Sidhartha Sinha

All Publications

• Oral Vancomycin Is Associated With Less IBD Therapy Intensification in PSC-IBD Talamantes, S. M., Kulkarni, C., Cholankeril, G., Fardeen, T., Sinha, S. LIPPINCOTT WILLIAMS & WILKINS. 2023: S830-S831

  View details for Web of Science ID 001091849302206

• Wireless Patches Reveal Differences in Gastric and Colonic Motility Between Crohn's Disease Patients in Flare and Remission Axelrod, L., Axelrod, S., Navalgund, A., Patel, A., Brogadir, S., Sinha, S. LIPPINCOTT WILLIAMS & WILKINS. 2023: S860-S861

  View details for Web of Science ID 001091849302243

• Colonoscopy Prep Is Associated With Increased Risk of Flare Among Patients With Previously Inactive Inflammatory Bowel Disease Kulkarni, C., Talamantes, S. M., Sinha, S. LIPPINCOTT WILLIAMS & WILKINS. 2023: S840

  View details for Web of Science ID 001091849302218

• Development and Validation of a Machine Learning System to Identify Reflux Events in Esophageal 24-hour pH/Impedance Studies. Clinical and translational gastroenterology Zhou, M. J., Zikos, T., Goel, K., Goel, K., Gu, A., Re, C., Rodriguez, D., Clarke, J. O., Garcia, P., Fernandez-Becker, N., Sonu, I., Kamal, A., Sinha, S. R. 2023

  Abstract

  INTRODUCTION: Esophageal 24-hour pH/impedance testing is routinely performed to diagnose gastroesophageal reflux disease (GERD). Interpretation of these studies is time-intensive for expert physicians and has high inter-reader variability. There are no commercially available machine learning tools to assist with automated identification of reflux events in these studies.METHODS: A machine learning system to identify reflux events in 24-hour pH/impedance studies was developed, which included an initial signal processing step and a machine learning model. Gold standard reflux events were defined by a group of expert physicians. Performance metrics were computed to compare the machine learning system, current automated detection software (Reflux Reader v6.1), and an expert physician reader.RESULTS: The study cohort included 45 patients (20/5/20 patients in the training/validation/test sets, respectively). Mean age was 51 (standard deviation [SD] 14.5) years, 47% of patients were male, and 78% of studies were performed off proton pump inhibitor (PPI). Comparing the machine learning system vs. current automated software vs. expert physician reader, AUC was 0.87 (95% CI 0.85-0.89) vs. 0.40 (95% CI 0.37-0.42) vs. 0.83 (95% CI 0.81-0.86), respectively; sensitivity was 68.7% vs. 61.1% vs. 79.4%, respectively; and specificity was 80.8% vs. 18.6% vs. 87.3%, respectively.DISCUSSION: We trained and validated a novel machine learning system to successfully identify reflux events in 24-hour pH/impedance studies. Our model performance was superior to that of existing software and comparable to that of a human reader. Machine learning tools could significantly improve automated interpretation of pH/impedance studies.

  View details for DOI 10.14309/ctg.0000000000000634

  View details for PubMedID 37578060

• Microbiomic and Metabolomic Analyses Unveil the Protective Effect of Saffron in a Mouse Colitis Model. Current issues in molecular biology Singh, G., Brim, H., Haileselassie, Y., Varma, S., Habtezion, A., Rashid, M., Sinha, S. R., Ashktorab, H. 2023; 45 (7): 5558-5574

  Abstract

  Despite the existence of effective drugs used to treat inflammatory bowel disease (IBD), many patients fail to respond or lose response over time. Further, many drugs can carry serious adverse effects, including increased risk of infections and malignancies. Saffron (Crocus sativus) has been reported to have anti-inflammatory properties. Its protective role in IBD and how the microbiome and metabolome play a role has not been explored extensively. We aimed to establish whether saffron treatment modulates the host microbiome and metabolic profile in experimental colitis. Colitis was induced in C57BL/6 mice with 3% DSS and treated with either saffron in a dose of 20 mg/kg body weight or vehicle through daily gavage. On day 10, stool pellets from mice were collected and analyzed to assess saffron's effect on fecal microbiota and metabolites through 16S rRNA sequencing and untargeted primary metabolite analysis. Saffron treatment maintained gut microbiota homeostasis by counter-selecting pro-inflammatory bacteria and maintained Firmicutes/Bacteroides ratio, which was otherwise disturbed by DSS treatment. Several metabolites (uric acid, cholesterol, 2 hydroxyglutaric acid, allantoic acid, 2 hydroxyhexanoic acid) were altered significantly with saffron treatment in DSS-treated mice, and this might play a role in mediating saffron's colitis-mitigating effects. These data demonstrate saffron's therapeutic potential, and its protective role is modulated by gut microbiota, potentially acting through changes in metabolites.

  View details for DOI 10.3390/cimb45070351

  View details for PubMedID 37504267

  View details for PubMedCentralID PMC10378474

• Dietary Exposures and Interventions in Inflammatory Bowel Disease: Current Evidence and Emerging Concepts. Nutrients Gubatan, J., Kulkarni, C. V., Talamantes, S. M., Temby, M., Fardeen, T., Sinha, S. R. 2023; 15 (3)

  Abstract

  Diet is intimately linked to the gastrointestinal (GI) tract and has potent effects on intestinal immune homeostasis. Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the GI tract. The therapeutic implications of diet in patients with IBD have received significant attention in recent years. In this review, we provide a contemporary and comprehensive overview of dietary exposures and interventions in IBD. Epidemiological studies suggest that ultra-processed foods, food additives, and emulsifiers are associated with a higher incidence of IBD. Exclusion and elimination diets are associated with improved symptoms in patients with IBD, but no effects on objective markers of inflammation. Specific dietary interventions (e.g., Mediterranean, specific carbohydrate, high fiber, ketogenic, anti-inflammatory diets) have been shown to reduce symptoms, improve inflammatory biomarkers, and quality of life metrics to varying degrees, but these studies are limited by study design, underpowering, heterogeneity, and confounding. To date, there is no robust evidence that any dietary intervention alone may replace standard therapies in patients with IBD. However, diet may play an adjunct role to induce or maintain clinical remission with standard IBD therapies. The results of novel dietary trials in IBD such as personalized fiber, intermittent fasting, and time-restricted diets are eagerly awaited.

