bluuebunny/crossref_metadata_2025_split huggingface dataset:
BURDEN OF ILLNESS OF OSTEOPOROTIC FRACTURES COMPARED TO OTHER SERIOUS DISEASES AMONG IBD PATIENTS
Authors: Tariq Raseen , Tahir Muhammad Waqas , Tahir Zoya , Zaheer Faizan , Wahab Abdul 
Published: January 2022

Abstract

INTRODUCTION
Inflammatory bowel disease (IBD) patients are off and on treated with steroids which is associated with increased risk of osteoporosis and fragility fractures. We conducted an analysis to study the burden of osteoporotic fractures compared to acute myocardial infarction (AMI) or stroke in hospitalized patients with IBD.

METHODS
We used the National Inpatient Sample database from 2007 through 2014, to identify patients admitted with primary or secondary diagnosis of IBD using the ICD-9 codes. We identified primary diagnosis of osteoporotic fractures (excluding traumatic injuries, open fracture, readmission indicators), acute myocardial infarction and stroke using respective diagnostic codes. We analyzed trends in nationwide estimates for annual admissions, age at admission, length of stay (LOS), in-patient mortality and total hospital charge (adjusted for inflation).

RESULTS
Over the eight-year study period, there were an estimated 2,296,145 admissions with IBD. Overall, hip fractures as primary diagnosis accounted for 0.5% of these hospitalizations, non-hip fractures for 0.6%, AMI for 0.8% and stroke for 0.6%. Among patients over 50 years old, the prevalence was 1.0% for hip fractures, 0.9% for non-hip fractures, 1.3% for AMI and 1.0% for stroke. Temporal trend was unchanged over the studied period. More females were admitted with fractures (70.5%) and strokes (55.7%) as compared to AMI (42.4%). Highest mortality was seen among patients admitted for stroke (7.1%), followed by AMI (4.1%) and fractures where mortality with hip fractures was significantly higher than non-hip fractures (2.7% vs 1.7%, p&lt;0.05). The median age for patients with hip fractures was 78, much higher than for non-hip fractures (72), which was close to age for stroke (71), but higher than AMI (67). Mean LOS for stroke was 5.9 days, followed by hip fractures 5.8 days, non-hip fractures 5.6 days, and AMI 5.2 days. Mean charge for hospitalization was similar for hip fractures and non-hip fractures, ($52,399 vs $50,545) which was less than that for stroke ($55,569) and AMI ($70,970). After adjusting for inflation, there was a trend of increase in charge for all four admission diagnoses (Figure 1).

CONCLUSION
Proportion of IBD patients admitted primarily for nontraumatic fractures is similar to stroke admission, particularly in patients older than 50. Hip fractures are more common than non-hip fractures. Mortality is higher with hip fractures than non-hip fractures. LOS among studied causes is highest for hip fractures and stroke. Cost of hospitalization although not as much with fractures than AMI, showed a rising trend during the study period.
BURDEN OF NON-ALCOHOLIC FATTY LIVER DISEASE AMONG PATIENTS WITH CROHN’S DISEASE: ANALYSIS OF THE NATIONWIDE READMISSION DATABASE
Authors: Abomhya Ahmed , Mahmoodurrahman Mohammed , Mozell Daniel , Ayaz Salman , Hamad Hossam 
Published: January 2022

Abstract

INTRODUCTION
Non-alcoholic fatty liver disease (NAFLD) is a spectrum that ranges from hepatic steatosis to Non-alcoholic steatohepatitis (NASH). NASH can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma. (Chao CY et al. World J Gastroenterol). Both NAFLD and Crohn’s disease are associated with increased gut permeability. (Miele L et al Hepatology, Pearson AD et al. Br Med J). Current evidence has shown fatty liver disease to be the most common explanation for abnormal liver tests in patients with IBD. (Gisbert JP et al. Inflamm Bowel Dis). A practical approach may be pursued in identifying patients with IBD at risk for having NAFLD and subsequently identifying patients at an increased risk of morbidity and mortality.

METHODS
We collected data from the publicly available Healthcare Cost and Utilization Project (HCUP) Nationwide Readmission Databases (NRD) 2016, 2017, and 2018. We identified and analyzed the burden of NAFLD amongst individuals discharged with a diagnosis of CD or one of its complications (Figure 1). We studied the characteristics, co-morbidities, and hospitalization outcomes of CD patients with NAFLD. A subgroup analysis was performed for those with NASH. Patients who died in index hospitalization or were discharged in Dec. were excluded from the 30-day readmission analysis. Median and IQR were used to describe Continuous variables, and proportions were used with categorical variables. Comparison between groups was performed by Mann Whitney test for continuous variables and Chi-Square test for Categorical variables. We performed a binary logistic regression analysis for predictors of NAFLD among patients with CD. Statistical analyses were performed using SPSS Version 25 (IBM Corporation, Armonk, NY, USA).

