bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlates of patterns of cannabis use, abuse and dependence: evidence from two national surveys in Ireland
Authors: Millar Seán R , Mongan Deirdre , O’Dwyer Claire , Long Jean , Smyth Bobby P , Perry Ivan J , Galvin Brian 
Published: January 2021

Abstract

Background
Knowledge of factors relating to patterns of cannabis use is important for informing drug policy. This study determined factors associated with recent and current cannabis use. In addition, we explored factors related to having a cannabis use disorder (CUD)—defined using the Diagnostic and Statistical Manual of Psychiatric Disorders—among current users.

Methods
We analyzed data from Ireland’s 2010–11 and 2014–15 National Drug Prevalence Surveys, which recruited 5134 and 7005 individuals respectively, aged 15 years or more, living in private households. Multinomial logistic regression was used to identify factors associated with recent (last year) and current (last month) cannabis use compared to experiential use. Binary logistic regression was used to determine factors related to CUD among current users.

Results
The weighted prevalence of experiential cannabis use was 18.3%, with 3.0% and 3.3% of participants indicating recent or current use, respectively; 41.3% of current users indicated having a CUD. Factors associated with both recent or current cannabis use included younger age, not being married or cohabiting, having no dependent children and current use of tobacco or alcohol. Male gender, younger age and lower educational levels were significantly related to CUD among current users.

Conclusions
Males, adolescents/young adults and individuals with lower educational levels are more likely to be current users of cannabis and are at a greater risk of having a CUD. Health professionals should be aware of these factors to improve detection and prevention of CUD.
THE CUMULATIVE INCIDENCE OF POUCHITIS AND POUCH-RELATED COMPLICATIONS IN PEDIATRIC PATIENTS WITH ULCERATIVE COLITIS
Authors: Cowherd Ellen , Egberg Matthew , Kappelman Michael , Zhang Xian , Long Millie , Lightner Amy , Sandler Robert , Herfarth Hans , Barnes Edward 
Published: January 2021

Abstract

Background & Aims
Despite highly effective therapies, many children develop medically refractory ulcerative colitis (UC) and undergo proctocolectomy with ileal pouch anal anastomosis (IPAA). There is little real world evidence regarding IPAA outcomes in pediatric UC patients. We sought to determine the risk of pouchitis, recurrent pouchitis, and change in diagnosis to Crohn’s disease (CD) within two years of IPAA surgery among pediatric patients with UC using a large, geographically diverse insurance claims database.

Methods
Within the IQVIA Legacy PharMetrics Adjudicated Claims Database, we identified pediatric patients (age &lt;18 years) with UC who underwent proctocolectomy with IPAA between January 1, 2007 and June 30, 2015. We utilized International Classification of Diseases (ICD-9-CM or ICD-10-CM) codes to identify patients with UC and Current Procedural Terminology III codes to identify IPAA. The primary outcome was the development of pouchitis in the first 2 years following surgery, as identified by a previously validated case-finding definition. Secondary outcomes included the incidence of recurrent pouchitis, and the cumulative incidence of a new diagnosis of Crohn’s disease (CD) in the first two years post-IPAA. A change in diagnosis to CD was identified by an ICD-9-CM or ICD-10-CM code for CD on at least three separate occasions. Bivariate analyses were used for all comparisons, utilizing chi-square and t-test as appropriate.

Results
A total of 68 patients with an IPAA with at least two years of continuous health plan enrollment following surgery were identified. Among all patients undergoing surgery, the median age was 15 years (interquartile range 11.5–16), with 29 (43%) female patients. In the first 2 years following IPAA, the cumulative incidence of pouchitis was 54%. Characteristics and prior medical treatments in patients without pouchitis and with ≥ one episode of pouchitis were similar (Table 1). The cumulative incidence of recurrent pouchitis during this period was 22%. The cumulative incidence of a new diagnosis of CD in the two years after IPAA for UC was 9%.