  View details for DOI 10.3390/nu15030579

  View details for PubMedID 36771288

• Gut Microbiome in Inflammatory Bowel Disease: Role in Pathogenesis, Dietary Modulation, and Colitis-Associated Colon Cancer. Microorganisms Gubatan, J., Boye, T. L., Temby, M., Sojwal, R. S., Holman, D. R., Sinha, S. R., Rogalla, S. R., Nielsen, O. H. 2022; 10 (7)

  Abstract

  The gut microbiome has increasingly been recognized as a critical and central factor in inflammatory bowel disease (IBD). Here, we review specific microorganisms that have been suggested to play a role in the pathogenesis of IBD and the current state of fecal microbial transplants as a therapeutic strategy in IBD. We discuss specific nutritional and dietary interventions in IBD and their effects on gut microbiota composition. Finally, we examine the role and mechanisms of the gut microbiome in mediating colitis-associated colon cancer.

  View details for DOI 10.3390/microorganisms10071371

  View details for PubMedID 35889090

• Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives. Clinical and experimental gastroenterology Gubatan, J., Keyashian, K., Rubin, S. J., Wang, J., Buckman, C. A., Sinha, S. 2021; 14: 333-342

  Abstract

  Leukocyte trafficking to the gastrointestinal tract is recognized to play a role in the pathogenesis of inflammatory bowel disease (IBD). Integrins are expressed on immune cells and interact with cell adhesion molecules (CAM) to mediate leukocyte trafficking. Blockade of the gut-tropic integrin α4β7 and its subunits has been exploited as a therapeutic target in IBD. Natalizumab (anti-α4) is approved for moderate to severe Crohn's disease (CD), but its use is limited due to potential risk of progressive multifocal leukoencephalopathy. Vedolizumab (anti-α4β7) is approved for the treatment of ulcerative colitis (UC) and CD. It is the most widely used anti-integrin therapy in IBD and has been shown to be effective in both induction and maintenance therapy, with a favorable safety profile. Several models incorporating clinical, genetic, immune, gut microbial, and vitamin D markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. Large phase 3 clinical trials evaluating efficacy of etrolizumab in the induction and maintenance of patients with IBD are underway. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).

  View details for DOI 10.2147/CEG.S293272

  View details for PubMedID 34466013

  View details for PubMedCentralID PMC8402953

• Protective Effect of Saffron in Mouse Colitis Models Through Immune Modulation. Digestive diseases and sciences Singh, G., Haileselassie, Y., Ji, A. R., Maecker, H. T., Sinha, S. R., Brim, H., Habtezion, A., Ashktorab, H. 2021

  Abstract

  BACKGROUND: People with inflammatory bowel disease (IBD) including ulcerative colitis are at risk for colorectal cancer. Despite available effective drugs used to treat IBD, many patients fail or lose response over time with some displaying drug-induced adverse events. Saffron (Crocus sativus) has been reported to have anti-inflammatory properties. Its protective role in IBD has not been explored extensively.AIM: To establish whether saffron treatment alleviates inflammation in experimental colitis.METHODS: Colitis was induced in C57BL/6 mice with 3% DSS and treated with either saffron doses (7.5, 15, 20, 25mg/kg body weight) or vehicle through daily gavage. On day 11, mice were euthanized and analyzed for gross and microscopic inflammation. Distal colon segments were collected for mRNA and protein expression of HO-1 protein and GPX2, (the downstream targets of NRF-2). Nrf-2 translocation from cytosol to nucleus was confirmed by immunofluorescence, and further Nrf-2 protein expression in nuclear and cytosolic fraction of colon was analyzed by immunoblot. Immune cells were isolated from the lamina propria of mouse colon for flow cytometry-based immunophenotyping. Colitis was also induced in C57BL/6 Ahr knockout and wild type mice to explore the involvement of Ahr-dependent pathways in saffron's protective effect(s). The therapeutic effect of saffron was further validated in another TNBS model of colitis.RESULTS: Saffron 20mg/kg body weightshowed improved colon gross and histology features and led to better body weight, colon length, histology score, and reduced disease activity index (DAI). Saffron significantly decreased pro-inflammatory macrophages (M1), while increasing anti-inflammatory macrophages (M2) and IL10+dendritic cells. Saffron treatment also enhanced CD3+T and CD3+CD8+T cells followed by increase in different CD3+CD4+T cells subsets like CD25+T cells, FoxP3+CD25+regulatory T cells, and CD4+FOXP3+CD25-regulatory T cells. Immunoblot analysis showed a significant increase in HO-1/GPX2 protein expression. With saffron treatment, Nrf-2 translocation into nucleus from cytosol also supports the involvement of Nrf-2 and its downstream targets in the protective effect of saffron. Further, we demonstrated that saffron in part exert anti-inflammatory effect through activation of aryl hydrocarbon receptor (AhR)-nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways.CONCLUSION: These data demonstrate saffron's therapeutic potential and its protective role in part via Ahr/Nrf-2 pathways and regulatory innate and adaptive immune cells.