RESULTS
We analyzed 215,049 index hospital discharges with Crohn’s disease or one of its complications. 2.4% had NAFLD. Hypertension, diabetes, Dyslipidemia, Obesity, and metabolic syndrome are the five most recognized risk factors for NAFLD in the general population. 35.9% of CD patients with NAFLD had none of those risk factors (Table 1). 0.42 % of CD patients had a diagnosis of NASH. Subgroup analysis for CD patients with NASH showed increased mortality, increased length of stay, and a higher rate of 30-day readmission among CD patients with NASH (Table 2). Predictors of NAFLD in patients with CD are illustrated in Table 3. The chi-square test results indicate that our regression model is a significant improvement in fit relative to an intercept-only model (χ2 = 1593.171, p&lt;.001).

CONCLUSION
The presence of NAFLD in patients with CD is associated with metabolic syndrome components and CD-specific risk factors. The development of NASH is associated with increased morbidity and mortality in patients with CD. Further studies are needed to investigate the pathogenesis of NAFLD in CD patients.
IMPACT OF CURRENT AND FORMER SMOKING ON THE RISK OF ULCERATIVE COLITIS AMONG FAMILY HISTORY POSITIVE AND NEGATIVE INDIVIDUALS; EVIDENCE FOR GENE-SMOKING INTERACTION FROM LARGE SCALE POPULATION-BASED COHORT STUDY IN KOREA
Authors: Ahn Hyeong Sik , Kim Hyun Jung 
Published: January 2022

Abstract

BACKGROUND
The interaction between smoking and genetic predispositions in the pathogenesis of ulcerative colitis (UC) remains to be determined. Also the effect of smoking on UC in Asian populations is not well-studied.

OBJECTIVE
Our aim was to evaluate the association of smoking with UC and to assess the interaction between smoking and family history in UC development.

METHODS
Using the National Health Insurance and National Health Screening Database which covers the entire Korean population(N=50 million) and includes data on family relationships, smoking status and other lifestyle factors, we identified 7 million individuals, comprising 3.7 million families. To examine the association of UC with current and former smoking, Cox proportional hazard regression was used and hazard ratios (HRs) were computed with a 95% confidence interval (CI). We calculated the familial risk of UC using incidence risk ratios (IRRs), and adjusted IRRs for lifestyle risk factors, including smoking and body mass index. Interactions between family history and current and former smoking were assessed on additive and multiplicative scales.

RESULTS
A total of 7 million people were initially included in our study and among them, we identified 1.2 million current smokers, 0.7 million former smokers and 5.1 million non-smokers. Our findings show that current smoking was associated with a decreased risk of disease (HR 0.6), while former smoking was associated with an increased risk (HR 1.2), compared to non-smokers. In the separate analysis among familial and non-familial groups, the protective effect of current smoking was less pronounced in the familial group (HR 0.5 vs 0.8) and the risk associated with former smoking also diminished in the familial group (HR 1.5 vs 1.2). In interaction analysis, the joint effect of current smoking and a positive family history of UC was lower than the product of their individual risks (p&lt;0.05), suggesting a negative interaction. Also, the joint effect of former current smoking and family history was lower than the product of their individual risks with statistically significant interaction.

CONCLUSION
This large scale cohort study found that current smoking was associated with a decreased risk of UC and former smoking was associated with an increased risk. The impact of current and former smoking was different between family history positive and negative individuals. These results provide evidence for gene-smoking interaction in UC disease risk.
PREDICTORS OF CLINICAL RELAPSE AMONG PATIENTS WITH ULCERATIVE COLITIS IN ENDO-HISTOLOGIC REMISSION
Authors: Zeina Tanya , Gandhi Shiv , Mittal Akaash , Levy Alexander , Weinstock Joel , Jangi Sushrut 
Published: January 2022

Abstract

BACKGROUND AND AIMS
In patients with ulcerative colitis (UC), endo-histologic (deep) remission has been increasingly recognized to reduce the risk of clinical relapse above and beyond attainment of endoscopic remission alone. However, relapse rates among patients in deep remission, and predictors of relapse in this population remain uncharacterized.