Conclusions
In a geographically diverse cohort from the United States, 54% of pediatric patients undergoing proctocolectomy with IPAA for UC developed pouchitis within the first two years after surgery. Furthermore, 9% had a change in diagnosis to CD. These data indicate that for many pediatric UC patients, surgery is non-curative and patients continue to have a substantial burden of illness. Future efforts should attempt to identify novel, actionable, predictors of pouchitis in this population.
ADVANCING HIGH TECH DRUG DELIVERY SYSTEMS FOR THE TREATMENT OF CROHN’S DISEASE
Authors: Miller Douglas , Niichel Robert 
Published: January 2021

Abstract

Introduction
High tech drug delivery systems, which allow for precise location targeting and efficient delivery mechanisms, can reduce the risk of side effects and increase dosage effectiveness in the treatment of Crohn’s disease. We describe a revolutionary capsule technology which uses radiofrequency signaling to trigger an optimal release of the pharmaceutical contents to specified regions of the gastrointestinal tract.

System and method
Data were observed in two groups of female Yorkshire-Cross swine. Intra-cecal ports were surgically placed in Group 2 swine. After baseline analysis was complete, all study animals were administered the SmartTab capsule (Group 1 administration via balling device, Group 2 administration via intra-cecal port) containing caffeine, barium sulfate, citric acid, and sodium bicarbonate. SmartTab capsules were activated by a radiofrequency triggering event, immediately following administration in Group 2 swine and 30 minutes following administration in Group 1 swine. Blood samples were taken at 0.25, 0.50, 1, 2, 3, and 6 hours after dosing and capsule activation was confirmed using a C-Scan.

Results
Pharmacokinetic analysis revealed increased caffeine concentrations in the targeted areas. Absorption was significantly higher and more consistent in the cecum targeted administration of the SmartTab compared to the control. Although, caffeine concentrations in the stomach regions were fairly similar amongst both the experimental and control groups.

Conclusions
Via radiofrequency signaling, the SmartTab capsule can successfully administer active ingredients to the target site. With pre-installed onboard sensors, enabling the devices to send real-time data to physicians and personalize treatments using AI algorithms, this technique holds the potential to generate further advancement in high-tech drug delivery systems. Preparations are currently in order to reapply this technology in the form of an injection capsule.

All 6 PK Curves
MUC1-C IS A DRUGGABLE TARGET FOR TREATMENT OF COLITIS AND PROGRESSION OF COLITIS-ASSOCIATED COLORECTAL CANCER
Authors: Morimoto Yoshihiro , Li Wei , Zhang Ning , Takahashi Hidekazu , Jin Caining , Kufe Donald 
Published: January 2021

Abstract
The MUC1-C oncoprotein evolved in mammals to protect epithelial cells, such as those lining the gastrointestinal tract, from loss of homeostasis. In this way, MUC1-C activates pathways that contribute to inflammation, proliferation and remodeling associated with the wound healing response.
MUC1-C is upregulated in human tissues from inflamed ulcerative colitis (UC) mucosa as compared to that from normal and uninflamed UC mucosa. MUC1-C is also upregulated in a mouse MUC1+/-/IL-10-/- model of colitis, consistent with its involvement in the inflammatory response. MUC1-C forms a direct complex with NF-κB p65 and promotes the activation of NF-κB target genes, including MUC1 itself in an auto- inductive circuit. MUC1-C thereby drives proinflammatory NF-κB pathway genes in human inflamed UC tissues and in the genetically engineered mouse model (GEMM) of colitis. Mechanistically, MUC1-C induces the TGF-b-activated kinase 1 (TAK1), which is an essential effector of proinflammatory NF-κB signaling. Of further significance, MUC1-C drives the TAK1→NF-κB p65 pathway in human colon cancer cell lines, and MUC1 and TAK1 are upregulated in human colon cancers. These seminal findings supported the notion that MUC1-C contributes to colitis and progression to colon cancer.
To extend these studies, MUC1-C was targeted with an inhibitor that blocks its homodimerization and function. Remarkably, treatment of the MUC1+/-/IL-10-/- GEMM with the GO-203 inhibitor was associated with decreases in the severity of colitis and progression of colitis to dysplasia and carcinomas. Intestinal stem cells (ISCs) that express Lgr5 are of importance in the inflammatory response to colitis and in progression to colitis-associated colorectal cancer (CACC). Targeting MUC1-C with GO-203 in mouse models of colitis suppressed Lgr5 expression, as well as induction of MYC and other core pluripotency factors. By extension to human colon cancer cells, we found that MUC1- C drives MYC with activation of LGR5 and stemness. MUC1-C also induces cancer stem cell (CSC) markers (BMI1, ALDH1, FOXA1, LIN28B) and the OCT4, SOX2, and NANOG pluripotency factors. Consistent with driving the CSC state, targeting MUC1-C suppressed the capacity of CRC cells to promote wound healing, invasion, self-renewal, and tumorigenicity. Analysis of human tissues further demonstrated that MUC1 expression associates with activation of inflammatory pathways, development of colitis, and aggressiveness of CRCs.
These results collectively indicate that MUC1-C is of importance for integrating stemness and pluripotency in colitis and CRC. Of clinical relevance, the findings further indicate that MUC1-C represents a previously unrecognized target that is potentially druggable with orally administered GO-203 now being tested in the GEMMs for treating progression of colitis and CRC.
A BASELINE GENE EXPRESSION-BASED PROGNOSTIC FOR ANTI-TNFα THERAPY RESPONSE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Sakaram Suraj , He Yudong , Sweeney Timothy 
Published: January 2021