  View details for DOI 10.1007/s10620-021-07163-3

  View details for PubMedID 34275090

• Development and Validation of an Artificial Intelligence System to Optimize Clinician Review of Patient Records. JAMA network open Chi, E. A., Chi, G., Tsui, C. T., Jiang, Y., Jarr, K., Kulkarni, C. V., Zhang, M., Long, J., Ng, A. Y., Rajpurkar, P., Sinha, S. R. 2021; 4 (7): e2117391

  Abstract

  Importance: Physicians are required to work with rapidly growing amounts of medical data. Approximately 62% of time per patient is devoted to reviewing electronic health records (EHRs), with clinical data review being the most time-consuming portion.Objective: To determine whether an artificial intelligence (AI) system developed to organize and display new patient referral records would improve a clinician's ability to extract patient information compared with the current standard of care.Design, Setting, and Participants: In this prognostic study, an AI system was created to organize patient records and improve data retrieval. To evaluate the system on time and accuracy, a nonblinded, prospective study was conducted at a single academic medical center. Recruitment emails were sent to all physicians in the gastroenterology division, and 12 clinicians agreed to participate. Each of the clinicians participating in the study received 2 referral records: 1 AI-optimized patient record and 1 standard (non-AI-optimized) patient record. For each record, clinicians were asked 22 questions requiring them to search the assigned record for clinically relevant information. Clinicians reviewed records from June 1 to August 30, 2020.Main Outcomes and Measures: The time required to answer each question, along with accuracy, was measured for both records, with and without AI optimization. Participants were asked to assess overall satisfaction with the AI system, their preferred review method (AI-optimized vs standard), and other topics to assess clinical utility.Results: Twelve gastroenterology physicians/fellows completed the study. Compared with standard (non-AI-optimized) patient record review, the AI system saved first-time physician users 18% of the time used to answer the clinical questions (10.5 [95% CI, 8.5-12.6] vs 12.8 [95% CI, 9.4-16.2] minutes; P=.02). There was no significant decrease in accuracy when physicians retrieved important patient information (83.7% [95% CI, 79.3%-88.2%] with the AI-optimized vs 86.0% [95% CI, 81.8%-90.2%] without the AI-optimized record; P=.81). Survey responses from physicians were generally positive across all questions. Eleven of 12 physicians (92%) preferred the AI-optimized record review to standard review. Despite a learning curve pointed out by respondents, 11 of 12 physicians believed that the technology would save them time to assess new patient records and were interested in using this technology in their clinic.Conclusions and Relevance: In this prognostic study, an AI system helped physicians extract relevant patient information in a shorter time while maintaining high accuracy. This finding is particularly germane to the ever-increasing amounts of medical data and increased stressors on clinicians. Increased user familiarity with the AI system, along with further enhancements in the system itself, hold promise to further improve physician data extraction from large quantities of patient health records.

  View details for DOI 10.1001/jamanetworkopen.2021.17391

  View details for PubMedID 34297075

• Saffron Pre-Treatment Promotes Reduction in Tissue Inflammatory Profiles and Alters Microbiome Composition in Experimental Colitis Mice. Molecules (Basel, Switzerland) Banskota, S., Brim, H., Kwon, Y. H., Singh, G., Sinha, S. R., Wang, H., Khan, W. I., Ashktorab, H. 2021; 26 (11)

  Abstract

  Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with an incompletely understood pathogenesis. Long-standing colitis is associated with increased risk of colon cancer. Despite the availability of various anti-inflammatory and immunomodulatory drugs, many patients fail to respond to pharmacologic therapy and some experience drug-induced adverse events. Dietary supplements, particularly saffron (Crocus sativus), have recently gained an appreciable attention in alleviating some symptoms of digestive diseases. In our study, we investigated whether saffron may have a prophylactic effect in a murine colitis model. Saffron pre-treatment improved the gross and histopathological characteristics of the colonic mucosa in murine experimental colitis. Treatment with saffron showed a significant amelioration of colitis when compared to the vehicle-treated mice group. Saffron treatment significantly decreased secretion of serotonin and pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in the colon tissues by suppressing the nuclear translocation of NF-κB. The gut microbiome analysis revealed distinct clusters in the saffron-treated and untreated mice in dextran sulfate sodium (DSS)-induced colitis by visualization of the Bray-Curtis diversity by principal coordinates analysis (PCoA). Furthermore, we observed that, at the operational taxonomic unit (OTU) level, Cyanobacteria were depleted, while short-chain fatty acids (SCFAs), such as isobutyric acid, acetic acid, and propionic acid, were increased in saffron-treated mice. Our data suggest that pre-treatment with saffron inhibits DSS-induced pro-inflammatory cytokine secretion, modulates gut microbiota composition, prevents the depletion of SCFAs, and reduces the susceptibility to colitis.

  View details for DOI 10.3390/molecules26113351

  View details for PubMedID 34199466

• Saffron Pre-Treatment Promotes Reduction in Tissue Inflammatory Profiles and Alters Microbiome Composition in Experimental Colitis Mice MOLECULES Banskota, S., Brim, H., Kwon, Y., Singh, G., Sinha, S. R., Wang, H., Khan, W. I., Ashktorab, H. 2021; 26 (11)

  View details for DOI 10.3390/molecules26113351

  View details for Web of Science ID 000660367900001

• Therapeutic Implications of Diet in Inflammatory Bowel Disease and Related Immune-Mediated Inflammatory Diseases. Nutrients Jiang, Y., Jarr, K., Layton, C., Gardner, C. D., Ashouri, J. F., Abreu, M. T., Sinha, S. R. 2021; 13 (3)

  Abstract

  Despite being a focal issue to patients, the effect of diet on adult inflammatory bowel disease (IBD) remains underexplored with limited guidance. While promising clinical trials are currently underway, there is a need for further evidence-based recommendations. As such, we summarize the current evidence on various diets used in the treatment of IBD and also explore the potential applications of dietary data from related immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis and psoriasis, to provide additional information to inform IBD providers. To date, there have been multiple diets investigated as adjunctive therapy in IBD, but many associated studies are small, non-randomized, and not controlled. Mediterranean, vegetarian/vegan, and reduced-calorie/fasting diets have been studied and have shown some positive results in other IMIDs, which may suggest potential applicability to those with IBD, but larger, well-designed clinical trials are needed for further guidance. Gluten-free and low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP)diets do not appear to have an impact on IBD disease activity, but low FODMAP may potentially be helpful for those with concurrent functional gastrointestinal symptoms. Specific carbohydrate diets have been mainly assessed in children but show some potential in small adult studies.