METHODS
We performed a retrospective cohort study utilizing electronic medical records at Tufts Medical Center to identify patients in deep remission, classified as having both endoscopic remission [Mayo Endoscopic Score [MES] of 0 or 1] and histologic remission [Nancy Histologic Index [NHI] of grade 0 or grade 1]. We evaluated the cumulative risk of clinical relapse following attainment of deep remission, defined as patient-reported outcome (PRO-2 &gt; 2), adjusted for gender, age, disease duration, time duration of follow-up, baseline Mayo Endoscopic Score, and baseline depth of histologic remission.

RESULTS
Among 128 patients with UC in deep remission, 69 were female (54%). The median age was 55 years with median disease duration of 13 years. At time of deep remission, n=29 (23%) had a MES score of 1 and n=92 (72%) had a MES score of 0, with n=82 (64%) demonstrating a NHI of 1, and n=38 (30%) with a NHI of 0. Over a median follow up time of 10.5 years, 33% of patients had clinical relapse and 66% remained in remission. The cumulative risk of relapse among patients in deep remission was 12.2% at one year and 23% at three years. On univariate analysis, age, gender, disease duration, and baseline MES score did not predict relapse risk. However, the depth of histologic remission at time of deep remission was predictive of clinical relapse, with those demonstrating normalized mucosa (NHI of 0) less likely to relapse than those with chronic architectural changes (NHI of 1) at one year (5% vs 16%, HR = 2.80, p &lt; .05) and at three years (9% vs 27%) [Table 1, Figure 1].

CONCLUSIONS
Cumulative risk of relapse among patients in endo-histologic remission is as low as &lt;15% and &lt;25% at one and three years, respectively. Attainment of complete normalization reduces the risk of relapse to &lt;5% over the first year compared to histologic remission with chronic architectural changes (&lt;16%), with other clinical criteria unable to prognosticate risk of relapse. Achieving endo-histologic remission with complete normalization of mucosa may be the ideal clinical target in ulcerative colitis.
DECREASED EXPRESSION OF NHE3 IN COLON CANCER EPITHELIUM IS ASSOCIATED WITH DNA DAMAGE, INCREASED LOCAL INFLAMMATION AND TUMOR GROWTH
Authors: Laubitz Daniel , Gurney Michael , Midura-Kiela Monica , Clutter Christy , Chen Hao , Ghishan Fayez , Kiela Pawel 
Published: January 2022

Abstract

BACKGROUND & AIMS
Dysregulation of intracellular and extracellular pH in cancer is thought to contribute to extracellular matrix remodeling, cancer metastasis, and favors cell migration and proliferation. Although the primary attention has been focused on the role of the ubiquitous Na+/H+ exchanger 1 isoform (SLC9A1), the role of NHE3 (SLC9A3), the predominant apical isoform in colonic surface epithelium in the pathogenesis of colon cancer has not been investigated.

METHODS
We examined the NHE3 expression in matched colonic biopsies from patients with sporadic colorectal cancer, tested the effects of NHE3 knockout on intestinal carcinogenesis, inflammation, DNA damage, and gut microbiota in ApcMin/+ mice, and evaluated the intrinsic effects of NHE3 knockdown in colonic carcinoma SK-CO15 cells.

RESULTS
NHE3 mRNA expression was significantly reduced in colorectal cancer in human patients. NHE3-/-ApcMin/+ evaluated at 15 weeks of age (significant mortality was observed beyond this time point) had lower body weights, increased mucosal inflammation, increased colonic tumor numbers, evidence of enhanced DNA damage in the tumor surface epithelium, and demonstrated significant alteration in the gut microbiota. The latter was primarily driven by NHE3 deficiency. In the absence of the inflammatory and microbial pressors, ca. 70% knockdown of NHE3 expression in SK-CO15 cells led to reduced intracellular pH, elevated apical pH, dramatic differences in their transcriptomic profile, increased susceptibility to DNA damage, increased proliferation, decreased apoptosis and reduced adhesion to extracellular matrix proteins.

