ExpLOring the role of the intestinal MiCrobiome in InflammATory bowel disease-AssocIated SpONdylarthritis (LOCATION-IBD).

Background: Inflammatory Bowel Disease (IBD)-associated arthritis is a frequent and potentially debilitating complication of IBD, that can affect those with or without active intestinal disease, and is often difficult to treat. The microbiome is known to play a role in IBD development and has been shown to be associated with inflammatory arthritis without concomitant IBD, but its role in IBD-associated arthritis is still unexplored. Further, disease localization is associated with development of IBD-associated arthritis, and stool compositional profiles are predictive of disease localization, yet mucosal location-specific microbiomes have not been well characterized. To address this gap in understanding, we designed a study (LOCATION-IBD) to characterize the mucosa-associated intestinal microbiome and metabolome in IBD-associated arthritis. Methods: Adults with an established diagnosis of IBD undergoing clinical colonoscopy between May of 2021 and February of 2023 were invited to participate in this study; those interested in participation who met inclusion criteria were enrolled. Prior to enrollment, participants were stratified into those with or without IBD-associated arthritis. All participants were interviewed and had clinical and demographic data collected, and 97.8% completed clinical colonoscopy with biopsy collection. Results and conclusion: A total of 182 participants, 53 with confirmed IBD-associated arthritis, were enrolled in this study, resulting in 1151 biopsies obtained for microbiome and metabolome analysis (median 6, mean 6.3 per participant). Clinical and demographic data obtained from the study population will be analyzed with microbiome and metabolome data obtained from biopsies, with the goal of better understanding the mechanisms underpinning the host-microbiome relationship associated the development of IBD-associated arthritis.

Gastroenterology Fellowship and Postdoctoral Training in Omics and Statistics-Part I: Why Is It Needed?

A multitude of federally and industry-funded efforts are underway to generate and collect human, animal, microbial, and other sources of data on an unprecedented scale; the results are commonly referred to as "big data." Often vaguely defined, big data refers to large and complex datasets consisting of myriad datatypes that can be integrated to address complex questions. Big data offers a wealth of information that can be accessed only by those who pose the right questions and have sufficient technical knowhow and analytical skills. The intersection comprised of the gut-brain axis, the intestinal microbiome and multi-ome, and several other interconnected organ systems poses particular challenges and opportunities for those engaged in gastrointestinal and liver research. Unfortunately, there is currently a shortage of clinicians, scientists, and physician-scientists with the training needed to use and analyze big data at the scale necessary for widespread implementation of precision medicine. Here, we review the importance of training in the use of big data, the perils of insufficient training, and potential solutions that exist or can be developed to address the dearth of individuals in GI and hepatology research with the necessary level of big data expertise.

Gastroenterology Fellowship and Postdoctoral Training in Omics and Statistics-Part II: How Can It Be Achieved?

Data are being generated, collected, and aggregated in massive quantities at exponentially increasing rates. This "big data," discussed in depth in the first section of this two-part series, is increasingly important to understand the nuances of the gastrointestinal tract and its complex interactions and networks involving a host of other organ systems and microbes. Creating and using these datasets correctly requires comprehensive training; however, current instruction in the integration, analysis, and interpretation of big data appears to lag far behind data acquisition. While opportunities exist for those interested in acquiring the requisite training, these appear to be underutilized, in part due to widespread ignorance of their existence. Here, to address these gaps in knowledge, we highlight existing big data learning opportunities and propose innovative approaches to attain such training. We offer suggestions at both the undergraduate and graduate medical education levels for prospective clinical and basic investigators. Lastly, we categorize training opportunities that can be selected to fit specific needs and timeframes.

Revisiting the cortisol reference ranges in humans: the role of demographics.

The current study explores the effect of demographics on serum cortisol expression in a study group of 52 individuals to improve the current serum reference ranges to produce personalized expression profiles consequently increasing clinical confidence in the diagnosis. The serum cortisol concentration was inspected against demographical data like age, sex, and body mass index and showed an association with age and sex. The serum cortisol values also indicated a positive association with chronic illnesses however this finding requires a more focused study for establishment. Additionally, saliva samples are also collected from the same study group at the same time through drool and an absorbent sponge and correlated with serum values to draw an alternative route of serological testing. Salivary cortisol from drool showed a linear correlation with Pearson's correlation coefficients of 0.71 and 0.72 with serum cortisol and with saliva samples collected using a porous sponge respectively. Overall, the study shows the role of demographics in shaping the reference ranges for cortisol, suggesting a path for developing personalized diagnostics. The study also highlights the efficacy of saliva as an alternative to serum cortisol to facilitate cortisol measurement for efficient stress management.