  View details for DOI 10.3390/nu13030890

  View details for PubMedID 33801883

• Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives CLINICAL AND EXPERIMENTAL GASTROENTEROLOGY Gubatan, J., Keyashian, K., Rubin, S. S., Wang, J., Buckman, C. A., Sinha, S. 2021; 14: 333-342

  View details for DOI 10.2147/CEG.S293272

  View details for Web of Science ID 000688310400001

• Artificial intelligence applications in inflammatory bowel disease: Emerging technologies and future directions. World journal of gastroenterology Gubatan, J. n., Levitte, S. n., Patel, A. n., Balabanis, T. n., Wei, M. T., Sinha, S. R. 2021; 27 (17): 1920-1935

  Abstract

  Inflammatory bowel disease (IBD) is a complex and multifaceted disorder of the gastrointestinal tract that is increasing in incidence worldwide and associated with significant morbidity. The rapid accumulation of large datasets from electronic health records, high-definition multi-omics (including genomics, proteomics, transcriptomics, and metagenomics), and imaging modalities (endoscopy and endomicroscopy) have provided powerful tools to unravel novel mechanistic insights and help address unmet clinical needs in IBD. Although the application of artificial intelligence (AI) methods has facilitated the analysis, integration, and interpretation of large datasets in IBD, significant heterogeneity in AI methods, datasets, and clinical outcomes and the need for unbiased prospective validations studies are current barriers to incorporation of AI into clinical practice. The purpose of this review is to summarize the most recent advances in the application of AI and machine learning technologies in the diagnosis and risk prediction, assessment of disease severity, and prediction of clinical outcomes in patients with IBD.

  View details for DOI 10.3748/wjg.v27.i17.1920

  View details for PubMedID 34007130

  View details for PubMedCentralID PMC8108036

• Reply to Letter to the Editor: What is the incidence of COVID-19 in patients with IBD in western countries? Gastroenterology Gubatan, J. n., Sinha, S. R., Habtezion, A. n. 2021

  View details for DOI 10.1053/j.gastro.2021.01.014

  View details for PubMedID 33453234

• Vitamin D is Associated with α4β7+ Immunophenotypes and Predicts Vedolizumab Therapy Failure in Patients with Inflammatory Bowel Disease. Journal of Crohn's & colitis Gubatan, J., Rubin, S. J., Bai, L., Haileselassie, Y., Levitte, S., Balabanis, T., Patel, A., Sharma, A., Sinha, S. R., Habtezion, A. 2021

  Abstract

  Vitamin D downregulates the in vitro expression of the gut-tropic integrin α4β7 on immune cells. The clinical relevance of this finding in patients with inflammatory bowel disease (IBD) is unclear. We tested the hypothesis that vitamin D is associated with α4β7 immunophenotypes and risk of vedolizumab (anti- α4β7) failure in IBD.We performed single-cell immunophenotyping of peripheral and intestinal immune cells using mass cytometry (CyTOF) in vedolizumab-naïve patients with IBD (N=48). We analyzed whole-genome mucosal gene expression (GSE73661) from GEMINI I and GEMINI long-term safety (LTS) to determine the association between vitamin D receptor (VDR) and integrin alpha-4 (ITGA4) and beta-7 (ITGB7) genes. We estimated the odds of vedolizumab failure with low pre-treatment vitamin D in a combined retrospective and prospective IBD cohort (N= 252) with logistic regression.Immunophenotyping revealed that higher 25(OH)D was associated with decreased α4β7+ peripheral blood mononuclear cells (R = -0.400, P < 0.01) and α4β7+ intestinal leukocytes (R = -0.538, P= 0.03). Serum 25(OH)D was inversely associated with α4β7+ peripheral B cells and natural killer (NK) cells and α4β7+ intestinal B cells, NK cells, monocytes, and macrophages. Mucosal expression of VDR was inversely associated with ITGA4 and ITGB7 expression. In multivariate analysis, 25(OH)D < 25 ng/mL was associated with increased vedolizumab primary non-response during induction (OR 26.10, 95% CI 14.30-48.90, P<0.001) and failure at 1-year follow-up (OR 6.10, 95% CI 3.06-12.17, P<0.001).Low serum 25(OH)D is associated with α4β7+ immunophenotypes and predicts future vedolizumab failure in patients with IBD.

  View details for DOI 10.1093/ecco-jcc/jjab114

  View details for PubMedID 34180967

• Association of Anti-TNF Therapy With Increased Risk of Acute Cholangitis in Patients With Primary Sclerosing Cholangitis. Inflammatory bowel diseases Kulkarni, C., Murag, S., Cholankeril, G., Fardeen, T., Mannalithara, A., Lerrigo, R., Kamal, A., Ahmed, A., Goel, A., Sinha, S. R. 2020

  Abstract

  BACKGROUND: Patients with primary sclerosing cholangitis (PSC) are at increased risk of developing acute cholangitis. The majority of patients with PSC have comorbid inflammatory bowel disease, and many take immunosuppressive medications. The epidemiological risks for the development of acute cholangitis in patients with PSC, including the impact of immunosuppressive therapy, are unknown.METHODS: We conducted a 2-center, retrospective cohort study using data from 228 patients at Stanford University Medical Center and Santa Clara Valley Medical Center (CA), a county health care system. Patient demographics, medications, PSC disease severity, and inflammatory bowel disease status were extracted. Using stepwise variable selection, we included demographic and covariate predictors in the multiple logistic regression model assessing risk factors for cholangitis. Time-to-event analysis was performed to evaluate specific immunosuppressive medications and development of cholangitis.RESULTS: Thirty-one percent of patients had at least 1 episode of acute cholangitis (n = 72). Anti-tumor necrosis factor (TNF) therapy was associated with increased odds of acute cholangitis (odds ratio, 7.29; 95% confidence interval, 2.63-12.43), but immunomodulator use was protective against acute cholangitis (odds ratio, 0.23; 95% confidence interval, 0.05-0.76). Anti-TNF therapy was associated with decreased time-to-cholangitis, with a median time of 28.4 months; in contrast, only 11.1% of patients who were prescribed immunomodulators developed cholangitis over the same time period (P < 0.001).CONCLUSIONS: Our observations suggest that classes of immunosuppressive medications differentially modify the odds of acute cholangitis. Biologic therapy, ie, anti-TNF therapy, was shown to have significantly higher odds for patients developing acute cholangitis whereas immunomodulator therapy was shown to have a potential protective effect. These findings may help guide physicians in decision-making for determining appropriate immunosuppressive therapy.