CONCLUSION
Our findings suggest that loss of NHE3 in the surface epithelium of colonic tumors has profound consequences for cancer progression and behavior.
ADHERENT-INVASIVEE. COLI PROMOTE ER STRESS TO SUPPORT IL23R-DRIVEN AGR2-DEPENDENT ILEOCOLITIS
Authors: Viladomiu Monica , Khounlotham Manirath , Dogan Belgin , Lima Svetlana , Elsaadi Ahmed , Herzog Jeremy , Schoenborn Alexi , Ellermann Melissa , Liu Bo , Zhang Shiying , Gulati Ajay , Sartor R Balfour , Simpson Kenneth , Lipkin Steve , Longman Randy 
Published: January 2022

Abstract
Anterior gradient 2 (AGR2) is an epithelial protein disulfide isomerase critical for mucus production and endoplasmic reticulum (ER) homeostasis. Loss-of-function genetic variants in AGR2 are associated with Crohn’s disease (CD), and AGR2-deficient mice develop spontaneous ileocolitis, but the specificity of its impact on the host-microbe interaction driving disease is not well understood. Our new data reveals that AGR2 deficiency results in intestinal dysbiosis characterized by the expansion of adherent-invasive E. coli (AIEC). By re-deriving mice germ-free, we show that spontaneous ileocolitis is microbe-dependent and that AIEC isolates, but not other mucosa-associated microbes such as SFB, are sufficient to drive inflammatory disease in the absence of AGR2. AIEC induction of ER stress in AGR2-deficient mice enables further expansion of mucosal Enterobacteriaceae and is required for IL-23R-dependent Th17 cell ileocolitis. These findings reveal a central role for epithelial cell AGR2 in restraining ER stress induced by AIEC to prevent dysbiosis and inflammation in CD.
A NOVEL ORALLY ACTIVE METABOLITE REVERSES CROHN’S DISEASE-ASSOCIATED INTESTINAL FIBROSIS
Authors: Koon Hon Wai 
Published: January 2022

Abstract

BACKGROUND
Intestinal fibrosis is a debilitating complication of Crohn’s disease (CD) patients. Our groups and others discovered that intestinal metabolites are associated with intestinal fibrosis. We selected the most relevant metabolites and determined their anti-fibrogenic efficacies in three mouse models of intestinal fibrosis.

METHODS
We compared the intestinal metabolite profiles between non-IBD, stricturing CD, and non-stricturing CD patients in inflammatory bowel disease (IBD) multi-omics database to identify CD stricture-related metabolites. We compared the fecal metabolite profiles between trinitrobenzene sulfonic acid (TNBS)-treated mice with and without anti-fibrogenic drug CSA13 treatment to identify mouse intestinal fibrosis-related metabolites.

RESULTS
Compared to non-stricturing CD patients and non-IBD patients, stricturing CD patients had reduced fecal levels of hydrocinnamate (H), inosine (I), taurine (T), tauroursodeoxycholate (TUDCA), and sphingosine (S). Oral CSA13 increased fecal levels of inosine (I) and sphingosine (S) in the TNBS-treated mice. Overall disease activity (ODA) is a comprehensive assessment of histology and fibrosis scores and intestinal mRNA expression of fibrosis and inflammation markers. Sphingosine (10mg/kg/day for 7-14 days via oral gavages) showed the best anti-fibrogenic effects against spontaneous ileal fibrosis in 42-week-old SAMP1/YitFc mice (11% ODA), cecal fibrosis in Salmonella-infected mice (10% ODA), and colonic fibrosis in TNBS-treated mice (9% ODA). The other four metabolites were ineffective in reversing intestinal fibrosis. Sphingosine (10 microM), but not other metabolites, directly inhibited collagen expression in human colonic CCD-18Co fibroblasts and primary human intestinal fibroblasts from CD patients (CD-HIF). RNA-seq and proteomics identified that low MAPK3 and high ZEB1 mRNA expression in intestines are associated with intestinal fibrosis in CD patients. Sphingosine activated ERK1/2 phosphorylation and inhibited TGF-b1-induced ZEB1 expression in CCD-18Co fibroblasts. The sphingosine-mediated inhibition of collagen synthesis was reversed by ERK1/2 inhibitor PD98059 and ZEB1 overexpression. The anti-fibrogenic effect of sphingosine in the TNBS model was reversed by Zeb1 overexpression. Stricturing CD patients have higher circulating granulocyte-colony stimulating factor (G-CSF) levels than non-stricturing CD patients. Csf3 promoted collagen expression in CD-HIF, while Csf3 inhibition diminished cecal fibrosis in Salmonella-infected mice. Sphingosine diminished G-CSF secretion in primary human peripheral blood mononuclear cells (PBMCs). Sphingosine also inhibited cecal Csf3 mRNA expression and reduced circulating G-CSF levels in Salmonella-infected mice.

