 rats per group. Distribution of shRNA lentivirus with GFP expression in colonic mucosa and submucosa. Magnification 200x; scale bar = 50 µm (C), n = 5 rats. DAI score (D), n = 6 rats per group. Colons were harvested for hematoxylin and eosin (H&E)-stained colon sections (E) and histology score of colonic specimens (F). Magnification 200x; scale bar = 50 µm. E–F: n = 6 rats per group. IRF5 silencing in vivo attenuated M1 macrophage polarization to a greater extent in depressed than in nondepressed DSS-colitis rats without affecting the number of overall macrophages and M2 macrophage polarization (G–L). Shown are the representative images of colonic specimens stained by immunohistochemistry for CD68 as a pan-macrophage marker (G), CD86 as M1 macrophage marker (I), and CD163 as M2 macrophage marker (K). Positive cells appear in dark brown. Magnification 400x, scale bar = 20 µm. The statistical graphs summarize for each marker correspondingly the positive cells averaged in ten randomly selected nonoverlapping high-power fields (H, J, L). G-J: n = 6 rats per group. K and L: n = 10 rats per group. Colon specimens were collected for the measurement of TNF-α (M), IL-1β (N), and IL-10 (O). M and N: n = 6 rats per group. O: n = 10 rats per group. The data are presented as the mean ± SD. For all panels: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 by one-way ANOVA. Control + NS control rats with normal saline administered intrarectally, Control + NC-shRNA control rats treated with NC-shRNA lentiviral vector, Control + IRF5-shRNA control rats with intrarectal administration of IRF5-shRNA lentiviral, DSS + NS nondepressed DSS-colitis rats treated with intrarectal administration of normal saline, DSS + IRF5-shRNA nondepressed DSS-colitis rats treated with intrarectal administration of IRF5-shRNA lentiviral vector, DSS + NC-shRNA nondepressed DSS-colitis rats treated with NC-shRNA lentiviral vector, Depr depressed rats with normal saline administered intrarectally, Depr + IRF5-shRNA depressed rats treated with IRF5-shRNA lentiviral vector, Depr + NC-shRNA depressed rats treated with NC-shRNA lentiviral vector, DSS + depr + NS depressed DSS-colitis rats treated with normal saline intrarectal administration, DSS + depr + IRF5-shRNA depressed DSS-colitis rats treated with IRF5-shRNA lentiviral vector, DSS + depr + NC-shRNA depressed DSS-colitis rats treated with NC-shRNA lentiviral vector
Background and AimsPatients with inflammatory bowel disease (IBD) and concurrent depression are predisposed to severer disease activity and a worse prognosis. Macrophage polarization toward the M1 phenotype may contribute to the exacerbation of IBD with comorbid depression. Moreover, interferon regulatory factor 5 (IRF5) is involved in the pathogenesis of IBD. The aim of this study was to explore the role of IRF5 in macrophage polarization in the impact of depression upon colitis.Methods Depressive-like behavior was induced by repeated forced swim stress. Colon length, disease activity index (DAI), colon morphology, histology, ultrastructure of epithelial barrier, lamina propria macrophage polarization, and expression of IRF5 were compared between DSS colitis rats with and without depressive-like behavior. IRF5 shRNA was constructed to affect the rat peritoneal macrophages polarization in vitro. After IRF5 shRNA lentivirus was introduced into colon by enema, the colitis severity, lamina propria macrophage polarization, and TNF-α, IL-1β, and IL-10 of colon tissues were measured.ResultsThe study found severer colonic inflammation in depressed versus non-depressed DSS-colitis rats. Depressed DSS-colitis rats exhibited smaller subepithelial macrophages size and reduced intracellular granule diversity compared with nondepressed DSS-colitis rats. Increased polarization toward the M1 phenotype, elevated expression of IRF5, and co-expression of IRF5 with CD86 were found in depressed versus nondepressed DSS-colitis rats. Lentivirus-mediated shRNA interference with IRF5 expression switched rat peritoneal macrophage polarization from the M1 to the M2 phenotype, downregulated TNF-α, IL-1β expression to a greater extent in depressed versus nondepressed colitis rats.ConclusionsIRF5-mediated macrophage polarization may likely underlie the deterioration of DSS-induced colitis caused by depression.
 
Unadjusted and inverse probability treatment weighted covariate balance
Association between infection type and number of organ failures, stratified by admission MELD-Na
Association between infection type and 90-day mortality for A increasing ACLF grades and B increasing number of organ failures
Background Acute-on-chronic liver failure (ACLF) is a syndrome in patients with cirrhosis with high short-term mortality. Infection is a frequent precipitant of ACLF; however, it is unclear if prognosis varies by difference infectious sources. To address this knowledge gap, we utilized a large national database of patients with cirrhosis.Methods This was a retrospective cohort study of patients with cirrhosis in the Veterans Health Administration between 2008 and 2016. First ACLF hospitalizations were identified and infections were classified using validated algorithms, categorized as bacteremia, fungal, spontaneous bacterial peritonitis (SBP), pyelonephritis/urinary tract infection, or skin and soft tissue/musculoskeletal infection (SST/MSK). Inverse probability treatment weighing for infection-associated ACLF followed by multivariable logistic regression was used to evaluate the association between infection type and 90-day mortality.ResultsA total 22,589 ACLF hospitalizations were included, 3998 (17.7%) of which had ACLF grade 3. Infection was associated with 12,405 (54.9%) of ACLF hospitalizations. In regression models, SBP was associated with a 1.79-fold increased odds of 90-day mortality vs. no infection (95% confidence interval [CI] 1.58–2.02, p < 0.001), whereas SST/MSK infections had a lower relative odds of mortality (odds ratio 0.48, 95% CI 0.42–0.53, p < 0.001). There was a significant interaction between infection category and ACLF grade on the outcome of 90-day mortality (p < 0.001).Conclusions The impact of infection on short-term mortality in ACLF varies depending on the source of infection. This has relevance for ACLF prognostication and challenges previous notions that bacterial infection invariably worsens prognosis among all patients with ACLF.
 