Big Data in Gastroenterology Research.

Studying individual data types in isolation provides only limited and incomplete answers to complex biological questions and particularly falls short in revealing sufficient mechanistic and kinetic details. In contrast, multi-omics approaches to studying health and disease permit the generation and integration of multiple data types on a much larger scale, offering a comprehensive picture of biological and disease processes. Gastroenterology and hepatobiliary research are particularly well-suited to such analyses, given the unique position of the luminal gastrointestinal (GI) tract at the nexus between the gut (mucosa and luminal contents), brain, immune and endocrine systems, and GI microbiome. The generation of 'big data' from multi-omic, multi-site studies can enhance investigations into the connections between these organ systems and organisms and more broadly and accurately appraise the effects of dietary, pharmacological, and other therapeutic interventions. In this review, we describe a variety of useful omics approaches and how they can be integrated to provide a holistic depiction of the human and microbial genetic and proteomic changes underlying physiological and pathophysiological phenomena. We highlight the potential pitfalls and alternatives to help avoid the common errors in study design, execution, and analysis. We focus on the application, integration, and analysis of big data in gastroenterology and hepatobiliary research.

Matrix metalloproteinases as biomarkers and therapeutic targets in colitis-associated cancer.

Colorectal cancer (CRC) remains a major cause of morbidity and mortality. Therapeutic approaches for advanced CRC are limited and rarely provide long-term benefit. Enzymes comprising the 24-member matrix metalloproteinase (MMP) family of zinc- and calcium-dependent endopeptidases are key players in extracellular matrix degradation, a requirement for colon tumor expansion, invasion, and metastasis; hence, MMPs are an important research focus. Compared to sporadic CRC, less is known regarding the molecular mechanisms and the role of MMPs in the development and progression of colitis-associated cancer (CAC) - CRC on a background of chronic inflammatory bowel disease (IBD) - primarily ulcerative colitis and Crohn's disease. Hence, the potential of MMPs as biomarkers and therapeutic targets for CAC is uncertain. Our goal was to review data regarding the role of MMPs in the development and progression of CAC. We sought to identify promising prognostic and therapeutic opportunities and novel lines of investigation. A key observation is that since MMPs may be more active in early phases of CAC, using MMPs as biomarkers of advancing neoplasia and as potential therapeutic targets for adjuvant therapy in those with advanced stage primary CAC rather than overt metastases may yield more favorable outcomes.

Aging resistance of infiltrated monolithic zirconia compared to noninfiltrated monolithic zirconia: A systematic review of in vitro studies.

Aim: The aim of the study is to systematically assess the impact of low-temperature degradation (LTD) simulation in an autoclave on mechanical and microstructural properties of infiltrated monolithic zirconia compared to the noninfiltrated zirconia. Settings and Design: Systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 guidelines. Materials and Methods: An electronic search was done within these databases: PubMed, Scopus, and Web of Science, Science Direct, Embase, Wiley, Google Scholar for articles published between 2000 and March 2021. Search results that met eligibility criteria were categorized into two groups based on properties assessed of infiltrated monolithic zirconia exposed to LTD (also called aging simulation) - (a) mechanical (flexural strength and fracture toughness) and (b) microstructural properties (phase transformation rate and m content). Statistical Analysis Used: Qualitative analysis. Results: The search identified 272 preliminary results. After discarding duplicates, and screening of titles, abstracts, and full texts, 10 articles finally met inclusion criteria. Data were collected on author's details and their countries, journal and year of publication, type and percentage of infiltration, aging protocol (duration and temperature), mechanical, and microstructural properties. All the included studies invariably revealed better aging resistance without a change in mechanical properties for infiltrated monolithic zirconia as compared to noninfiltrated species. Conclusion: Infiltration within monolithic zirconia can reduce degradation and simultaneously maintain their mechanical properties by preventing water entry into grain contours. The final m content was less for infiltrated Zirconium, indicating a lesser phase transformation and better aging resistance. Other Information: Systematic review protocol registered at PROSPERO CRD42021248153.

A Retrospective Study of Climate Change Affecting Dengue: Evidences, Challenges and Future Directions.