  View details for DOI 10.1093/ibd/izaa317

  View details for PubMedID 33300561

• Efficacy of Dietary Supplements in Inflammatory Bowel Disease and Related Autoimmune Diseases. Nutrients Jadhav, P., Jiang, Y., Jarr, K., Layton, C., Ashouri, J. F., Sinha, S. R. 2020; 12 (7)

  Abstract

  The microbiome is an important contributor to a variety of fundamental aspects of human health, including host metabolism, infection, and the immune response. Gut dysbiosis has been identified as a contributor to the errant immune response in a variety of immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and psoriatic disease (psoriasis and psoriatic arthritis). Given this, probiotics and prebiotics have been investigated as therapeutic options in these disease states. In our review, we highlight the current evidence on prebiotics and probiotics as well as other supplements (such as fish oils, vitamin D, and curcumin) as therapies for IBD. Recommendations, however, regarding the specific use of such supplements in IBD have been lacking, particularly from professional societies, often due to study limitations related to small sample sizes and design heterogeneity. Hence, we additionally examine the literature on the use of prebiotics, probiotics, and other supplements in related IMIDs, namely RA and psoriasis/psoriatic arthritis, as these diseases share many approved therapeutic options with IBD. Based on these combined findings, we offer additional evidence that may help guide clinicians in their treatment of patients with IBD (and other IMIDs) and provide recommendations on potential next steps in therapeutic research in this area.

  View details for DOI 10.3390/nu12072156

  View details for PubMedID 32698454

• Dysbiosis-Induced Secondary Bile Acid Deficiency Promotes Intestinal Inflammation. Cell host & microbe Sinha, S. R., Haileselassie, Y., Nguyen, L. P., Tropini, C., Wang, M., Becker, L. S., Sim, D., Jarr, K., Spear, E. T., Singh, G., Namkoong, H., Bittinger, K., Fischbach, M. A., Sonnenburg, J. L., Habtezion, A. 2020

  Abstract

  Secondary bile acids (SBAs) are derived from primary bile acids (PBAs) in a process reliant on biosynthetic capabilities possessed by few microbes. To evaluate the role of BAs in intestinal inflammation, we performed metabolomic, microbiome, metagenomic, and transcriptomic profiling of stool from ileal pouches (surgically created resevoirs) in colectomy-treated patients with ulcerative colitis (UC) versus controls (familial adenomatous polyposis [FAP]). We show that relative to FAP, UC pouches have reduced levels of lithocholic acid and deoxycholic acid (normally the most abundant gut SBAs), genes required to convert PBAs to SBAs, and Ruminococcaceae (one of few taxa known to include SBA-producing bacteria). In three murine colitis models, SBA supplementation reduces intestinal inflammation. This anti-inflammatory effect is in part dependent on the TGR5 bile acid receptor. These data suggest that dysbiosis induces SBA deficiency in inflammatory-prone UC patients, which promotes a pro-inflammatory state within the intestine that may be treated by SBA restoration.

  View details for DOI 10.1016/j.chom.2020.01.021

  View details for PubMedID 32101703

• Mass cytometry reveals systemic and local immune signatures that distinguish inflammatory bowel diseases. Nature communications Rubin, S. J., Bai, L., Haileselassie, Y., Garay, G., Yun, C., Becker, L., Streett, S. E., Sinha, S. R., Habtezion, A. 2019; 10 (1): 2686

  Abstract

  Inflammatory bowel disease (IBD) includes Crohn's disease and ulcerative colitis. Each disease is characterized by a diverse set of potential manifestations, which determine patients' disease phenotype. Current understanding of phenotype determinants is limited, despite increasing prevalence and healthcare costs. Diagnosis and monitoring of disease requires invasive procedures, such as endoscopy and tissue biopsy. Here we report signatures of heterogeneity between disease diagnoses and phenotypes. Using mass cytometry, we analyze leukocyte subsets, characterize their function(s), and examine gut-homing molecule expression in blood and intestinal tissue from healthy and/or IBD subjects. Some signatures persist in IBD despite remission, and many signatures are highly represented by leukocytes that express gut trafficking molecules. Moreover, distinct systemic and local immune signatures suggest patterns of cell localization in disease. Our findings highlight the importance of gut tropic leukocytes in circulation and reveal that blood-based immune signatures differentiate clinically relevant subsets of IBD.

  View details for DOI 10.1038/s41467-019-10387-7

  View details for PubMedID 31217423

• The high resource impact of reformatting requirements for scientific papers. PloS one Jiang, Y. n., Lerrigo, R. n., Ullah, A. n., Alagappan, M. n., Asch, S. M., Goodman, S. N., Sinha, S. R. 2019; 14 (10): e0223976

  Abstract

  Most research manuscripts are not accepted for publication on first submission. A major part of the resubmission process is reformatting to another journal's specific requirements, a process separate from revising the scientific content. There has been little research to understand the magnitude of the burden imposed by the current resubmission process.We analyzed original research article submission requirements from twelve randomly selected journals in each of eight scientific and clinical focus areas from the InCites Journal Citation Reports database. From the 96 journals selected, we randomly identified three recently published manuscripts and sent surveys to those first and/or corresponding authors (288 total) to solicit information on time spent reformatting resubmissions and opinions on the process.There was significant variation in manuscript submission requirements for journals within the same scientific focus and only 4% of journals offered a fully format-free initial submission. Of 203 authors responding (71.5% response rate), only 11.8% expressed satisfaction with the resubmission process and 91% desired reforming the current system. Time spent on reformatting delays most publications by at least two weeks and by over three months in about 20% of manuscripts. The effort to comply with submission requirements has significant global economic burden, estimated at over $1.1 billion dollars annually when accounting for a research team's time.We demonstrate that there is significant resource utilization associated with resubmitting manuscripts, heretofore not properly quantified. The vast majority of authors are not satisfied with the current process. Addressing these issues by reconciling reformatting requirements among journals or adopting a universal format-free initial submission policy would help resolve a major subject for the scientific research community and provide more efficient dissemination of findings.