Background The COVID-19 pandemic has brought new problems to patients infected with hepatitis B virus (HBV). AimWe aim to know the effects of HBV infection on patients with COVID-19.Methods We searched PubMed, Embase, and Web of Science for data and utilized Stata 14.0 software for this meta-analysis with a random-effects model. This paper was conducted in alignment with the preferred reporting items for systematic review and meta-analysis (PRISMA) guideline.ResultsIn total, 37,696 patients were divided into two groups: 2591 COVID-19 patients infected with HBV in the experimental group and 35,105 COVID-19 patients not infected with HBV in the control group. Our study showed that the in-hospital mortality of the experimental group was significant higher than that of the control group (OR = 2.04, 95% CI 1.49–2.79). We also found that COVID-19 patients infected with HBV were more likely to develop severe disease (OR = 1.90, 95% CI 1.32–2.73) than COVID-19 patients not infected with HBV. Upon measuring alanine aminotransferase (SMD = 0.62, 95% CI 0.25–0.98), aspartate aminotransferase (SMD = 0.60, 95% CI 0.30–0.91), total bilirubin (SMD = 0.45, 95% CI 0.23–0.67), direct bilirubin (SMD = 0.36, 95% CI 0.24–0.47), lactate dehydrogenase (SMD = 0.32, 95% CI 0.18–0.47), we found that HBV infection led to significantly higher laboratory results in COVID-19 patients.ConclusionCOVID-19 patients infected with HBV should receive more attention, and special attention should be given to various liver function indices during treatment.
 
Receiver-operating characteristic curves (females and males) for different variables used for assessment of nutritional status
Background Inflammatory bowel disease (IBD) is associated with an increased risk of malnutrition and sarcopenia. Aims To evaluate the nutritional status of patients with IBD and determine the threshold values of different parameters of nutritional assessment to identify malnutrition. Methods This was a single-centre cross-sectional analysis of adult patients with IBD [ulcerative colitis (UC) and Crohn’s disease (CD)] who underwent anthropometry [body mass index (BMI), mid upper arm circumference (MUAC) and triceps-fold thickness (TSF)], body composition analysis and assessment for sarcopenia [hand-grip strength and skeletal muscle index (SMI) at L3 vertebral level)]. Age- and gender-matched healthy adults served as controls. Malnutrition was defined according to the European Society of Clinical Nutrition and Metabolism (ESPEN) criteria. Results A total of 406 patients [336 (82.76%) UC and 70 (17.24%) CD; mean age 40.56 ± 13.67 years; 215 (52.95%) males] with IBD and 100 healthy controls (mean age 38.69 ± 10.90 years; 56 (56%) males) were enrolled. The mean BMI, MUAC, TSF thickness, fat and lean mass, hand-grip strength, and SMI at L3 vertebral level were lower in patients with IBD compared to controls. The prevalence of malnutrition was similar in UC and CD [24.40% (n = 82) and 28.57% (n = 20), respectively (p = 0.46)]. Thresholds for fat mass in females (15.8 kg) and visceral fat index in males (0.26) were both sensitive and specific to detect malnutrition. The cutoff values of MUAC and TSF thickness to identify malnutrition were 23.25 cm and 25.25 cm, and 16.50 mm and 8.50 mm, in females and males, respectively. Conclusion Malnutrition and sarcopenia were common in patients with IBD, with the prevalence being similar in patients with both UC and CD.
 