Abstract

Background
Although anti-TNFα therapies have revolutionized the management and care of IBD, their administration and usage remain suboptimal because 1) over 50% of patients do not have a lasting therapeutic response, 2) they increase risk of infections, liver problems, arthritis, and lymphoma, and 3) they are expensive. With approximately 1.6 million people suffering from IBD in the US and global prevalence of IBD on the rise, a predictive test for anti-TNFα response would greatly improve the efficacy and cost-to-benefit ratio of these biologics.

Methods
We hypothesized that a multicohort analysis of the publicly available IBD gene expression datasets would yield a robust set of mRNAs for distinguishing anti-TNFα responders vs non-responders in the IBD patient population prior to treatment. We identified 5 datasets (n = 160) where whole-genome transcriptomic data was derived from colonic mucosal biopsies of IBD patients who were then subjected to anti-TNFα therapy and subsequently adjudicated for response. We used the MetaIntegrator framework which leverages a leave-one-study-out cross-validation technique in conjunction with effect size and FDR adjusted p-value to identify significant differentially expressed (DE) genes associated with a patient’s predisposition to a response outcome. DE genes were subjected to a greedy forward search to derive a parsimonious gene signature for a response score (geometric mean of the expression level for all positive mRNAs minus the geometric mean of the expression level of all negative mRNAs, multiplied by the ratio of counts of positive to negative genes). Area under the receiver operating characteristic curve (AUC) was subsequently calculated in a leave-one-study-out manner to assess discriminatory performance.

Results
We first identified 170 genes that were present in at least 40% of cohorts and significantly differentially expressed between responders and non-responders with effect size &gt; 0.8 and q value &lt; 0.1. A score based on these genes predicts responder vs non-responder across the 5 discovery cohorts with AUC of 0.82. Optimizing the variables with a greedy forward search algorithm allowed us to downselect to 7 genes from the set, and a score based on this parsimonious set of 7 genes improved the discriminatory performance to an AUC of 0.87. Choosing a high sensitivity (90%) for a rule-in scenario, the score had moderate specificity (60%); alternatively choosing a high specificity (90%) for a rule-out scenario, the score still had a good sensitivity (80%).

Conclusions
These initial findings suggest that there is a strong signal for predicting anti-TNFα response in colonic biopsies. In particular, we showed using the leave-one-study-out approach that a predictive signature using mRNA can be generalizable (works in independent cohorts). These initial results warrant further investigation.
THE MUCOSAL MICRORNA PROFILE RELATES TO AGE AND SEVERITY OF DISEASE IN PATIENTS WITH ULCERATIVE COLITIS
Authors: Malham Mikkel , James Jaslin , Jakobsen Christian , Høgdall Estrid , Holmstroem Kim , Wewer Vibeke , Nielsen Boye S , Riis Lene 
Published: January 2021