CONCLUSIONS
Sphingosine exerts the most potent anti-fibrogenic effects by modulating ERK1/2, ZEB1, and G-CSF expression.
BRAIN FOG IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE, AND ASSOCIATION WITH USE OF PROBIOTICS
Authors: Dadlani Apaar , Gala Khushboo , Rai Jayesh , Rai Shesh , Dryden Gerald 
Published: January 2022

Abstract

INTRODUCTION
Brain fog has been extensively studied in patients with inflammatory bowel disease (IBD). Probiotics have been shown to increase the incidence of brain fog in patients independently. There is a high prevalence of probiotic consumption in patients with IBD in clinical practice, whether by a physician or not. We aimed to study if there was an association between brain fog and IBD patients who took probiotics and those who did not.

METHODS
We conducted a cross-sectional study of patients visiting IBD clinic. Patients over the age of 18 with a biopsy-proven diagnosis of inflammatory bowel disease, without any known pre-existing psychiatric illness or current use of opioid medications were included. They were divided into 2 groups: those with history of probiotic use and those without. Patients were given a questionnaire that included details about symptoms of brain fog. Groups were analyzed by chi-square for differences in baseline demographics, and Mann Whitney U test with repeated measures to compare outcomes between groups. A p value &lt; 0.05 was considered statistically significant.

RESULTS
Of the 66 patients included (mean age 44±2 years), 35 (53%) were female and 59 (89.4%) were Caucasian. Among these patients, 31.8% (n=21) were on probiotics as dietary supplement with majority (67%, n= 14) taking probiotics for over a year. Overall, there was trend for an association between probiotic use and brain fog in all patients (p=0.080) but no statistical significance was attained. However, brain fog was significantly associated with probiotic use among Caucasian patients (p=0.044). Furthermore, there was a statistically significant association between brain fog and male patients using probiotics (p=0.004). Duration of probiotic use was also associated with brain fog (p=0.038).

CONCLUSION
Consumption of probiotics was independently associated with brain fog in men, as well as Caucasian patients with IBD respectively. Future prospective studies are warranted to examine causal relationship between probiotics and IBD-associated brain fog to guide prescription of probiotic supplements for IBD.
KLEBSIELLA PNEUMONIAE IN THE COLONIC MUCUS LAYER INFLUENCESCLOSTRIDIODES DIFFICILE PATHOGENESIS
Authors: Ticer Taylor , Stine Rachel , Engevik Amy , Engevik Melinda 
Published: January 2022

Abstract

BACKGROUND
Clostridoides difficile is an intestinal pathogen responsible for 500,000 infections and 30,000 deaths annually in the US. Alarmingly, C. difficile infection is increased in patients with inflammatory bowel disease (IBD). When C. difficile infection is superimposed on colitis, it synergistically worsens both conditions. C. difficile infection is initiated by disruption of the gut microbiota; and it is well appreciated that IBD patients already have an altered fecal and mucus-associated microbiota. At present, it is not fully understood how gut microbes, particularly microbes found in IBD, influence C. difficile. Using stool-seeded bioreactors with mucus-coated inserts, we identified Klebsiella pneumoniae in the mucus-associated microbiota with C. difficile. K. pneumoniae is present at increased levels in IBD patients and we hypothesized that K. pneumoniae may promote C. difficile intestinal colonization.

METHODS & RESULTS
To test this hypothesis, we cultured 12 strains of K. pneumoniae with four ribotypes of C. difficile in a fully defined bacteria media (ZMB1). Growth curve analysis of 24 hour cultures revealed that cell-free supernatant from all K. pneumoniae strains enhanced the growth of all C. difficile strains, suggesting that K. pneumoniae could produce metabolites that enhanced C. difficile growth. Importantly, C. difficile grew well with K. pneumoniae bacteria and both bacteria were present in the cultures by gram stain. Non-targeted metabolomics revealed that the presence of K. pneumonia shifted the metabolism of C. difficile away from carbohydrate utilization and toward alternative fuel sources. K. pneumoniae is well known for its ability to create biofilms. To examine biofilm production, we grew C. difficile alone or with K. pneumoniae and examined biofilm by crystal violet staining. Although biofilms were nominally enhanced with K. pneumoniae compared to C. difficile alone, these biofilms were significantly lower than K. pneumoniae alone; indicating that biofilm synthesis is not a significant component of C. difficile-Klebsiella interactions. Finally, we examined how K. pneumoniae impacts C. difficile infection in vitro using colonic organoids by RNA sequencing. Sequencing revealed significantly elevated pro-inflammatory pathways when C. difficile and K. pneumonia were incubated together than either pathogen alone.

CONCLUSIONS
These results suggest that K. pneumoniae can influence C. difficile metabolism and exacerbate inflammation.