sCD30 levels in A all patients with UC and non-UC, B treatment-naïve patients with UC and non-UC, C patients with or without endoscopic remission and D with or without clinical remission. UC ulcerative colitis
Correlation between sCD30 levels and A C-reactive protein, B platelet count, C erythrocyte sedimentation rate, D albumin and E fecal calprotectin. Patients are grouped according to diagnosis and clinical remission status. CD Crohn’s disease, IBD-U inflammatory bowel disease unclassified, UC ulcerative colitis
Proportion of A CD30 + live cells and B CD30 + CD4 T lymphocytes in individual bowel segments in patients with UC and non-UC. UC ulcerative colitis
A representation of individual mucosal lymphocyte subsets in individual bowel segment in patients with UC and non-UC. UC ulcerative colitis
Background Inflammatory bowel diseases (IBD) frequently manifest in pediatric age, but may have atypical clinical, histological and laboratory features. Their underlying immune pathophysiology is incompletely understood, rendering quick diagnosis followed by tailored therapy difficult. The tumor necrosis factor superfamily receptor CD30 has been proposed as a potential marker of ulcerative colitis (UC) and has also been associated with elevated Th2 helper T cells.MethodsA cohort of pediatric patients with UC and Crohn’s disease (CD) was evaluated for serum soluble CD30 (sCD30) using ELISA and expression of CD30 and subpopulations of Th1/Th2/Th17 lymphocytes in the gastrointestinal mucosa using flow cytometry (FCM). The dataset is supported by endoscopic and microscopic activity of the disease and basic laboratory markers of inflammation.ResultsThe cohort consisted of 102 observations from 94 patients. sCD30 levels did not differ between patients with CD or UC. However, sCD30 levels correlated with levels of CRP, ESR, fecal calprotectin and albumin and also with clinical activity of the disease in patients with both UC and CD. FCM was not helpful in evaluation of mucosal CD30, which was lowly expressed and not associated with the diagnosis or disease activity. We show augmented Th2 and Th1/17 response in terminal ileum and right-sided colon and decreased Th1/17 response in left-sided colon of UC patients. T lymphocyte subsets were also affected by anti-TNF treatment and patients’ age.Conclusions Neither sCD30 nor mucosal CD30 expression was helpful in differentiating between UC and CD. sCD30 seems to reflect a degree of systemic inflammation and clinical activity in IBD.
 
IntroductionDupilumab blocks IL4/IL13 and is used in atopic disease. There are concerns that blockade may lead to inflammatory bowel disease (IBD) inception or activity. Limited data exist on the use of this therapy in patients with IBD; we aimed to describe our experience using dupilumab in IBD to treat concomitant atopic dermatitis (AD) or anti-TNF-induced dermatitis.Methods We analyzed the electronic medical records (2018–2022) in a single, tertiary care center to identify patients with IBD on dupilumab. Clinical and demographic data were gathered, including disease location/behavior, personal/family history of atopy, indication for and response to dupilumab, IBD medication history, and adverse events.ResultsSeventeen patients (65% Crohn’s) were identified with IBD on dupilumab for dermatitis; 9 for severe AD and 8 for a worsened dermatitis, either AD or psoriasiform dermatitis (PD), induced by anti-TNF. They were treated for a median 1.2 [IQR 0.6–2.3] years. All patients had a dermatologic response to dupilumab and remained on dupilumab at last follow-up. No adverse events were identified, including no increase in IBD activity. In those with dermatitis worsened or induced by anti-TNF, all started dupilumab in combination with another biologic: 3 with anti-TNF, 4 with ustekinumab, and 1 with vedolizumab. Seven of the eight had a response to the initial combination of biologics; however, one patient using dupilumab–anti-TNF ultimately changed to combination dupilumab–ustekinumab to achieve resolution of the dermatitis.Conclusion Dupilumab is safe and effective for dermatitis in patients with IBD, both primary atopic dermatitis and dermatitis induced or worsened by anti-TNF.
 
Background Colorectal cancer is a leading cause of cancer-related death worldwide and approximately 20% of cases can be attributed to a mutation in the BRAF oncogene. Curcumin is a promising chemopreventive agent with various anti-cancer benefits. Although curcumin has been reported to have poor bioavailability, this limitation has been overcome by the formulation of nano-carriers. In this preclinical study, we investigated the ability of an improved formulation of curcumin to reduce the incidence of Braf mutant carcinoma. Aim To investigate curcumin as a chemopreventive for Braf mutant colorectal cancer in a preclinical study utilizing a murine model of serrated neoplasia. Methods An intestine-specific Braf mutant murine model (Braf V637E/+ /Villin-Cre ERT2/+) was administered curcumin micelles (240 mg/kg, n = 69) in normal drinking water. Mice in the control group consumed normal drinking water (n = 83). Mice were euthanized at 14 months and the incidence of murine serrated lesions and carcinoma in each cohort were determined by histologic examination. Results At completion of the study (14 months), it was found that curcumin did not reduce the incidence or multiplicity of murine serrated lesions but did significantly reduce the number of invasive carcinomas (RR 0.83, 95% CI 0.69-0.9985, P = 0.0360) compared to control. Conclusions We have performed the first long-term study assessing curcumin's effect on the development of serrated neo-plasia. We found that curcumin significantly reduces the risk of developing Braf mutant colorectal cancer. Our data supports further investigation of curcumin as a chemopreventive to reduce the risk of colorectal cancer arising via the serrated pathway.
 
