Local Pentraxin-2 Deficit Is a Feature of Intestinal Fibrosis in Crohn's Disease.
Digestive diseases and sciences
BACKGROUND: Pentraxin-2 (PTX-2) is a homo-pentameric plasma protein showing evidence of antifibrotic activity in Phase 2 clinical trials in idiopathic pulmonary fibrosis (IPF). Whether PTX-2 plays a role in other fibrotic diseases, including intestinal fibrosis which commonly occurs in inflammatory bowel disease (IBD), remains unknown.AIMS: This study aimed to qualitatively and quantitatively assess PTX-2 expression in fibrostenotic Crohn's disease (FCD) and determine whether expression is correlated with postsurgical restenosis.METHODS: Immunohistochemistry was performed in histologic sections of small bowel resected from patients with fibrostenotic Crohn's disease (FCD), comparing strictured segments with adjacent surgical margins from the same patient. Ileal resections from patients without inflammatory bowel disease were examined as controls.RESULTS: PTX-2 signal was analyzed in 18 patients with FCD and 15 patients without IBD and localized predominantly to submucosal vasculature, including arterial subendothelium and internal elastic lamina, and perivascular connective tissue. PTX-2 signal in the surgical margins from patients with FCD strictures (where tissue architecture was normal) was consistently lower than non-IBD samples. Fibrostenotic regions showed increased PTX-2 signal relative to surgical margins from the same patient in 14/15 paired samples. Submucosal/mural PTX-2 signal in fibrostenotic tissue was lower in patients who subsequently experienced re-stenosis (P=0.015).CONCLUSIONS: This exploratory study is the first analysis of PTX-2 within the intestine, and demonstrates that PTX-2 signal is reduced in the architecturally normal bowel of patients with FCD. Lower submucosal PTX-2 levels in patients with re-stenosis raises the possibility of a protective role of PTX-2 in intestinal fibrosis.
View details for DOI 10.1007/s10620-023-07909-1
View details for PubMedID 36884186
Effects of CFTR modulators on serum biomarkers of liver fibrosis in children with cystic fibrosis.
2023; 7 (2): e0010
The cystic fibrosis (CF) transmembrane conductance regulator corrector/potentiator combinations lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor improve sweat chloride, pulmonary function, and nutrition. Yet it is unclear whether they may also impact the progression of liver fibrosis, which is a substantial source of morbidity and mortality for patients with CF. We conducted a retrospective, single-center analysis of children and adolescents with CF treated with lumacaftor/ivacaftor and/or elexacaftor/tezacaftor/ivacaftor therapy, focusing on alterations in liver function tests and fibrosis indices using previously-established thresholds that corresponded with increased liver elastography. In pairwise comparisons of before and during treatment timepoints, we found that those with CF-associated liver involvement experienced significant decreases in gamma-glutamyl transferase, aspartate aminotransferase-to-platelet index, and gamma-glutamyl transferase-to-platelet ratio while on lumacaftor/ivacaftor. These differences were not observed in patients treated with elexacaftor/tezacaftor/ivacaftor, nor were they observed in patients without underlying CF-associated liver disease. These results provide the first evidence that lumacaftor/ivacaftor may improve liver fibrosis in children and adolescents with CF and suggest it may be beneficial in the treatment of CF-associated liver disease.
View details for DOI 10.1097/HC9.0000000000000010
View details for PubMedID 36662672
Warning Labels and High-Powered Magnet Exposures.
BACKGROUND AND OBJECTIVES: High-powered magnets are among the most dangerous childhood foreign bodies. Consumer advocates and physicians have called for these products to be effectively banned, but manufacturers assert warning labels would sufficiently mitigate risk.METHODS: Subjects from Injuries, Morbidity, and Parental Attitudes Concerning Tiny High-powered Magnets (IMPACT of Magnets), a retrospective, multicenter study of children with high-powered magnet exposures (ie, ingestion or bodily insertion), were contacted. Consenting participants responded to a standardized questionnaire regarding the presence and utility of warning labels, magnet product manufacturer, and attitudes around risk.RESULTS: Of 596 patients in the IMPACT study, 173 parents and 1 adult patient were reached and consented to participate. The median age was 7.5 years. Subjects reported not knowing if a warning label was present in 60 (53.6%) cases, whereas 25 (22.3%) stated warnings were absent. Warnings were present in 28 (24.1%) cases but only 13 (46.4%) reported reading them. A manufacturer was identified by families in 28 (16.1%) exposures; 25 of these were domestic and 27 had warnings. Subjects reported knowing magnets were dangerous in 58% of the cases, although 44.3% believed they were children's toys and only 6.9% knew high-powered magnets were previously removed from the United States market.CONCLUSIONS: Over 90% of subjects from the IMPACT study didn't know if warning labels were present or failed to read them if they were, whereas almost half believed high-powered magnets were children's toys. Warning labels on high-powered magnet products are, therefore, unlikely to prevent injuries in children.