Abstract
Despite significant evidence that the expression of several microRNA’s (miRNA) impacts on disease activity in patients with ulcerative colitis (UC), it remains unknown if the more severe disease phenotype seen in pediatric-onset UC can be explained by altered miRNA expression. In this study, we aimed to assess the relationship between miRNA expression, age, and disease severity in pediatric and adult patients with UC. Using RT-qPCR, we analyzed the expression of miR-21, miR-31, miR-126, miR-142, and miR-155 in paraffin-embedded rectum biopsies from 30 pediatric and 30 adult-onset UC patients, and found that lesions from adult patients had significantly higher expression levels of miR-21 compared to pediatric patients and that the expression levels of miR-31 (all patients) and miR-155 (pediatric patients only) correlated inversely with histological assessed disease severity. Using in situ hybridization followed by image analysis, the expression estimates of miR-21 and miR-126 were found to correlate with histological assessed disease severity. In conclusion, we found that the expression of miRNAs depends on the age of the patient and/or the severity of the disease, suggesting that miRNAs may contribute to the regulation of inflammation in UC and could be useful biomarkers in the surveillance of disease severity.
MODERATE TO SEVERE ENDOSCOPIC INFLAMMATION IS FREQUENT AFTER ACHIEVING CLINICAL REMISSION IN PEDIATRIC ULCERATIVE COLITIS
Authors: Sarbagili-Shabat Chen , Weiner Dror , Wardi Joram , Abramas Lee , Yaakov Michal , Levine Arie 
Published: January 2021

Abstract

Background
Pediatric ulcerative colitis (UC) is characterized by low sustained remission rates and frequent extension of disease even if clinical remission is obtained with therapy. Moderate to severe endoscopic activity is a risk factor for relapse while evidence regarding early mucosal healing or persistence of inflammation after remission in children is not available. Our aim was to evaluate if persistence of significant inflammation is common and could explain the high relapse rate in pediatric UC.

Methods
Pediatric UC patients with clinical remission, defined as pediatric UC activity index (PUCAI) scores &lt; 10, were prospectively assessed for mucosal healing by endoscopy 3–5 months after remission was documented. Mayo score was assessed for each segment by a blinded adult gastroenterologist using central reading. Symptomatic patients prior to sigmoidoscopy were excluded Sustained remission was assessed retrospectively at 18 months follow-up.

Results
Forty-six children were enrolled, 28 children in continuous clinical remission at time of sigmoidoscopy were included in the final analysis. Mayo 0 was present in 12/28 (42.86%), Mayo 1 in 2/28 (7.1%) and Mayo 2–3 in 14/28 (50.0%) endoscopies. Among 23/28 patients with follow-up through 18 months, remission was sustained in 2/11 (18.18%) of patients with Mayo 2 and 3 versus 6/12 (50.0%) with Mayo score 0–1.

Conclusion
Over 50% of children assessed for mucosal healing 3–5 months after clinical remission is obtained have residual disease activity, primarily moderate to severe inflammation which was associated with lower sustained remission. Early sigmoidoscopy after clinical remission for assessment of mucosal disease should be considered in pediatric UC.
A RARE AND UNFORTUNATE CASE OF PARESTHESIAS SECONDARY TO INFLIXIMAB
Authors: Dasu Neethi , Blair Brian , Khalid Yaser 
Published: January 2021

Abstract

Introduction
The tumor necrosis factor-α (TNF-α) antagonists infliximab, adalimumab, and etanercept have been approved for treatment of inflammatory bowel disease (IBD). We describe a rare manifestation of a demyelinating neuropathy affecting the peripheral nervous system in a patient on Infliximab for the treatment of Crohn’s disease following progression of his disease.

Case Report
A 34-year-old male with a past medical history of Crohn’s disease presented for progressive and worsening diffuse numbness and paresthesias over two months in almost all of his extremities except the right side of his face, his sternum and center of his back. His symptoms were well controlled on mesalamine for 16 years until he had a progression of his disease which was seen on endoscopy and colonoscopy so he was switched to treatment with infliximab. He had finished induction with a third infusion two months prior to onset of parasthesias leading to control of symptoms. However, he started to experience non bloody diarrhea and diffuse, dull abdominal pain, weight loss of 15 pounds, gait dysfunction, lower extremity weakness, bilateral knee erythema and tenderness, and tight and stiff muscles, which were not typical for his Crohn’s disease flare-ups. On physical exam, his vitals were unremarkable and there was decreased sensation to light touch. He also had paresthesias as well as weakness most pronounced in his lower extremities. Laboratory tests and Imaging with CT, MRI, EMG, and Lumbar Puncture were all negative. The patient had 70% improvement of his symptoms following discontinuation of Infliximab, although his symptoms never completely resolved in his feet despite additional treatment with B12, thiamine, gabapentin, prednisone, and baclofen.