Schematic presentation of the main environmental factors associated with the development of IBD during childhood (with appropriate references)
a Deductive methodology and keywords. b Flowchart of the evidence selection process
To review and discuss recent findings on the associations between pediatric/early-life exposures to ambient air pollution and the risk of pediatric-onset inflammatory bowel diseases (IBD). A scoping review was conducted using the Peters Micah et al. framework. We searched, selected, extracted, and reviewed information from published peer-reviewed papers from three bibliographic databases, chosen to cover a broad range of disciplines. Limits on date (last decade), language, and subject were placed on the database search. The search identified 109 papers from 2010 to June 2021. After screening, we identified nine articles with data on air pollution as a risk factor for IBD, but only four epidemiologic studies directly investigated the association between air pollution and IBD development in children and young adults. These four papers show that air pollution components have different associations with pediatric IBD (pIBD) incidence. Consequently, sulfur dioxide (SO2), nitrogen dioxide (NO2), and the oxidant capacity of air pollution (Ox) were positively associated with pIBD incidence, whereas the association effects of particulate matter (PM) and ozone (O3) exposures were not clear. Despite good scientific rationale and some studies, the evidence on the role that air pollution has in IBD development is limited, highlighting the need for further investigation. Future studies should include the epidemiology of air pollutants and its sources, identifying and understanding mechanisms linking air pollution and pIBD, and identifying signatures of biological responses to air pollutants. Graphical Abstract
 
Longitudinal hospitalization-related outcomes in patients with IBD with and without psychiatric comorbidity
Background and Aims Patients with inflammatory bowel disease (IBD) frequently experience comorbid psychiatric disorders, which negatively impact quality of life. We characterized the longitudinal burden of hospitalization-related healthcare utilization in adults with IBD with and without comorbid anxiety, depression, or bipolar disorder. Methods In the 2017 Nationwide Readmissions Database (NRD), we identified 40,177 patients with IBD who were hospitalized between January 1, 2017 and June 30, 2017 and who were followed until December 31, 2017. In this cohort, we compared the annual burden (i.e., total days spent in hospital), costs, risk of readmission, inpatient mortality, and IBD-related surgery in patients with and without comorbid psychiatric disorders (anxiety, depression, or bipolar disorder). Results Of the 40,177 adults who were hospitalized for IBD, 25.7% had comorbid psychiatric disorders. Over a 10 month-long period of follow-up, patients with comorbid psychiatric disorders spent more days in the hospital (median, 7 days vs. 5 days, p < 0.01), experienced higher 30-day (31.3 vs. 25.4%; p < 0.01) and 90-day (42.6 vs. 35.3%, p < 0.01) readmission rates, and had higher hospitalization-related costs (median, $41,418 vs. $39,242, p < 0.01). However, they were less likely to undergo IBD-related procedures or surgeries. There were no differences in risk of mortality. On Cox proportional hazard analysis, the presence of comorbid psychiatric disorders was associated with a 16% higher risk of readmission (HR, 1.16; 95% CI, 1.13–1.20) and a 13% higher risk of severe IBD-related hospitalization (HR, 1.13; 95% CI, 1.08–1.16). Conclusions In adults with IBD, comorbid psychiatric disorders were independently associated with a higher burden and cost of hospitalization, without an increase in the risk of IBD-related surgery or procedures. Population-based interventions aimed at treating psychiatric comorbidities may decrease the risk of unplanned healthcare utilization.
 
Recruitment and Retention of Patient Participants
Background Women with inflammatory bowel disease (IBD) with poor IBD-specific reproductive knowledge experience more childlessness and fear of IBD medications in pregnancy. The Pregnancy in IBD Decision Aid (PIDA), developed by an international multidisciplinary team, offers personalized online decision support regarding pregnancy in IBD. Aims Assess the impact of PIDA on quality of reproductive decision-making and pregnancy-related knowledge among preconception (PC) and pregnant patients with IBD, and evaluate acceptability to patients and clinicians. Methods PC and pregnant patients with IBD aged 18–45 completed questionnaires pre- and post-PIDA to assess quality of decision-making (Decisional Conflict Scale (DCS); Decision Self-Efficacy Scale (DSES) and IBD-in-pregnancy knowledge (Crohn's and Colitis Pregnancy Knowledge Score (CCPKnow)). Paired t test assessed for differences pre- and post-PIDA. Patients and clinicians completed acceptability surveys. Results DCS and DSES were completed by 74 patients (42 Crohn’s disease, 32 ulcerative colitis); 41 PC and 33 pregnant. DCS improved significantly post-PIDA in PC patients regarding pregnancy planning (t(40) = 4.83, p < 0.0001, Cohen’s dz = 0.75) and in pregnant patients regarding medication management (t(32) = 2.37, p = 0.0242, dz = 0.41). DSES for PC patients improved significantly post-PIDA (t(40) = -3.56, p = 0.001, dz = -0.56). CCPKnow improved significantly post-PIDA in PC (t(42) = 4.93, p < 0.0001, dz = -0.75) and pregnant patients (t(32) = 5.1, p < 0.0001, dz = -0.89). PIDA was deemed optimal for length, readability, and content amount and considered highly useful by patients (n = 73) and clinicians (n = 14). Conclusions Patients using PIDA developed an improved quality of reproductive decision-making and IBD-in-pregnancy knowledge. PIDA is an accessible tool that can empower women with IBD to make values-congruent, evidence-based decisions regarding pregnancy and may reduce voluntary childlessness.
 