  View details for DOI 10.1371/journal.pone.0223976

  View details for PubMedID 31665156

• Age-Related Changes inGut Microbiota AlterPhenotype of Muscularis Macrophages and Disrupt Gastrointestinal Motility. Cellular and molecular gastroenterology and hepatology Becker, L., Spear, E. T., Sinha, S. R., Haileselassie, Y., Habtezion, A. 2019; 7 (1): 243

  View details for PubMedID 30585161

• Using Social Media to Characterize Public Sentiment Toward Medical Interventions Commonly Used for Cancer Screening: An Observational Study. Journal of medical Internet research Metwally, O., Blumberg, S., Ladabaum, U., Sinha, S. R. 2017; 19 (6)

  Abstract

  Although cancer screening reduces morbidity and mortality, millions of people worldwide remain unscreened. Social media provide a unique platform to understand public sentiment toward tools that are commonly used for cancer screening.The objective of our study was to examine public sentiment toward colonoscopy, mammography, and Pap smear and how this sentiment spreads by analyzing discourse on Twitter.In this observational study, we classified 32,847 tweets (online postings on Twitter) related to colonoscopy, mammography, or Pap smears using a naive Bayes algorithm as containing positive, negative, or neutral sentiment. Additionally, we characterized the spread of sentiment on Twitter using an established model to study contagion.Colonoscopy-related tweets were more likely to express negative than positive sentiment (negative to positive ratio 1.65, 95% CI 1.51-1.80, P<.001), in contrast to the more positive sentiment expressed regarding mammography (negative to positive ratio 0.43, 95% CI 0.39-0.47, P<.001). The proportions of negative versus positive tweets about Pap smear were not significantly different (negative to positive ratio 0.95, 95% CI 0.87-1.04, P=.18). Positive and negative tweets tended to share lexical features across screening modalities. Positive tweets expressed resonance with the benefits of early detection. Fear and pain were the principal lexical features seen in negative tweets. Negative sentiment for colonoscopy and mammography spread more than positive sentiment; no correlation with sentiment and spread was seen for Pap smear.Analysis of social media data provides a unique, quantitative framework to better understand the public's perception of medical interventions that are commonly used for cancer screening. Given the growing use of social media, public health interventions to improve cancer screening should use the health perceptions of the population as expressed in social network postings about tests that are frequently used for cancer screening, as well as other people they may influence with such postings.

  View details for DOI 10.2196/jmir.7485

  View details for PubMedID 28592395

• Using Social Media to Characterize Public Sentiment Toward Medical Interventions Commonly Used for Cancer Screening: An Observational Study. Journal of medical Internet research Metwally, O., Blumberg, S., Ladabaum, U., Sinha, S. R. 2017; 19 (6)

  Abstract

  Although cancer screening reduces morbidity and mortality, millions of people worldwide remain unscreened. Social media provide a unique platform to understand public sentiment toward tools that are commonly used for cancer screening.The objective of our study was to examine public sentiment toward colonoscopy, mammography, and Pap smear and how this sentiment spreads by analyzing discourse on Twitter.In this observational study, we classified 32,847 tweets (online postings on Twitter) related to colonoscopy, mammography, or Pap smears using a naive Bayes algorithm as containing positive, negative, or neutral sentiment. Additionally, we characterized the spread of sentiment on Twitter using an established model to study contagion.Colonoscopy-related tweets were more likely to express negative than positive sentiment (negative to positive ratio 1.65, 95% CI 1.51-1.80, P<.001), in contrast to the more positive sentiment expressed regarding mammography (negative to positive ratio 0.43, 95% CI 0.39-0.47, P<.001). The proportions of negative versus positive tweets about Pap smear were not significantly different (negative to positive ratio 0.95, 95% CI 0.87-1.04, P=.18). Positive and negative tweets tended to share lexical features across screening modalities. Positive tweets expressed resonance with the benefits of early detection. Fear and pain were the principal lexical features seen in negative tweets. Negative sentiment for colonoscopy and mammography spread more than positive sentiment; no correlation with sentiment and spread was seen for Pap smear.Analysis of social media data provides a unique, quantitative framework to better understand the public's perception of medical interventions that are commonly used for cancer screening. Given the growing use of social media, public health interventions to improve cancer screening should use the health perceptions of the population as expressed in social network postings about tests that are frequently used for cancer screening, as well as other people they may influence with such postings.

  View details for DOI 10.2196/jmir.7485

  View details for PubMedID 28592395

• Use of Tumor Necrosis Factor Alpha Inhibitors for Inflammatory Bowel Disease Patients with Concurrent Heart Failure. Digestive diseases and sciences Jiang, Y., Lin, O., Sinha, S. R. 2017; 62 (6): 1597-1606

  Abstract

  Prescribing information for tumor necrosis factor alpha (TNFα) inhibitors, a mainstay of treatment for moderate to severe inflammatory bowel disease (IBD), instructs cautious use in those with heart failure (HF). However, the limited data behind these warnings are inconclusive and should be weighed against mounting evidence demonstrating worse cardiac outcomes in active IBD.To assess whether TNFα inhibitor use is reduced in patients with IBD and HF by analyzing physician practice and prescription patterns.Using a Stanford University database, we queried TNFα inhibitor prescriptions in 8905 patients with an ICD-9 diagnosis of Crohn's disease or ulcerative colitis. Detailed chart review analysis was done for patients with a concurrent diagnosis of HF who were prescribed anti-TNFα agents. In addition, we collected survey data from 25 gastroenterologists on their usage of these drugs for patients with IBD and HF.TNFα inhibitors were prescribed to 10/455 (2.2%) IBD patients with HF compared to 1265/8450 (15.0%) in IBD patients without HF (p < 0.0001). Of those ten with HF prescribed TNFα inhibitors, only one had it discontinued because of HF exacerbation while on drug. Survey data indicated few (5/25) providers do not actively avoid TNFα inhibitors for those with HF.IBD patients with HF are prescribed significantly less TNFα inhibitors than those without HF. The majority of providers are either uncertain about or actively avoid use of anti-TNFα medications for those with HF. The risks and benefits of anti-TNFα use in HF patients must be investigated further.

