bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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<.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

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<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

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 > 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 < .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 <15% and <25% at one and three years, respectively. Attainment of complete normalization reduces the risk of relapse to <5% over the first year compared to histologic remission with chronic architectural changes (<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

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

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

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

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 < 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

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.
EXPLORING SELF-MANAGEMENT CHALLENGES OF ADOLESCENTS AND YOUNG ADULTS WITH INFLAMMATORY BOWEL DISEASE IN AN ONLINE INSTAGRAM SUPPORT COMMUNITY
Authors: Malloy Caeli , Rawl Susan , Miller Wendy
Published: January 2022

PURPOSE

The purpose of this qualitative study was to explore disease self-management challenges posted in an online Instagram support community by adolescents and young adults (AYAs) with inflammatory bowel disease (IBD).

BACKGROUND

For the estimated 6.8 million people worldwide living with IBD, effective disease self-management is paramount to supporting positive disease outcomes including quality of life. IBD self-management is highly individualized and can include a combination of medication management, ostomy management, and lifestyle modification. Self-management can be a complex process as it is often influenced by unpredictable disease trajectory. AYAs are disproportionately affected by IBD and experience myriad psychosocial and self-management challenges considering their stage of development and disease status. Youth with chronic conditions often turn to social media as a source of information and support. Instagram is a popular social media platform among AYAs, with more than one-third of users falling between 13 and 24 years of age. Harnessing this real-world data can reveal the authentic self-management challenges of AYAs with IBD.

METHODS

Public Instagram posts between January and December 2019 were manually extracted from an online IBD support community with over 16,7000 followers (see examples in Figure 1). We extracted posts about self-management from Instagram users who: 1) indicated they had IBD; and 2) stated they were 13-24 years old or in middle school, high school, or college. Using thematic analysis, authors independently coded and identified emerging themes about IBD self-management challenges (Figure 2). Authors discussed any disagreement about identified themes through an iterative process until consensus was reached.

RESULTS

Out of 2,700 posts assessed for eligibility, 83 met inclusion criteria. Six major themes about self-management emerged: Desire for Normalcy, Dietary Changes, Education and Career, Healthcare System, Relationships with Others, and Symptoms and Complications. Additionally, nine subthemes emerged: Finding Balance, Wanting a Normal Life, Transitioning to College and Work, Handling School, Understanding Diagnosis, Accessing Health Services, Navigating Treatment and Side Effects, Managing Significant Relationships, and Seeking Peers with IBD. Self-management challenges permeated every aspect of life, including relationships, school activities, and aspirations for the future.

CONCLUSIONS

Our findings represent the first thematic analysis of Instagram posts in an online IBD community and provide a crucial perspective of the concerns of AYAs with IBD. Self-management challenges were wide-ranging and complex, highlighting the gap between self-management needs and skills in this population. Future research should further explore these challenges to develop tailored self-management interventions to improve quality of life in AYAs with IBD.
TRANSPORTATION ACCESS AND DELAY IN DIAGNOSIS FOR PEDIATRIC INFLAMMATORY BOWEL DISEASE PATIENTS
Authors: Zeky Nicole , LeBlanc Colleen , McDonough Elizabeth , Moulton Dedrick
Published: January 2022

PURPOSE

Inflammatory bowel disease (IBD), consisting of both Crohn’s Disease (CD) and ulcerative colitis (UC), affects nearly 80,000 children in the United States. African American patients have more perirectal phenotype which might indicate more severe disease activity however it is unclear why. There is no published data on transportation access and how it relates to pediatric IBD. The purpose of this study is to compare pediatric IBD patients with low access to care to those with more access to care and their severity of disease at diagnosis. Our hypothesis is that those patients who live farther from the children’s hospital and bus stops will have more of a lag time in their diagnosis as defined by two or more visits with another provider for complaints concerning for IBD compared to those patients with more ease of access to care. We aim to assess the impact of proximity to care facilities, bus stops and primary children’s hospital and disease severity at the time of diagnosis for pediatric IBD population.