Climate change is unexpected weather patterns that can create an alarming situation. Due to climate change, various sectors are affected, and one of the sectors is healthcare. As a result of climate change, the geographic range of several vector-borne human infectious diseases will expand. Currently, dengue is taking its toll, and climate change is one of the key reasons contributing to the intensification of dengue disease transmission. The most important climatic factors linked to dengue transmission are temperature, rainfall, and relative humidity. The present study carries out a systematic literature review on the surveillance system to predict dengue outbreaks based on Machine Learning modeling techniques. The systematic literature review discusses the methodology and objectives, the number of studies carried out in different regions and periods, the association between climatic factors and the increase in positive dengue cases. This study also includes a detailed investigation of meteorological data, the dengue positive patient data, and the pre-processing techniques used for data cleaning. Furthermore, correlation techniques in several studies to determine the relationship between dengue incidence and meteorological parameters and machine learning models for predictive analysis are discussed. In the future direction for creating a dengue surveillance system, several research challenges and limitations of current work are discussed.

The Sincerest Form of Flattery? Biosimilars in Inflammatory Bowel Disease.

Biosimilar medications have the potential to significantly reduce the cost of treatment in patients with inflammatory bowel disease. Observational studies have shown similar efficacy and safety of biosimilars to biologic reference products. Shared decision-making is crucial to the successful implementation of these agents.

Forecasting Dengue Hotspots Associated With Variation in Meteorological Parameters Using Regression and Time Series Models.

For forecasting the spread of dengue, monitoring climate change and its effects specific to the disease is necessary. Dengue is one of the most rapidly spreading vector-borne infectious diseases. This paper proposes a forecasting model for predicting dengue incidences considering climatic variability across nine cities of Maharashtra state of India over 10 years. The work involves the collection of five climatic factors such as mean minimum temperature, mean maximum temperature, relative humidity, rainfall, and mean wind speed for 10 years. Monthly incidences of dengue for the same locations are also collected. Different regression models such as random forest regression, decision trees regression, support vector regress, multiple linear regression, elastic net regression, and polynomial regression are used. Time-series forecasting models such as holt's forecasting, autoregressive, Moving average, ARIMA, SARIMA, and Facebook prophet are implemented and compared to forecast the dengue outbreak accurately. The research shows that humidity and mean maximum temperature are the major climate factors and exhibit strong positive and negative correlation, respectively, with dengue incidences for all locations of Maharashtra state. Mean minimum temperature and rainfall are moderately positively correlated with dengue incidences. Mean wind speed is a less significant factor and is weakly negatively correlated with dengue incidences. Root mean square error (RMSE), mean absolute error (MAE), and R square error (R2) evaluation metrics are used to compare the performance of the prediction model. Random Forest Regression is the best-fit regression model for five out of nine cities, while Support Vector Regression is for two cities. Facebook Prophet Model is the best fit time series forecasting model for six out of nine cities. Based on the prediction, Mumbai, Thane, Nashik, and Pune are the high-risk regions, especially in August, September, and October. The findings exhibit an effective early warning system that would predict the outbreak of other infectious diseases. It will help the relevant authorities to take accurate preventive measures.

Comparative Evaluation of Marginal Integrity of Three Esthetic Restorative Materials - An In-vitro Study.

CONTEXT: Microleakage is the major cause for the failure of dental restorations, especially in Class V cavities, as margins of such restorations are generally located in dentin or cementum. Microleakage evaluation is necessary as a means of evaluation of the marginal integrity of restorative materials. This would assist in developing techniques and materials that would reduce damage caused by the failure of the restorative marginal seal. AIM: The aim of this study is to analyze and compare the marginal integrity among three esthetic restorative materials, namely GC Fuji II LC, GC G-Aenial anterior composite resin, and GC Equia forte fil. SETTING AND DESIGN: Sixty orthodontically extracted caries-free premolar teeth with Class V restorations were divided into three groups. Microleakage was measured using an ordinal scale of 0-4, as given by Khera and Chan, in increasing order of dye penetration, which was observed under a microscope. MATERIALS AND METHODS: Study was conducted in sound human extracted premolars in which Standardized Class V cavities were prepared. Teeth were randomly and equally assigned to three groups (GC Fuji II LC, GC G-Aenial anterior composite resin, and GC Equia forte fil). Teeth were sectioned longitudinally into two halves using diamond discs and the sectioned halves of the teeth were evaluated for dye penetration under stereomicroscope. STATISTICAL ANALYSIS USED: Intergroup comparison of mean dye penetration scores were compared using the Kruskal-Wallis test along with post hoc pairwise comparison by Mann Whitney U test. The level of statistical significance was set at 0.05. RESULTS AND CONCLUSION: All the three groups (GC Fuji II LC, GC G-Aenial anterior composite resin, and GC Equia forte fil) tested showed microleakage at the tooth restoration interface. It was evident that microleakage was found to be highest with the Fuji II LC, both at occlusal and cervical levels. GC Equia forte exhibited the best performance in limiting microleakage around the restoration margins.