PRISMA flowchart describing the study screening and selection process
Objectives During the summer of 2021, case reports began to emerge documenting a small number of individuals who developed autoimmune hepatitis (AIH) following COVID-19 vaccination. These cases are rare and novel, and very little is known. In our systematic review, we analyzed every published case of AIH and reviewed their characteristic findings, treatment, and outcomes. Methods We searched PubMed, Embase, and Web of Science from December 1, 2019, to November 1, 2021. Two researchers independently extracted information from the articles about vaccine type, patient history, laboratory values, histology results, treatment regimens, and disease course. Results Thirty-two patients developed AIH-like syndromes after receiving a COVID-19 vaccine. Jaundice was the most frequently reported symptom (81%), and 19% of patients were initially asymptomatic and presented with elevated liver enzymes found during routine bloodwork. Mean alanine transaminase, aspartate transaminase, and total bilirubin were 1231 U/L, 921 U/L, and 14 mg/dL, respectively. Anti-nuclear antibody was positive in 56%, and anti-smooth muscle antibody in 28% of patients. Steroids were used in 75% of patients. Improvement or complete resolution was seen in 97% of patients. One patient died despite aggressive steroid treatment. Conclusion COVID-19 vaccine-induced AIH is an uncommon association with just 32 documented cases in the literature. Clinicians should be vigilant for AIH in patients who present with liver injury following vaccination. These new findings should under not deter individuals from getting vaccinated, as the benefits of vaccination far outweigh the risks. Fortunately, COVID-19 vaccine-induced AIH appears amendable to corticosteroid therapy and appears to have a favorable outcome.
 
Background Cereals are known to trigger for wheat allergy, celiac disease and non-celiac wheat sensitivity (NCWS). Inflammatory processes and intestinal barrier impairment are suspected to be involved in NCWS, although the molecular triggers are unclear. Aims We were interested if different bread types influence inflammatory processes and intestinal barrier function in a mouse model of inflammatory bowel disease. Methods Epithelial caspase-8 gene knockout (Casp8ΔIEC) and control (Casp8fl) mice were randomized to eight groups, respectively. The groups received different diets for 28 days (gluten-free diet, gluten-rich diet 5 g%, or different types of bread at 50 g%). Breads varied regarding grain, milling and fermentation. All diets were isocaloric. Results Regardless of the diet, Casp8ΔIEC mice showed pronounced inflammation in colon compared to ileum, whereas Casp8fl mice were hardly inflamed. Casp8fl mice could tolerate all bread types. Especially yeast fermented rye and wheat bread from superfine flour but not pure gluten challenge increased colitis and mortality in Casp8ΔIEC mice. Hepatic expression of lipopolysaccharide-binding protein and colonic expression of tumor necrosis factor-α genes were inversely related to survival. The bread diets, but not the gluten-rich diet, also decreased colonic tight junction expression to variable degrees, without clear association to survival and inflammation. Conclusions Bread components, especially those from yeast-fermented breads from wheat and rye, increase colitis and mortality in Casp8ΔIEC mice highly susceptible to intestinal inflammation, whereas control mice can tolerate all types of bread without inflammation. Yet unidentified bread components other than gluten seem to play the major role.
 
Flow chart of the study
Kaplan–Meier curves of the rates of distal biliary stent migration between straight and double-pigtail stents
Kaplan–Meier curves of the rates of distal biliary stent migration between straight and double-pigtail stents in the subset (n = 297) of temporary stenting procedures (up to 6 months)
Background Prolonged biliary stenting may be considered in high-risk patients with irretrievable bile duct stones (IBDS). Distal stent migration (DSM) is a known complication, although data beyond the recommended interval of temporary stenting (3–6 months) are lacking. We compared the long-term incidence of DSM between straight and double-pigtail stents in patients with IBDS. Methods Consecutive patients with IBDS undergoing plastic biliary stenting (1/2009–12/2019) were retrospectively reviewed. DSM was confirmed on follow-up examination when the stent was no longer present at the papillary orifice nor fluoroscopically visible in the bile duct. Kaplan–Meier and Cox regression analyses were used to determine estimates and predictors of DSM. Results Overall, 618 biliary stenting procedures (410 patients) were included: 289 with a straight stent (group A) and 329 with a double-pigtail (group B). By Kaplan–Meier analysis, the DSM rates were 8.4 and 14.6% at 6 months, 21.4 and 27.7% at 12 months, 27 and 43.5% at 18 months, and 37.2 and 60.4% at 24 months, for groups A and B, respectively (p = 0.004). Double-pigtail stents were at higher risk for DSM (HR = 7.38, p = 0.04), whereas an inverse correlation was noted with age (HR = 0.97, p = 0.0001). Considering only temporary stenting procedures (≤ 6 months; n = 297), the probability of DSM was not significantly different between the two groups (p = 0.07). Conclusions In a setting of prolonged stenting for IBDS, the probability of DSM appears to be higher when a double-pigtail stent is used and in younger patients. A relative anti-migratory advantage of double-pigtail over straight stents appears negligible in this study.
 