METHODS

This study is a retrospective chart review of patients seen by the Louisiana State University Health Science Center Pediatric Gastroenterology division at Children’s Hospital New Orleans from 2019 until 2021. A list of patients with the diagnosis of either CD or UC after 2019 was generated. Both qualitative and quantitative data was collected. Patient’s addresses were used to determine the distance to their primary gastroenterologist clinic. Data collected also included their proximity location to bus stops, number of visits prior to diagnosis of IBD.

RESULTS

There were 71 pediatric patients diagnosed during the study period. The patients were predominantly male (51%) and white (65%) with average age at diagnosis of 12 years old (± 3.3 years). Forty-eight (68%) patients were diagnosed with CD. More Crohn’s Disease patients had 2 or more visits before diagnosis compared to those with UC (48% versus 30%). The average distance for African American patients to the children’s hospital was 50.5 miles (± 55.9 miles) which was similar to the white patients (53.0 ± 59.8 miles). Of the 23 African American patients included in the study 14 (61%) had at least 2 visits before being diagnosed with IBD. In comparison, 15 of the 46 (33%) white patients had at least 2 visits before receiving a diagnosis of IBD. Most patients had a pediatrician listed as their primary care provider for both African American and white patients (70% versus 80%).

CONCLUSION

The significance of a delay in diagnosis and pediatric IBD is unclear, however further studies to determine if less access of care is predictive of greater disease severity and activity at presentation may be warranted. Additional studies will be completed to determine the relationship between proximity to bus stops and disease burden at diagnosis.
HIGH DOSE TOFACITINIB AS SALVAGE THERAPY IN STEROID REFRACTORY ACUTE SEVERE ULCERATIVE COLITIS FOLLOWING NON-RESPONSE TO INFLIXIMAB
Authors: Khan Muhammad , Mushtaq Kamran , Yakoob Rafie , AlSoub Deema
Published: January 2022

INTRODUCTION

Acute Severe Ulcerative Colitis (ASUC) requiring hospitalization remains a serious concern in patients with Ulcerative colitis. In patients with steroid-refractory disease, Intravenous infliximab salvage therapy is used. Colectomy is reserved for patients refractory, even to salvage therapy. We present a young female with ASUC, who was successfully treated with high dose Tofacitinib after Steroids and Infliximab failure.

CASE HISTORY

A 23 years old female was diagnosed with pan-UC six months prior to the first presentation at our center. Since then, she has had a Steroid dependent disease. She was on the maximum 5-Aminosalicylic dose and could not tolerate azathioprine in the past. At the presentation, she had iron deficiency anemia (10.1 gm/dL), hypoalbuminemia (27 gm/L), C-reactive protein

4 mg/L and calprotectin of 670 mg/Kg. The colonoscopy showed pan-colitis Mayo score 3. Given her steroid dependency for the last six months, she was started on Infliximab induction followed by maintenance. After the second Induction dose of Infliximab, the patient was admitted with worsening of her clinical symptoms. Sigmoidoscopy was performed for the patient, which showed severe colitis. Biopsy showed cytomegalovirus inclusion by immunohistochemistry. The third dose of Infliximab was postponed, and the patient received IV ganciclovir followed by oral therapy for two weeks duration. She responded clinically but before her third dose again had worsening of the disease. At the time of admission, she had a hemoglobin of 7.1 gm/dL, albumin 21 gm/L, CRP 72 mg/L, and calprotectin of 1352 mg/Kg. She met Truelove and Witts criteria for ASUC with a Mayo score of 12. Sigmoidoscopy again showed pan-colitis but was negative for cytomegalovirus. The patient did not respond to 60 mg methylprednisolone daily for five days. She was re-inducted with High dose infliximab and was given two doses 10 mg/Kg one week apart. However, the Mayo score showed no improvement, and surgery was consulted for possible colectomy. After discussing with the patient, we started her on a high dose Tofacitinib of 10 mg three times a day as salvage therapy. She showed dramatic improvement within the next 72 hours, and by day five, was discharged home. Her hemoglobin improved, CRP normalized. At three months, calprotectin was less than 100 mg/Kg, and colonoscopy showed mucosal healing with a Mayo score of 1.