Age-dependency of terminal ileum tissue resident memory T cell responsiveness profiles to S. Typhi following oral Ty21a immunization in humans.

BACKGROUND: The impact of aging on the immune system is unequivocal and results in an altered immune status termed immunosenescence. In humans, the mechanisms of immunosenescence have been examined almost exclusively in blood. However, most immune cells are present in tissue compartments and exhibit differential cell (e.g., memory T cells -TM) subset distributions. Thus, it is crucial to understand immunosenescence in tissues, especially those that are exposed to pathogens (e.g., intestine). Using a human model of oral live attenuated typhoid vaccine, Ty21a, we investigated the effect of aging on terminal ileum (TI) tissue resident memory T (TRM) cells. TRM provide immediate adaptive effector immune responsiveness at the infection site. However, it is unknown whether aging impacts TRM S. Typhi-responsive cells at the site of infection (e.g., TI). Here, we determined the effect of aging on the induction of TI S. Typhi-responsive TRM subsets elicited by Ty21a immunization. RESULTS: We observed that aging impacts the frequencies of TI-lamina propria mononuclear cells (LPMC) TM and TRM in both Ty21a-vaccinated and control groups. In unvaccinated volunteers, the frequencies of LPMC CD103- CD4+ TRM displayed a positive correlation with age whilst the CD4/CD8 ratio in LPMC displayed a negative correlation with age. We observed that elderly volunteers have weaker S. Typhi-specific mucosal immune responses following Ty21a immunization compared to adults. For example, CD103+ CD4+ TRM showed reduced IL-17A production, while CD103- CD4+ TRM exhibited lower levels of IL-17A and IL-2 in the elderly than in adults following Ty21a immunization. Similar results were observed in LPMC CD8+ TRM and CD103- CD8+ T cell subsets. A comparison of multifunctional (MF) profiles of both CD4+ and CD8+ TRM subsets between elderly and adults also showed significant differences in the quality and quantity of elicited single (S) and MF responses. CONCLUSIONS: Aging influences tissue resident TM S. Typhi-specific responses in the terminal ileum following oral Ty21a-immunization. This study is the first to provide insights in the generation of local vaccine-specific responses in the elderly population and highlights the importance of evaluating tissue immune responses in the context of infection and aging. TRIAL REGISTRATION: This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT03970304 , Registered 29 May 2019 - Retrospectively registered).

TELEmedicine for Patients With Inflammatory Bowel Disease (TELE-IBD) Does Not Improve Depressive Symptoms or General Quality of Life Compared With Standard Care at Tertiary Referral Centers.

BACKGROUND: Depression is common in patients with inflammatory bowel disease (IBD) and contributes to poor quality of life (QoL). The use of information technology for the remote management of patients with IBD is growing, but little is known about its impact on depressive symptoms (DS) and QoL. We aimed to evaluate the impact of telemedicine on DS and generic QoL in IBD patients. METHODS: We analyzed data from the Telemedicine for Patients with IBD (TELE-IBD) study. During this 12-month clinical trial, patients were randomized to receive text message-based telemedicine weekly (TELE-IBD W), every other week (TELE-IBD EOW), or to standard care. Depressive symptoms and QoL were assessed over time with the Mental Health Inventory 5 (MHI-5) and the Short Form 12 (SF-12), respectively. We compared the change in MHI-5 and SF-12 (with separate physical (PCS) and mental component summary (MCS) scores) between the study arms. RESULTS: A total of 217 participants were included in this analysis. After 1 year, there was no significant difference in the change in MHI-5 (TELE-IBD W +3.0 vs TELE-IBD EOW +0.7 vs standard care +3.4; P = 0.70), MCS (TELE-IBD W +1.4 vs TELE-IBD EOW +1.0 vs standard care +2.5; P = 0.89), and PCS scores (TELE-IBD W +0.4 vs TELE-IBD EOW +0.6 vs standard care +3.7; P = 0.06) between the groups. CONCLUSIONS: Text message-based telemedicine does not improve DS or QoL when compared with standard care in IBD patients treated at tertiary referral centers. Further studies are needed to determine whether telemedicine improves DS or QoL in settings with few resources.

Analyse the effect of different investment techniques and pattern materials on surface roughness of raw Ni-Cr castings - An In Vitro study.