View details for DOI 10.1542/peds.2022-056325
View details for PubMedID 36189482
Rates and Predictors of Long-term Clinical Outcomes in Patients With Perianal Crohn's Disease on Biologic Therapy.
Journal of clinical gastroenterology
Perianal Crohn's disease (pCD) represents an aggressive phenotype with limited studies on long-term outcomes. We evaluated 5-year outcomes of these patients on biologic therapies.We performed a retrospective analysis of patients with pCD at a tertiary medical center. We used Kaplan-Meier curves to estimate rates and multivariate logistic regression to identify predictors of long-term outcomes.We included 311 patients with pCD of which 168 patients were started on biologics [138 anti-tumor necrosis factor (TNF) α, 14 vedolizumab, 16 ustekinumab] at the time of diagnosis. Anti-TNF use at the time of diagnosis was associated with decreased rates of perianal abscess recurrence [hazard ratio (HR)=0.48, 95% confidence interval (CI): 0.32-0.74], whereas ustekinumab use was associated with increased rates of perianal fistula closure (HR=3.58, 95% CI: 1.04-12.35) and decreased rates of perianal abscess recurrence (HR=0.20, 95% CI: 0.07-0.56) at follow-up. Among patients who failed their first anti-TNF, switching to another anti-TNF was associated with decreased rates of colectomy (HR=0.20, 95% CI: 0.04-0.90) and permanent diversion (HR=0.16, 95% CI: 0.03-0.94) compared with ustekinumab, whereas vedolizumab use was associated with decreased perianal fistula closure (HR=0.22, 95% CI: 0.05-0.96) compared with ustekinumab. Predictors of colectomy included colonic disease (odds ratio=2.71, 95% CI: 1.36-5.38) and anal stenosis (odds ratio=4.44, 95% CI: 1.59-12.43).Type of biologic use at the time of pCD diagnosis or after first anti-TNF failure may be associated with long-term outcomes in patients with pCD.
View details for DOI 10.1097/MCG.0000000000001729
View details for PubMedID 35703262
High-Powered Magnet Exposures in Children: A Multi-Center Cohort Study.
BACKGROUND AND OBJECTIVES: High-powered magnets were effectively removed from the US market by the Consumer Product Safety Commission (CPSC) in 2012 but returned in 2016 after federal court decisions. The United States Court of Appeals for the 10th Circuit cited imprecise data among other reasons as justification for overturning CPSC protections. Since then, incidence of high-powered magnet exposure has increased markedly, but outcome data are limited. In this study, we aim to describe the epidemiology and outcomes in children seeking medical care for high-powered magnets after reintroduction to market.METHODS: This is a multicenter, retrospective cohort study of patients aged 0 to 21 years with a confirmed high-powered magnet exposure (ie, ingestion or insertion) at 25 children's hospitals in the United States between 2017 and 2019.RESULTS: Of 596 patients with high-powered magnet exposures identified, 362 (60.7%) were male and 566 (95%) were <14 years of age. Nearly all sought care for magnet ingestion (n = 574, 96.3%), whereas 17 patients (2.9%) presented for management of nasal or aural magnet foreign bodies, 4 (0.7%) for magnets in their genitourinary tract, and 1 patient (0.2%) had magnets in their respiratory tract. A total of 57 children (9.6%) had a life-threatening morbidity; 276 (46.3%) required an endoscopy, surgery, or both; and 332 (55.7%) required hospitalization. There was no reported mortality.CONCLUSIONS: Despite being intended for use by those >14 years of age, high-powered magnets frequently cause morbidity and lead to high need for invasive intervention and hospitalization in children of all ages.
View details for DOI 10.1542/peds.2021-054543
View details for PubMedID 35112127
SINGLE-CENTER RETROSPECTIVE ANALYSIS OF THE EFFECT OF LUMACAFTOR/IVACAFTOR AND ELEXACAFTOR/TEZACAFTOR/IVACAFTOR ON BIOMARKERS OF LIVER DISEASE IN CYSTIC FIBROSIS
WILEY. 2021: 1178A-1179A
View details for Web of Science ID 000707188005340
Biologic Therapy in Patients With Perianal Crohn's Disease and Association With Long-Term Rates of Surgical and Clinical Outcomes
LIPPINCOTT WILLIAMS & WILKINS. 2021: S354
View details for Web of Science ID 000717526101241
Clinical use of shear-wave elastography for detecting liver fibrosis in children and adolescents with cystic fibrosis.