DISCUSSION

In Steroid refractory ASUC, with non-response to Infliximab, High-dose tofacitinib can be used as rescue therapy. Our patient showed clinical and biochemical remission within three days. At three months follow up, the patient remained colectomy-free and was in sustained remission.
IMPACT OF THIOPURINE DOSE IN COMBINATION THERAPY IN INFLAMMATORY BOWEL DISEASE
Authors: Nawaz Ahmad , Glick Laura , Li Darrick , Gaidos Jill , Proctor Deborah , Al-Bawardy Badr
Published: January 2022

BACKGROUND

Multiple studies have suggested that combination therapy with thiopurines and anti-TNFs is superior to monotherapy in Crohn’s disease (CD) and ulcerative colitis (UC). The optimal dose of thiopurines in combination therapy remains unclear. Our aim was to determine the impact of thiopurine dosing in combination therapy on the formation of anti-TNF antibodies and clinical outcomes in inflammatory bowel disease (IBD).

METHODS

This is a single-center, retrospective cohort study of all IBD patients treated with thiopurine and anti-TNF combination therapy between 1/1/2012 and 11/1/2020. Therapeutic dose of thiopurines was defined as ≥ 1 mg/kg for 6-mercaptopurine (6-MP) and ≥ 2 mg/kg for azathioprine (AZA). The primary outcome was anti-TNF antibody formation between patients on a therapeutic dose of thiopurines (TD) versus those on non-therapeutic doses (NTD). Secondary outcomes included steroid-free clinical remission (SFCR), endoscopic healing (absence of ulcers/erosions in CD and Mayo endoscopic score ≤ 1 for UC), and normal serum C-reactive protein (CRP) (defined as ≤ 5 mg/L) in patients who were on combination therapy. Continuous variables were analyzed using an unpaired student’s t-test. Categorical variables were analyzed using a chi-square test.

RESULTS

A total of 108 patients were included. The median age was 31.5 years (range 13-69), and 58.3% were male (Table 1). A total of 81 patients (75%) were on infliximab (IFX), while 27 patients (25%) were on adalimumab (ADA). Therapeutic dose of thiopurine was used in 19% (n=21). TPMT activity data was available for 56 patients. Normal TPMT activity was noted in 100% (n=7) in the TD group vs. 81.6% (n=40) in the NTD group (p=0.10). There were no significant differences between the TD vs. NTD groups in terms of baseline and disease characteristics (Table 2).

Anti-TNF antibody formation was observed in 31 patients (32.1% of patients on IFX and 18.5% of patients on ADA). In the TD group 23.8% developed anti-TNF antibodies vs. 29.9% (p=0.58) in the NTD group. The mean anti-TNF drug level was 19.8 ± 13.8 vs. 16.9 ± 15.5 μg/mL (p=0.44) in the TD vs. NTD groups, respectively. SFCR was observed in 57.1% vs. 60.9% (p=0.75) and 38.1% vs. 37.9% discontinued anti-TNF treatment in the TD vs. NTD groups, respectively. Endoscopic healing was achieved in 55 % vs 60% (p=0.69), and normal CRP was observed in 52.4% vs. 46% (p=0.27) in the TD vs. NTD groups, respectively.