  View details for DOI 10.1007/s10620-017-4574-2

  View details for PubMedID 28417241

• Use of Tumor Necrosis Factor Alpha Inhibitors for Inflammatory Bowel Disease Patients with Concurrent Heart Failure. Digestive diseases and sciences Jiang, Y., Lin, O., Sinha, S. R. 2017; 62 (6): 1597-1606

  Abstract

  Prescribing information for tumor necrosis factor alpha (TNFα) inhibitors, a mainstay of treatment for moderate to severe inflammatory bowel disease (IBD), instructs cautious use in those with heart failure (HF). However, the limited data behind these warnings are inconclusive and should be weighed against mounting evidence demonstrating worse cardiac outcomes in active IBD.To assess whether TNFα inhibitor use is reduced in patients with IBD and HF by analyzing physician practice and prescription patterns.Using a Stanford University database, we queried TNFα inhibitor prescriptions in 8905 patients with an ICD-9 diagnosis of Crohn's disease or ulcerative colitis. Detailed chart review analysis was done for patients with a concurrent diagnosis of HF who were prescribed anti-TNFα agents. In addition, we collected survey data from 25 gastroenterologists on their usage of these drugs for patients with IBD and HF.TNFα inhibitors were prescribed to 10/455 (2.2%) IBD patients with HF compared to 1265/8450 (15.0%) in IBD patients without HF (p < 0.0001). Of those ten with HF prescribed TNFα inhibitors, only one had it discontinued because of HF exacerbation while on drug. Survey data indicated few (5/25) providers do not actively avoid TNFα inhibitors for those with HF.IBD patients with HF are prescribed significantly less TNFα inhibitors than those without HF. The majority of providers are either uncertain about or actively avoid use of anti-TNFα medications for those with HF. The risks and benefits of anti-TNFα use in HF patients must be investigated further.

  View details for DOI 10.1007/s10620-017-4574-2

  View details for PubMedID 28417241

• A Thermo-Sensitive Delivery Platform for Topical Administration of Inflammatory Bowel Disease Therapies. Gastroenterology Sinha, S. R., Nguyen, L. P., Inayathullah, M., Malkovskiy, A., Habte, F., Rajadas, J., Habtezion, A. 2015; 149 (1): 52-55 e2

  Abstract

  Systemic therapies for inflammatory bowel disease are associated with increased risk of infections and malignancies. Topical therapies reduce systemic exposure, but can be difficult to retain or have limited proximal distribution. To mitigate these issues, we developed a thermo-sensitive platform, using a polymer-based system that is liquid at room temperature but turns into a viscous gel upon reaching body temperature. Following rectal administration to mice with dextran sulphate sodium-induced colitis, the platform carrying budesonide or mesalamine becomes more viscoelastic near body temperature. Mice given the drug-containing platform gained more weight and had reduced histologic and biologic features of colitis than mice given the platform alone or liquid drugs via enema. Image analysis showed that enemas delivered with and without the platform reached similar distances in the colons of mice, but greater colonic retention was achieved by using the platform.

  View details for DOI 10.1053/j.gastro.2015.04.002

  View details for PubMedID 25863215

• Effect of Intratonsillar Injection of Steroids on the Palatine Tonsils of Rabbits LARYNGOSCOPE Cho, D., Sinha, S. R., Gardner, J. M., Schaller, M. P., Pamnani, R. D., Felt, S. A., Barral, J. K., Messner, A. H. 2014; 124 (12): 2811-2817

  Abstract

  Nasal steroids may significantly improve nasal obstructive symptoms with a reduction of adenoid size in children, but they do not consistently yield the same concurrent effect on enlarged palatine tonsils. Failure of nasal steroids to decrease the size of palatine tonsils is believed to be attributable to location and washout by saliva. The purpose of this study was to determine if direct application of steroid via intratonsillar injection would reduce the size of palatine tonsils in the rabbit model.Prospective animal study.Eight rabbits (16 tonsils) were administered intratonsillar injections of fluticasone (n = 8, 1 mg/ml) or saline (n = 8, 0.1 ml) on days 0, 3, 7, 10, 14, and 17. Two rabbits (4 tonsils) received a single steroid injection to compare single versus multiple steroid injections. The rabbit's tonsil size was measured before each injection. After the fifty injections, the tonsils were harvested for histologic analysis.A total of 16 tonsils were analyzed. After five steroid injections, the reduction (-7.7 mm(2)  ± 4.27) in size was statistically significant when compared to reduction (6.12 mm(2)  ± 6.57) in the saline injected group (P = 0.001). Repeated steroid injection was more potent than a single injection (-3.00 mm(2)  ± 3.08) in reducing the size (P = 0.006). In histologic analysis, tonsils after repeated steroid injections were significantly smaller than saline-injected tonsils (P = 0.014), without obvious lymphoid follicles.Repeated focal tonsillar injections of corticosteroids significantly reduced the size of palatine tonsils as compared to saline-injected controls. A single injection of corticosteroids appears to be effective, but not as effective, as multiple injections.N/A.