Conclusion
Due to the chronological progression and manifestation of the neurological symptoms with infliximab therapy for our patient, it is very likely that this drug triggered or caused his demyelinating neuropathy. There are only a few case reports in the literature and small review studies demonstrating Guillain-Barre Syndrome, demyelinating polyneuropathy, and neurologic disease due to infliximab. Various clinical patterns have been described. Chronic demyelinating neuropathy developed either after change of anti–TNF-α drug or spontaneously after treatment discontinuation without any drug reintroduction. There have been case reports describing treatment of demyelinating polyneuropathy related to TNF-alpha inhibitors with IVIG 1 or 2 g/kg with good results. Gabapentin has also been tried for treatment. Influence of anti–TNF-α treatment continuation on the long-term course of neuropathy is variable, suggesting that anti–TNF-α treatment withdrawal is not always necessary for neuropathy control. For future cases, our case highlights the importance of close inpatient and outpatient follow up for patients on infliximab.
COLON SPECIFIC ROLE FOR SELENOPROTEIN P IN COLITIS AND COLITIS-ASSOCIATED CARCINOMA
Authors: Short Sarah , Pilat Jennifer , Reddy Vishruth , Haberman Yael , Hendren Jared , Washington Mary , Hyams Jeffrey , Denson Lee , Rosen Michael , Williams Christopher 
Published: January 2021

Abstract
Selenium (Se) is an essential trace element incorporated into selenoproteins (SEPs), which provide a broad scope of antioxidant functions. Se status inversely correlates with inflammatory bowel disease (IBD) severity, and animal models have shown that Se deficiency worsens colitis and colitis-associated cancer (CAC). One of the most highly expressed and functionally critical SEPs is Selenoprotein P (SEPP1/SELENOP). SELENOP serves two known roles: 1) distributing Se throughout the organism, and 2) acting as a lipid peroxidase. SELENOP is also markedly reduced in IBD. Global SELENOP reduction augmented experimental CAC. SELENOP is primarily produced in the liver for tissue distribution through the plasma; however, liver-specific SELENOP deletion failed to modify CAC, thus implicating epithelial SELENOP as a primary disease modifier. As the roles of intestinal epithelial SELENOP in colitis and CAC remain unknown, we investigated these roles using the Vil-CreERT2 driver to inducibly delete intestinal epithelial SELENOP in AOM/DSS inflammatory carcinogenesis models.
First, Selenop deletion was confirmed in intestinal epithelial cells of tamoxifen-induced Vil-CreERT2; Selenopfl/fl mice (ΔIEC). Epithelial-specific SELENOP loss promoted tumor initiation, as evidenced by greater tumor multiplicity visible by colonoscopy in ΔIEC mice. Upon sacrifice, ΔIEC mice demonstrated increased colon tumor number and size. Additionally, ΔIEC colon tumors displayed greater apoptosis (cleaved caspase-3), DNA damage (pγH2AX), and dysplasia severity. Overall, these results are consistent with our model that epithelial SELENOP loss promotes tumor formation through increased intratumoral oxidative stress and resultant genomic instability. To further investigate SELENOP’s contributions in pure epithelial cultures, we determined that both CACO2 cells and human colonoids produce SELENOP in a sodium selenite-dependent fashion; furthermore, polarized CACO2 cells preferentially secrete SELENOP basolaterally, suggesting a local extracellular role for SELENOP in the immediate colonic epithelial microenvironment. Also, SELENOP knockdown in human intestinal organoids derived from ulcerative colitis (UC) patients increased oxidative stress, increased sensitivity to H2O2 treatment, and reduced organoid growth, implicating SELENOP in modulating the epithelial ROS-protective response. RNA-seq analysis from the PROTECT cohort revealed reduced SELENOP expression in pediatric UC biopsies that inversely correlated with disease activity and S100A8 (calprotectin) levels. Lastly, SELENOP RNA in situ hybridization of adult UC/Crohn’s Disease and CAC TMAs demonstrated decreased epithelial transcript in IBD and stage-dependent reductions in CAC. These data collectively indicate critical roles for SELENOP in epithelial and colonic microenvironment antioxidant defenses in IBD.