CONCLUSION

In our cohort, a therapeutic dose of thiopurine in combination therapy was not associated with lower rates of anti-TNF antibody formation compared to non-therapeutic doses. In addition, there were no significant differences in clinical outcomes such as normal CRP, SFCR, and endoscopic healing. Larger and prospective studies are needed to further elucidate the effect of thiopurine dosing in combination therapy for IBD.
The Androgen Receptor: A Therapeutic Target in Desmoplastic Small Round Cell Sarcoma
Authors: Lamhamedi-Cherradi Salah-Eddine , Maitituoheti Mayinuer , Menegaz Brian A. , Krishnan Sandhya , Vetter Amelia M. , Camacho Pamela , Wu Chia-Chin , Beird Hannah C. , Porter Robert W. , Ingram Davis R. , Ramamoorthy Vandhana , Mohiuddin Sana , McCall David , Truong Danh D. , Cuglievan Branko , Futreal P. Andrew , Velasco Alejandra Ruiz , Anvar Nazanin Esmaeili , Utama Budi , Titus Mark , Lazar Alexander J. , Wang Wei-Lien , Rodriguez-Aguayo Cristian , Ratan Ravin , Livingston John A. , Rai Kunal , MacLeod A. Robert , Daw Najat C. , Hayes-Jordan Andrea , Ludwig Joseph A.
Published: January 2022

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have immediate clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.

ONE SENTENCE SUMMARY

We demonstrate that DSRCT, an aggressive pediatric cancer, is an AR-driven malignancy capable of responding to androgen deprivation therapy.
Neutralization of Omicron SARS-CoV-2 by 2 or 3 doses of BNT162b2 vaccine
Authors: Xia Hongjie , Zou Jing , Kurhade Chaitanya , Cai Hui , Yang Qi , Cutler Mark , Cooper David , Muik Alexander , Jansen Kathrin U. , Xie Xuping , Swanson Kena A. , Shi Pei-Yong
Published: January 2022

We report the antibody neutralization against Omicron SARS-CoV-2 after 2 and 3 doses of BNT162b2 mRNA vaccine. Vaccinated individuals were serially tested for their neutralization against wild-type SARS-CoV-2 (strain USA-WA1/2020) and an engineered USA-WA1/2020 bearing the Omicron spike glycoprotein. Plaque reduction neutralization results showed that at 2 or 4 weeks post-dose-2, the neutralization geometric mean titers (GMTs) were 511 and 20 against the wild-type and Omicron-spike viruses, respectively, suggesting that two doses of BNT162b2 were not sufficient to elicit robust neutralization against Omicron; at 1 month post-dose-3, the neutralization GMTs increased to 1342 and 336, respectively, indicating that three doses of vaccine increased the magnitude and breadth of neutralization against Omicron; at 4 months post-dose-3, the neutralization GMTs decreased to 820 and 171, respectively, suggesting similar neutralization decay kinetics for both variants. The data support a three-dose vaccine strategy and provide the first glimpse of the neutralization durability against Omicron.
The Goldilocks Principle conferred by LDH isoenzymes controls murine T cell glycolysis and differentiation
Authors: Chen Xuyong , Liu Lingling , Wang Ruoning
Published: January 2022

Isoenzyme divergence is a prevalent mechanism governing tissue-specific and developmental stage-specific metabolism in mammals. The isoenzyme pattern (spectrum) of lactate dehydrogenase (LDH) reflects the status of glucose metabolism in different organs such as muscle, liver, and heart. T cells are highly dependent on glucose metabolism for survival, proliferation, and differentiation. However, the LDH isoenzyme spectrum in T cells and its potential impact on T cell-mediated immune response remain unclear. Here, we discovered that the LDH spectrum in murine T cells is characterized by three tetrameric isoenzymes composed of LDHA and LDHB (LDH-3/4/5). Genetic deletion of LDHA or LDHB altered the isoenzyme spectrum by removing all heterotetramers and leaving T cell with LDH-1 (the homotetramer of LDHB) or LDH-5 (the homotetramer of LDHA), respectively. Accordingly, altering the isoenzyme spectrum by deleting LDHA or LDHB compromises T cell metabolic fitness and effector cell differentiation in vivo. Unexpectedly, deleting LDHA suppressed glycolysis, whereas deleting LDHB further enhanced it, indicating that an optimal zone of glycolytic activity is critical to driving effector T cell differentiation. Mechanistically, the LDH isoenzyme spectrum imposed by LDHA and LDHB is required to optimize glycolysis to maintain a balanced NAD+/NADH pool, a hallmark of metabolic fitness. Together, our results suggest that the LDH isoenzyme spectrum enables “Goldilocks levels” of glycolytic and redox activity (i.e., not too high, not too low, but just right) to control T cell differentiation function.
Price promotion in omnichannel retailing: how much is too much?
Authors: Quach Sara , Barari Mojtaba , Thaichon Park , Moudrý Dann Vit
Published: January 2022