Complications from liver cirrhosis are a leading cause of death in children with cystic fibrosis. Identifying children at risk for developing liver cirrhosis and halting its progression are critical to reducing liver-associated mortality.Quantitative US imaging, such as shear-wave elastography (SWE), might improve the detection of liver fibrosis in children with cystic fibrosis (CF) over gray-scale US alone. We incorporated SWE in our pediatric CF liver disease screening program and evaluated its performance using magnetic resonance (MR) elastography.Ninety-four children and adolescents with CF underwent 178 SWE exams, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and platelet measurements. Of these, 27 children underwent 34 MR elastography exams. We evaluated SWE performance using 6-MHz and 9-MHZ point SWE, and 9-MHz two-dimensional (2-D) SWE.The 6-MHz point SWE was the only method that correlated with MR elastography (r=0.52; 95% confidence interval [CI] 0.20-0.74; P=0.003). SWE of 1.45 m/s distinguished normal from abnormal MR elastography (79% sensitivity, 100% specificity, 100% positive predictive value [PPV], 55% negative predictive value [NPV], area under the receiver operating characteristic [AUROC] curve 0.94). SWE of 1.84 m/s separated mild-moderate (3.00-4.77 kPa) from severe (>4.77 kPa) MR elastography (88% sensitivity, 86% specificity, 78% PPV, 93% NPV, AUROC 0.79). Elevations of AST, ALT, GGT and thrombocytopenia were associated with higher SWE. AST-to-platelet ratio index of 0.42, fibrosis-4 of 0.29, and GGT-to-platelet ratio of 1.43 all had >95% NPV for SWE >1.84 m/s.Given its correlation with MR elastography, SWE might be a clinically useful predictor of liver fibrosis. We identified imaging criteria delineating the use of SWE to identify increased liver stiffness in children with CF. With multicenter validation, these data might be used to improve the detection and monitoring of liver fibrosis in children with CF.
View details for DOI 10.1007/s00247-021-05015-w
View details for PubMedID 33759025
Artificial intelligence applications in inflammatory bowel disease: Emerging technologies and future directions.
World journal of gastroenterology
2021; 27 (17): 1920-1935
Inflammatory bowel disease (IBD) is a complex and multifaceted disorder of the gastrointestinal tract that is increasing in incidence worldwide and associated with significant morbidity. The rapid accumulation of large datasets from electronic health records, high-definition multi-omics (including genomics, proteomics, transcriptomics, and metagenomics), and imaging modalities (endoscopy and endomicroscopy) have provided powerful tools to unravel novel mechanistic insights and help address unmet clinical needs in IBD. Although the application of artificial intelligence (AI) methods has facilitated the analysis, integration, and interpretation of large datasets in IBD, significant heterogeneity in AI methods, datasets, and clinical outcomes and the need for unbiased prospective validations studies are current barriers to incorporation of AI into clinical practice. The purpose of this review is to summarize the most recent advances in the application of AI and machine learning technologies in the diagnosis and risk prediction, assessment of disease severity, and prediction of clinical outcomes in patients with IBD.
View details for DOI 10.3748/wjg.v27.i17.1920
View details for PubMedID 34007130
View details for PubMedCentralID PMC8108036
Vitamin D is Associated with α4β7+ Immunophenotypes and Predicts Vedolizumab Therapy Failure in Patients with Inflammatory Bowel Disease.
Journal of Crohn's & colitis
Vitamin D downregulates the in vitro expression of the gut-tropic integrin α4β7 on immune cells. The clinical relevance of this finding in patients with inflammatory bowel disease (IBD) is unclear. We tested the hypothesis that vitamin D is associated with α4β7 immunophenotypes and risk of vedolizumab (anti- α4β7) failure in IBD.We performed single-cell immunophenotyping of peripheral and intestinal immune cells using mass cytometry (CyTOF) in vedolizumab-naïve patients with IBD (N=48). We analyzed whole-genome mucosal gene expression (GSE73661) from GEMINI I and GEMINI long-term safety (LTS) to determine the association between vitamin D receptor (VDR) and integrin alpha-4 (ITGA4) and beta-7 (ITGB7) genes. We estimated the odds of vedolizumab failure with low pre-treatment vitamin D in a combined retrospective and prospective IBD cohort (N= 252) with logistic regression.Immunophenotyping revealed that higher 25(OH)D was associated with decreased α4β7+ peripheral blood mononuclear cells (R = -0.400, P < 0.01) and α4β7+ intestinal leukocytes (R = -0.538, P= 0.03). Serum 25(OH)D was inversely associated with α4β7+ peripheral B cells and natural killer (NK) cells and α4β7+ intestinal B cells, NK cells, monocytes, and macrophages. Mucosal expression of VDR was inversely associated with ITGA4 and ITGB7 expression. In multivariate analysis, 25(OH)D < 25 ng/mL was associated with increased vedolizumab primary non-response during induction (OR 26.10, 95% CI 14.30-48.90, P<0.001) and failure at 1-year follow-up (OR 6.10, 95% CI 3.06-12.17, P<0.001).Low serum 25(OH)D is associated with α4β7+ immunophenotypes and predicts future vedolizumab failure in patients with IBD.