Study flowchart
Comparison of cecal intubation time between the supine position and left lateral position groups
Comparison of cecal intubation times among individual endoscopists between the supine position and left lateral position groups
Background A history of abdominal surgery is associated with difficulty in colonoscopy insertion. Few studies have reported effective colonoscopy insertion for patients who underwent abdominal surgery due to stomach cancer. Aim We aimed to compare the impact of supine position (SP) and left lateral position (LLP) as the starting position of colonoscopy insertion in patients who underwent abdominal surgery due to stomach cancer. Methods This was a prospective, randomized controlled trial. Patients undergoing colonoscopy for screening or post-polypectomy surveillance after gastrectomy due to stomach cancer were enrolled and randomized to the SP or LLP group as the starting position of colonoscopy insertion. All colonoscopic examinations were performed with a transparent cap. The primary outcome was to compare the cecal intubation time between the two groups. Results A total of 224 patients were enrolled. The mean cecal intubation time was not significantly different between the SP and LLP groups (364.5 s versus 306.9 s; p = 0.105). In patients with a lower body mass index (< 21 kg/m²) or who underwent gastrectomy within three years, the mean cecal intubation time of the LLP group was shorter than the SP group. In the multivariate analysis for the factors affecting to increase in the cecal intubation time (> 5 min), the starting position was not an independent factor. Conclusion Either the SP or LLP could serve as a possible starting position of colonoscopy insertion for patients who underwent abdominal surgery due to stomach cancer.
 
Background and Aims Acute pancreatitis (AP) is an acute inflammatory disease that can lead to death. Mir-325-3p is strongly and abnormally expressed in many diseases, necessitating exploration of its function and mechanism in AP. Methods Blood samples from AP patients and mice were analyzed. The expression levels of miR-325-3p in AP patients and mouse were detected. Whether miR-325-3p targets RIPK3 gene was predicted by TargetScan online database and dual luciferase reporter assay. In vitro experiments verified the effect of miR-325-3p overexpression on caerulein-induced MPC83 pancreatic acinar cancer cell line. In vivo experiments verified the effect of overexpression of miR-325-3p on the disease degree of pancreatic tissues in AP mice. Results Analysis of blood samples from AP patients and experiments in mice demonstrated that expression of miR-325-3p was significantly reduced during the process of AP in humans and mice. Predicted using the TargetScan online database and through dual luciferase reporter assay detection, miR-325-3p directly targets the RIPK3 gene. In vitro experiments revealed that overexpression of miR-325-3p reversed caerulein-induced apoptosis and necroptosis in MPC83 pancreatic acinar cancer cell line. We used Z-VAD-FMK to assess necroptosis and demonstrated that miR-325-3p targets necroptosis to reduce cell damage. In subsequent experiments in mice, we verified that overexpression of miR-325-3p reduces inflammation, edema, hemorrhage, and necrosis in acute pancreatitis. Characteristic western blot, immunohistochemistry, and transmission electron microscopy results revealed that overexpression of miR-325-3p reduces the severity of acute pancreatitis by inhibiting pancreatic necroptosis in AP mice. Conclusions The current research results indicate that miR-325-3p directly targets RIPK3 and exerts a protective role in mouse AP. Necroptosis is still the primary mechanism of RIPK3 regulation. MiR-325-3p inhibits acute pancreatitis by targeting RIPK3-dependent necroptosis, which may represent a novel treatment method for acute pancreatitis.
 
Health Belief Model of H. pylori Eradication Treatment. The left panel in the framework represents context (blue box), which includes the existing knowledge and experiences that an individual draws upon to make a decision regarding whether to accept H. pylori eradication treatment. Participants’ experience with the healthcare system and their existing knowledge and understanding of H. pylori and eradication treatment comprised the major contextual themes for decision-making. The central panel (green box) of the framework includes the current attitudes and beliefs that the patient holds about H. pylori including perceived severity of H. pylori, perceived susceptibility to cancer, antibiotic beliefs, and perceived treatment efficacy. New knowledge (yellow box) includes the categories of information typically conveyed by providers, ideally as the foundation of shared decision-making. The decision regarding therapy is additionally influenced by internal and external cues to action for treating H. pylori. Experienced barriers (tan box) may function as a modifier of health beliefs, or may directly influence the decision to seek treatment. Beliefs, new knowledge, barriers, and cues to action all interact to influence H. pylori treatment decisions
Background Helicobacter pylori eradication is associated with reduced gastric cancer and peptic ulcer disease incidence and mortality. Factors influencing patients’ experiences surrounding H. pylori diagnosis and management are not well-described. Current patient perceptions can influence adherence to treatment, and also their anxieties related to this potentially carcinogenic condition. The objective of this study was to understand the patient experience surrounding H. pylori management and to qualitatively construct a contextual framework to inform and guide providers who manage patients with H. pylori infection. Methods We conducted a qualitative analysis using a focus group and one-on-one telephone interviews. An iterative inductive/deductive approach was applied to recorded transcripts to identify and hierarchically order themes. Patient experience was defined according to major themes within a structured health behavior framework. Results Theme saturation was achieved with thirteen participants (mean age 50.4 years; 62% female; 38% non-Hispanic white). Qualitative analysis yielded a total of 987 codes that resulted in five major themes related to the patient H. pylori experience: context of decision-making; health beliefs; barriers experienced; cues to action; and impact of new knowledge. These themes aligned with the Health Behavior Model framework. Participants were motivated to treat H. pylori. However, the experience was more often perceived negatively versus positively. The perceived patient-provider interaction contributed most prominently to the negative experience compared to other patient experiences, including treatment-related side effects. Internal cues, including symptoms and fear of cancer, modified participants’ perceptions and motivation to accept treatment. Conclusions Patient experiences related to H. pylori management are predominantly negative. Increasing providers’ awareness about patients’ values, beliefs, anxieties, and expectations surrounding H. pylori diagnosis/treatment may improve provider-patient communication and, ideally, related outcomes.
 