Purpose

The study aims to investigate customers' emotional and behavioral responses to price promotion in omnichannel retailing through the integration of the expectancy-disconfirmation theory, feelings-as-information-theory and regret regulation theory.

Design/methodology/approach

An online survey was designed in Qualtrics and distributed by an online survey to collect data from 786 (main study) and 150 (a follow-up study) customers from the USA. The participants were randomly assigned to different scenarios related to the need to purchase a toothbrush, laptop or health supplement. After the first purchase, the participants received a discount on the same product that has just been purchased. The discount can be used at an online store or a physical store. The three levels of price promotion after the purchase were 10% (low), 25% (moderate) and 50% (high).

Findings

The study found that consumers are likely to feel more surprised and less discontented when being offered a higher discount. The emotions further significantly impact their anticipated regret. Further, different discount levels influence patronage intention and omnichannel usage via emotional responses and anticipated regret. These relationships are moderated by product involvement.

Originality/value

The study extends knowledge of price promotion and provides insights that can assist retailers in increasing the effectiveness of their sales promotion strategy. Addressing the lacuna in the current literature, which predominantly focuses on the cost and benefits analysis of sales promotion, the study revealed that cross-channel price promotion results in consumers' sophisticated emotional responses.
What’s hidden behind bulk deals? A study on Indian stock market
Authors: Rajvanshi Vivek , Paul Samit
Published: January 2022

Purpose

Emerging market, like India, is characterised by poor institutional structure, weaker regulations and higher information asymmetry which may lead to stock price manipulation. This study shed some light on such manipulation by investigating front-running behaviour around the bulk deals of stocks traded at the National Stock Exchange (NSE) from 2010 to 2019.

Design/methodology/approach

The authors employ an event study methodology to identify front-running in pre-event period of bulk deals. The bulk deals are classified into Only Buy, Only Sell, Partial Buy and Partial Sell trades. They are further subsampled based on the category of investors. Through cross-sectional regression, the authors also identify factors explaining such front-running.

Findings

The results show that the front-runners can achieve 5%–7% returns within a week around the event day. Abnormal Returns (AR) before the deals are higher for “Buy” deals than “Sell” deals. The authors also examine the role of volume and delivery in explaining the AR and cumulative abnormal returns (CAR). Lagged CAR, change in volume and change in delivery explain the AR. The results are robust after controlling for Bullish and Bearish Periods.

Originality/value

To the best of authors’ knowledge, this is the first study that explores the front-running in “Partial Buy” and “Partial Sell” bulk deals. Further, it investigates whether the category of investors has any role in front running. It empirically tests the asymmetric market reaction between “Buy” and “Sell” trades. Finally, it examines the role of volume and delivery in front-running.
Break-even inflation rates: the Italian case
Authors: Fanari Marco , Di Iorio Alberto
Published: January 2022

Purpose

This work aims to study the break-even inflation rates (BEIRs), a widely used market-based measure of expected inflation. The authors focus on Italian Government bonds, one of the most liquid debt markets in the euro area.