  View details for DOI 10.1002/lary.24396

  View details for Web of Science ID 000345344200034

• Effect of intratonsillar injection of steroids on the palatine tonsils of rabbits. Laryngoscope Cho, D., Sinha, S. R., Gardner, J. M., Schaller, M. P., Pamnani, R. D., Felt, S. A., Barral, J. K., Messner, A. H. 2014; 124 (12): 2811-2817

  Abstract

  Nasal steroids may significantly improve nasal obstructive symptoms with a reduction of adenoid size in children, but they do not consistently yield the same concurrent effect on enlarged palatine tonsils. Failure of nasal steroids to decrease the size of palatine tonsils is believed to be attributable to location and washout by saliva. The purpose of this study was to determine if direct application of steroid via intratonsillar injection would reduce the size of palatine tonsils in the rabbit model.Prospective animal study.Eight rabbits (16 tonsils) were administered intratonsillar injections of fluticasone (n = 8, 1 mg/ml) or saline (n = 8, 0.1 ml) on days 0, 3, 7, 10, 14, and 17. Two rabbits (4 tonsils) received a single steroid injection to compare single versus multiple steroid injections. The rabbit's tonsil size was measured before each injection. After the fifty injections, the tonsils were harvested for histologic analysis.A total of 16 tonsils were analyzed. After five steroid injections, the reduction (-7.7 mm(2)  ± 4.27) in size was statistically significant when compared to reduction (6.12 mm(2)  ± 6.57) in the saline injected group (P = 0.001). Repeated steroid injection was more potent than a single injection (-3.00 mm(2)  ± 3.08) in reducing the size (P = 0.006). In histologic analysis, tonsils after repeated steroid injections were significantly smaller than saline-injected tonsils (P = 0.014), without obvious lymphoid follicles.Repeated focal tonsillar injections of corticosteroids significantly reduced the size of palatine tonsils as compared to saline-injected controls. A single injection of corticosteroids appears to be effective, but not as effective, as multiple injections.N/A.

  View details for DOI 10.1002/lary.24396

  View details for PubMedID 24114886

• Strategies for last mile implementation of global health technologies. The Lancet. Global health Chao, T. E., Lo, N. C., Mody, G. N., Sinha, S. R. 2014; 2 (9): e497-8

  View details for DOI 10.1016/S2214-109X(14)70253-0

  View details for PubMedID 25304406

• Ethnic Disparities in the Association of Body Mass Index with the Risk of Hypertension and Diabetes JOURNAL OF COMMUNITY HEALTH Wong, R. J., Chou, C., Sinha, S. R., Kamal, A., Ahmed, A. 2014; 39 (3): 437-445

  Abstract

  Despite having lower body mass index (BMI) compared to other ethnic groups, Asians continue to develop significant metabolic diseases such as hypertension and diabetes. To evaluate the disparate association of BMI and risk of hypertension and diabetes in Asians. We retrospectively studied 150,753 adults from the 1985-2011 California Behavioral Risk Factor Survey. Trends in prevalence of obesity, hypertension, and diabetes were stratified by ethnicity. Multivariate logistic regression models evaluated the incremental effect of one unit BMI increase on risk of hypertension and diabetes and the disparate risks of hypertension and diabetes at different BMI thresholds. Asians had the lowest BMI among all groups. However, the impact of increasing BMI on risk of hypertension and diabetes was significantly greater in Asians. For each one unit increase in BMI, Asians were significantly more likely to have hypertension (OR 1.15; 95 % CI 1.13-1.18) compared to non-Hispanic whites, blacks, and Hispanics. Similar trends were seen for diabetes (Asians: OR 1.15; 95 % CI 1.13-1.18). The risk of hypertension in Asians with BMI ≥ 22 was similar to non-Hispanic whites with BMI ≥ 27 and blacks with BMI ≥ 28. The risk of diabetes in Asians with BMI ≥ 28 was similar to non-Hispanic whites with BMI ≥ 30. Despite lower overall BMI compared to other groups, weight gain in Asians is associated with significantly higher risks of hypertension and diabetes. Compared to other ethnic groups, similar risks of hypertension and diabetes are seen in Asians at much lower BMI.

  View details for DOI 10.1007/s10900-013-9792-8

  View details for Web of Science ID 000335392600005

  View details for PubMedID 24276618

• Severe Iron Deficiency: Rare Etiology, Easy Treatment DIGESTIVE DISEASES AND SCIENCES Sinha, S. R., Triadafilopoulos, G., Shah, N. 2014; 59 (3): 538-542

  View details for DOI 10.1007/s10620-013-2880-x

  View details for Web of Science ID 000331957400007

  View details for PubMedID 24077943

• Effect of intra-tonsillar injection of Steroids on the palatine tonsils of rabbits. Laryngoscope Cho, D., Sinha, S. R., et al 2013
• Severe Iron Deficiency: Rare Etiology, Easy Treatment. Digestive Diseases and Sciences Sinha, S. R., Triadafilopoulos, G., Shah, N. 2013
• Enhanced imaging technologies in detecting dysplasia in IBD: narrowing or widening our options? Gastroenterology Sinha, S. R., Shah, S. B. 2012; 143 (4): 1108-1110

  View details for DOI 10.1053/j.gastro.2012.08.019

  View details for PubMedID 22917863

• Health Technologies and Innovation in the Global Health Arena NEW ENGLAND JOURNAL OF MEDICINE Sinha, S. R., Barry, M. 2011; 365 (9): 779-782

  View details for Web of Science ID 000294405200002

  View details for PubMedID 21879894

• Protecting health: thinking small BULLETIN OF THE WORLD HEALTH ORGANIZATION Sinha, S. R., Batniji, R. 2010; 88 (9): 713-715

  View details for DOI 10.2471/BLT.09.071530

  View details for Web of Science ID 000282673900016

  View details for PubMedID 20865078

  View details for PubMedCentralID PMC2930363

• Shaping National Health Financing Systems: How Can Micro-banking Contribute? World Health Organization Technical Brief Durairaj V, Sinha SR, et al. 2009