Background Alcoholic hepatitis (AH) is a clinically diagnosed syndrome with high short-term mortality for which liver transplantation may be curative. A lack of validated algorithms to identify AH hospitalizations has hindered clinical epidemiology research. Methods This was a retrospective cohort study of patients with cirrhosis using Veterans Health Administration (VHA) data from 2008 to 2015. We randomly sampled hospitalizations based upon abnormal liver tests and administrative codes for acute hepatitis or alcohol-associated liver disease (ALD). Hospitalizations were manually adjudicated for AH per society guidelines. A priori algorithms were evaluated to compute positive predicted value (PPV) and positive likelihood ratio (LR+), and were tested in an external University of Pennsylvania Health System (UPHS) cohort. Results Of 368 hospitalizations, 142 (38.6%) were adjudicated as AH. AH patients were younger (55 vs. 58 years, p < 0.001), less likely to have prior cirrhosis decompensation (57% vs. 73.9%, p < 0.001), and had higher AST-to-ALT ratios (median 2.9 vs. 1.9 mg/dL, p < 0.001) and higher bilirubin levels (median 2.9 vs. 1.9 mg/dL, p < 0.001). Algorithms combining clinical laboratory criteria (AST > 85 U/L but < 450 U/L, AST-to-ALT ratio > 2, total bilirubin > 5 mg/dL) and administrative coding criteria yielded the highest PPV (96.4%, 95% CI 87.7–99.6) and the highest LR+ (43.0, 95% CI 10.6–173.5). Several algorithms demonstrated 100% PPV for definite AH in the UPHS external cohort. Conclusion We have identified algorithms for AH hospitalizations with excellent PPV and LR+. These high-specificity algorithms may be used in VHA datasets to identify patients with high likelihood of AH, but should not be used to study AH incidence.
 
G-POEM and direct biopsy of the MP inside a submucosal tunnel. Upper: GPOEM procedure: Incision, tunneling, pyloric myotomy, endoclip closure. Lower: direct biopsy of ICC inside the submucosal tunnel at GPOEM
ICC in gastric biopsy sample in patients with gastroparesis. Hematoxylin and eosin-stained sections of smooth muscle cells, blue arrows (A-4 × magnification and B-10 × magnification). DOG-1* immunohistochemical stain highlighting Interstitial Cells of Cajal, blue arrows(C-4 × magnification and D-10 × magnification)
Background The role of Interstitial Cells of Cajal (ICC) in the pathogenesis of gastroparesis has been suggested by previous studies due to their involvement in the transmission of neuronal signaling to the smooth muscles of the GI tract. However, studies have been limited by the inability to obtain a gastric muscle sample, since routine endoscopy can only biopsy the mucosa. We present a new technique of muscle biopsy during per-oral endoscopic pyloromyotomy (GPOEM), a novel endoscopic procedure for treatment of gastroparesis.Patients and Methods All enrolled patients had diagnosed gastroparesis and had biopsies of the muscular layer at the antrum/pylorus during POEM. All GPOEM procedures took place from August 2019 to December 2019. Various demographic, disease-related, and procedure-related data were collected from chart review. ICC in the biopsy specimen was examined and quantitated.ResultsThrough this method, we readily expose the gastric muscle of 21 patients through dissection of a gastric submucosal tunnel during GPOEM and provide reliable muscle sample for ICC quantification. Average number of ICC were higher in clinical responders (88 ICC ± 63 vs. 39 ICC ± 24, p = 0.02), defined as those who experienced significant improvement in nausea and vomiting symptoms after GPOEM.Conclusions This study provides a reliable novel biopsy method for safely biopsy gastric muscle for quantitating the number of gastric ICC in patients with gastroparesis. The number of ICC may be related to the outcome of GPOEM therapy. However, further studies with larger number of patients are needed to confirm the results.
 