Design/methodology/approach

The authors set up an auto-regressive distributed lag model and regress the BEIR on a set of variables that proxy inflation, market risk aversion, protection against deflation, credit as well as liquidity risk to get some insights into the importance of these factors. Subsequently, to disentangle market participants’ inflation expectations from their associated risk premia, the authors estimate a term structure model for the joint pricing of the Italian Government’s nominal and real yield curves, considering also a credit and a liquidity pricing factor.

Findings

The results show that BEIRs could be a misleading measure of the expected inflation due to the importance of the inflation risk premium and the credit risk effect. According to the estimates, the decrease of market-based measures of inflation observed in the last part of the sample period seems to reflect a lowering of both inflation expectations and risk premia. Inflation premia co-move with a measure of the tail risk of the long-term inflation distribution, signalling that investors become more concerned with downside risks.

Originality/value

This study complements the existing literature primarily based on the USA and euro area data focusing on the Italian market. To this end, the authors modify and adapt a well-known term structure model developed for nominal and real curves.
Decision Science Can Help Address the Challenges of Long‐Term Planning in the Colorado River Basin
Authors: Smith Rebecca , Zagona Edith , Kasprzyk Joseph , Bonham Nathan , Alexander Elliot , Butler Alan , Prairie James , Jerla Carly
Published: January 2022

“Deep uncertainty” is a term that describes planning contexts in which it is impossible to determine the likelihood of any given set of future conditions, there are conflicting performance objectives and priorities, and decision outcomes are unpredictable. Evidence of the relevance of this term in the Colorado River Basin can be found in the unexpected severity and length of the ongoing drought, the existence of a wide range of future streamflow and demand projections and anticipated system requirements, as well as in the diverse range of stakeholders, viewpoints, and priorities that must be considered when developing and analyzing future operating policies. Decision Making under Deep Uncertainty (DMDU) is a branch of decision science devoted to developing planning approaches that can address these challenges. Reclamation began exploring DMDU techniques in 2012 in the Colorado River Basin Water Supply and Demand Study when it used the concepts of adaptation, vulnerability, and robustness in the design and evaluation of portfolios of options and strategies to address a potential supply‐demand imbalance in coming decades. This article presents the basis for continuing to explore DMDU techniques and briefly describes how Reclamation’s recent and ongoing DMDU studies could contribute to future planning efforts in the Colorado River Basin.
Radiation therapy induces an abscopal effect and upregulates programmed death‐ligand 1 expression in a patient with non‐small cell lung cancer
Authors: Morita Yutaka , Saijo Atsuro , Nokihara Hiroshi , Mitsuhashi Atsushi , Yoneda Hiroto , Otsuka Kenji , Ogino Hirokazu , Bando Yoshimi , Nishioka Yasuhiko
Published: January 2022

Radiation therapy (RT) activates the antigen presentation of dendritic cells and priming of cancer‐specific cytotoxic CD8+ T cells, occasionally resulting in a systemic immune response to the tumor outside of the treatment field. The phenomenon of tumor regression at the site distant from irradiated fields is known as the abscopal effect. Several case reports have indicated a potential role of RT in overcoming primary and acquired resistance against immune checkpoint inhibitors in non‐small cell lung cancer (NSCLC) and melanoma patients. We herein report an NSCLC patient who developed acquired resistance to an RT‐induced abscopal effect and subsequently experienced reactivation of the systemic antitumor immune response by pembrolizumab, an antiprogrammed death 1 antibody. In this case, RT not only induced an abscopal effect but also upregulated the programmed death‐ligand 1 expression outside of the irradiated field when the patient developed resistance to the abscopal effect. This case can facilitate our understanding of the mechanism underlying the RT‐induced systemic immune response against cancer cells and adaptive resistance mechanism of cancer cells from immune surveillance. These findings highlight the promising results of current clinical trials combining RT and immune checkpoint inhibitors. Ongoing clinical trials will further establish evidence supporting combination therapy with RT and immune checkpoint inhibitors.