View details for DOI 10.1093/ecco-jcc/jjab114
View details for PubMedID 34180967
Prevalence, risk factors and clinical outcomes of COVID-19 in patients with a history of pancreatitis in Northern California.
View details for DOI 10.1136/gutjnl-2020-321772
View details for PubMedID 32493828
SARS-CoV-2 Testing, Prevalence, and Predictors of COVID-19 in Patients with Inflammatory Bowel Disease in Northern California.
View details for DOI 10.1053/j.gastro.2020.05.009
View details for PubMedID 32387541
Biologics During Pregnancy in Women With Inflammatory Bowel Disease and Risk of Infantile Infections: A Systematic Review and Meta-Analysis.
The American journal of gastroenterology
Biologics, such as tumor necrosis factor inhibitors, anti-integrins and anticytokines, are therapies for inflammatory bowel disease (IBD) that may increase the risk of infection. Most biologics undergo placental transfer during pregnancy and persist at detectable concentrations in exposed infants. Whether this is associated with an increased risk of infantile infections is controversial. We performed a systematic review and meta-analysis evaluating the risk of infantile infections after in utero exposure to biologics used to treat IBD.We searched PubMed, Embase, Scopus, Web of Science, and CENTRAL from inception to June 2020 to evaluate the association of biologic therapy during pregnancy in women with IBD and risk of infantile infections. Odds ratios of outcomes were pooled and analyzed using a random effects model.Nine studies met the inclusion criteria comprising 8,013 women with IBD (5,212 Crohn's disease, 2,801 ulcerative colitis) who gave birth to 8,490 infants. Biologic use during pregnancy was not associated with an increased risk of all infantile infections (odds ratio [OR] 0.91, 95% confidence interval [CI] 0.73-1.14, I = 30%). In a subgroup analysis for the type of infection, biologic use was associated with increased infantile upper respiratory infections (OR 1.57, 95% CI 1.02-2.40, I = 4%). Biologic use during pregnancy was not associated with infantile antibiotic use (OR 0.91, 95% CI 0.73-1.14, I = 30%) or infection-related hospitalizations (OR 1.33, 95% CI 0.95-1.86, I = 26%).Biologics use during pregnancy in women with IBD is not associated with the overall risk of infantile infections or serious infections requiring antibiotics or hospitalizations but is associated with an increased risk of upper respiratory infections.
View details for DOI 10.14309/ajg.0000000000000910
View details for PubMedID 33110017
Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration
2016; 165 (1): 139-152
A zebrafish genetic screen for determinants of susceptibility to Mycobacterium marinum identified a hypersusceptible mutant deficient in lysosomal cysteine cathepsins that manifests hallmarks of human lysosomal storage diseases. Under homeostatic conditions, mutant macrophages accumulate undigested lysosomal material, which disrupts endocytic recycling and impairs their migration to, and thus engulfment of, dying cells. This causes a buildup of unengulfed cell debris. During mycobacterial infection, macrophages with lysosomal storage cannot migrate toward infected macrophages undergoing apoptosis in the tuberculous granuloma. The unengulfed apoptotic macrophages undergo secondary necrosis, causing granuloma breakdown and increased mycobacterial growth. Macrophage lysosomal storage similarly impairs migration to newly infecting mycobacteria. This phenotype is recapitulated in human smokers, who are at increased risk for tuberculosis. A majority of their alveolar macrophages exhibit lysosomal accumulations of tobacco smoke particulates and do not migrate to Mycobacterium tuberculosis. The incapacitation of highly microbicidal first-responding macrophages may contribute to smokers' susceptibility to tuberculosis.
View details for DOI 10.1016/j.cell.2016.02.034
View details for Web of Science ID 000372785600016
View details for PubMedCentralID PMC4819607