Modern civilization generates novel challenges to the immune system. Co-evolution with certain microbes prevalent in natural ecosystems provided selective pressure for human genes. However, with today’s modern lifestyle, the human population spends up to 90% of their lives indoors. This new sterile living environment and associated deficiency in infectious stimuli, together with excessive chemical exposure and physiological disturbances, leads to disruption of immune homeostasis
An overview of some frequently ingested classes of environmental factors, including intentional food and drink additives, such as emulsifiers, thickening/bulking agents, or sweeteners, and unintentional food and drink contaminants, such as persistent organic pollutants, pesticides, heavy metals, microplastics, particulates and advanced glycation end-products (AGEs)
A mechanism of environmental factor-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. (1) Environmental factor-induced endoplasmic reticulum (ER) stress leads to (2) release of calcium and reactive oxygen species (ROS) from the ER lumen into the cytoplasm. (3) Mitochondrial calcium uptake combined with environmental factor-induced mitochondrial dysfunction leads to (4) increased ROS production and release from the mitochondria into the cytoplasm (5) inducing oxidative stress. (6) Homeostasis-altering molecular processes (HAMP) detection (7) activates NLRP3 inflammasome formation with adaptor-apoptosis-associated-speck-like protein containing a caspase recruitment domain (ASC) and caspase-1
Mechanism for onset and maintenance of environmental factor-induced chronic inflammation in the gastrointestinal tract. Multiple steps may occur concurrently, such as: 1—Induction of gastrointestinal dysbiosis, associated with increased mucolytic bacteria and adherent-invasive bacteria. 2—Depletion of mucus by mucolytic bacteria and decreased mucin-2 expression. 3—Hyperpermeability due to downregulation of tight junction proteins and IEC cell death, with decreased renewal by IESCs. 4—Increased infiltration of commensal and pathogenic bacteria, endotoxins and environmental factors. 5—Cellular stress (endothelial stress and oxidative stress). 6—Immune cell activation and recruitment, endothelial cell activation. 7—Expression of pro-inflammatory cytokines. 8—Increased systemic dissemination of pathogens, endotoxins and environmental factors. Unintentional food contaminant (UFC), intentional food additive (IFA), dendritic cell (DC), endothelial cell (EC), T helper-1 cell (Th1), classically activated macrophage (M1), intestinal epithelial cell (IEC), intestinal epithelial stem cell (IESC), toll-like receptor (TLR-)4, lipopolysaccharide (LPS), tight junction (TJ), reactive oxygen species (ROS—red dots)
Chronic inflammatory disease of the gastrointestinal (GI) tract is defined by several pathophysiological characteristics, such as dysbiosis of the microbiota, epithelial barrier hyperpermeability, systemic dissemination of endotoxins and chronic inflammation. In addition to well-reported environmental factors in non-communicable disease, such as smoking, diet, and exercise, humans are frequently exposed to myriads more environmental factors, from pesticides to food additives. Such factors are ubiquitous across both our diet and indoor/outdoor environments. A major route of human exposure to these factors is ingestion, which frequently occurs due to their intentional addition (intentional food additives) and/or unintentional contamination (unintentional food contaminants) of food products—often linked to environmental pollution. Understanding how this persistent, diverse exposure impacts GI health is of paramount importance, as deterioration of the GI barrier is proposed to be the first step towards systemic inflammation and chronic disease. Therefore, we aim to evaluate the impact of ingestion of environmental factors on inflammatory processes in the GI tract. In this review, we highlight human exposure to intentional food additives (e.g. emulsifiers, bulking agents) and unintentional food contaminants (e.g. persistent organic pollutants, pesticides, microplastics), then present evidence for their association with chronic disease, modification of the GI microbiota, increased permeability of the GI barrier, systemic dissemination of endotoxins, local (and distal) pro-inflammatory signalling, and induction of oxidative stress and/or endoplasmic reticulum stress. We also propose a link to NLRP3-inflammasome activation. These findings highlight the contribution of common environmental factors towards deterioration of GI health and the induction of pathophysiology associated with onset and maintenance of chronic inflammation in the GI tract.
 
Patient selection flow chart
Coefficient plot of odds ratios and 95% confidence intervals for risk factors of gastric intestinal metaplasia (GIM) using multivariable GEE
Background Gastric intestinal metaplasia (GIM) is a precursor to gastric adenocarcinoma, making it an attractive target for early detection by endoscopy. The aim of this study was to determine the prevalence, risk factors, and associated histologic findings of GIM among patients undergoing endoscopy in a diverse US population. Methods We conducted a retrospective, cross-sectional study of patients undergoing elective endoscopy with gastric biopsies at 6 academic and community centers in Houston, Texas. GIM prevalence was estimated with a 95% confidence interval (CI), and patient demographic and clinical characteristics were summarized using mean with standard deviation, or frequency with percentage. Generalized estimating equations (GEE) were used to compare characteristics between those with and without GIM. Results Our final cohort consisted of 2685 patients, including 216 cases with GIM and 2469 controls. The prevalence of GIM in our cohort was 8.04% (95% CI 7.07%, 9.14%). The mean age of GIM cases was higher than in the control group (59.8 vs 54.7 years, p < 0.0001). The prevalence of GIM in Asians, Hispanic, Black and Non-Hispanic Whites (NHW) was 14.7%, 11.7%, 9.8% and 5.8%, respectively. On multivariable analysis, factors associated with GIM include age (adj. OR 1.32 per 10 year increase, p < 0.0001), habitual smoking (adj. OR 1.68, p < 0.0001), and race (compared to NHW: Asian, adj. OR 2.34, p = 0.010; Hispanic, adj. OR 2.15, p < 0.001; Black, adj. OR 1.61, p < 0.001). Conclusion Asians, Hispanics, and African Americans have higher rates of GIM than NHW. Ethnicity should be an important consideration on determining who to screen for GIM in the US.
 
Top-cited authors
Mark Pimentel
  • Cedars-Sinai Medical Center
Robert J. Wong
Peter H R Green
  • Columbia University
Ali Siddiqui
  • Thomas Jefferson University
Michel Kahaleh
  • Robert Wood Johnson University Hospital