AIMS: This study aimed to analyze the effect of different investment techniques and pattern materials on the surface roughness of raw castings from nickel-chromium alloy. SETTINGS AND DESIGN: This is an experimental in vitro study carried out in Bharati Vidyapeeth Dental College and Hospital, Sangli, Maharastra. MATERIALS AND METHODS: Sixty square-shaped wax patterns, measuring 10 mm × 10 mm × 2 mm, were divided into four groups. A phosphate-bonded investment material (Bellasun, Bego, Germany) was used to invest 15 samples of inlay wax and kept under normal atmospheric pressure and the remaining 15 wax patterns were invested under a pressure of 3 bars for 30 min, and then allowed to bench set for another 30 min. The same investing techniques were carried out for the remaining thirty samples made from pattern resin. STATISTICAL ANALYSIS USED: The surface roughness (µm) of the castings was measured by a profilometer. Student's "unpaired t-test" was used for the statistical analysis. RESULTS: Specimens that were invested at atmospheric pressure had significantly more surface roughness (µm) values than those invested under increased pressure (P < 0.01). CONCLUSIONS: Wax patterns exhibited the least surface roughness when invested under pressure and can be recommended as the material and technique of choice. In addition, resin patterns invested under increased pressure produced smoother casting surface than those invested at atmospheric pressure, and the difference is highly significant.

Effect of TELEmedicine for Inflammatory Bowel Disease on Patient Activation and Self-Efficacy.

INTRODUCTION: Limitations in inflammatory bowel disease (IBD) care necessitate greater patient activation and self-efficacy, measures associated with positive health outcomes. METHODS: We assessed change in patient activation and general self-efficacy from baseline to 12 months through our TELEmedicine for IBD trial, a multicenter, randomized controlled trial consisting of a web-based monitoring system that interacts with participants via text messaging. A total of 222 adults with IBD who had experienced an IBD flare within 2 years prior to the trial were randomized into either a control arm that received standard care (SC) or an intervention arm that completed self-testing through the TELE-IBD system every other week (EOW) or weekly (W). RESULTS: Changes in self-efficacy scores were not significantly different between control and experimental groups. Patient activation scores were significantly different between standard care and the TELE-IBD EOW group only (p = 0.03). CONCLUSIONS: Use of remote monitoring did not improve self-efficacy or patient activation compared to routine care.

Correction to: Effect of TELEmedicine for Inflammatory Bowel Disease on Patient Activation and Self-Efficacy.

This manuscript is a secondary analysis of a large multicenter randomized controlled trial. The primary study is Cross RK et al., A Randomized Controlled Trial of TELEmedicine for patients with Inflammatory Bowel Disease (TELE-IBD). Am J Gastroenterol, 2019 Mar.

Attenuated Oral Typhoid Vaccine Ty21a Elicits Lamina Propria and Intra-Epithelial Lymphocyte Tissue-Resident Effector Memory CD8 T Responses in the Human Terminal Ileum.

Tissue-resident memory T cells (TRM) are newly defined memory T cells (TM) distinct from circulating TM subsets which have the potential to mount rapid protective immune responses at the site of infection. However, very limited information is available regarding the role and contribution of TRM in vaccine-mediated immune responses in humans at the site of infection. Here, we studied the role and contribution of tissue resident memory T cells (TRM) located in the terminal ileum (TI) (favored site of infection for S. Typhi) following oral Ty21a immunization in humans. We examined TI-lamina propria mononuclear cells (LPMC) and intra-epithelial lymphocytes (IEL) CD8+ TRM subsets obtained from healthy volunteers undergoing medically-indicated colonoscopies who were either immunized with Ty21a or unvaccinated. No significant differences in the frequencies of LPMC CD8+ TRM and CD8+CD69+CD103- T cells subsets were observed following Ty21a-immunization. However, LPMC CD8+ TRM exhibited significantly higher levels of cytokines (IFN-γ, IL-17A, and TNF-α) ex-vivo in Ty21a-vaccinated than in unvaccinated volunteers. LPMC CD8+ TRMS. Typhi-specific responses were evaluated using S. Typhi-infected targets and found to produce significantly higher levels of S. Typhi-specific IL-17A. In contrast, LPMC CD8+CD69+CD103- T cells produced significantly increased S. Typhi-specific levels of IFN-γ, IL-2, and IL-17A. Finally, we assessed CD8+ TRM in IEL and observed that the frequency of IEL CD8+ TRM is significantly lower following Ty21a immunization. However, ex-vivo IEL CD8+ TRM elicited by Ty21a immunization spontaneously produced significantly higher levels of cytokines (IFN-γ, IL-17A, IL-2, and TNF-α). This study provides the first demonstration of the effect of oral Ty21a vaccination on CD8+ TRM subsets (spontaneous and S. Typhi-specific) responses in the LPMC and IEL compartment of the human terminal ileum mucosa, contributing novel information to our understanding of the generation of mucosal immune responses following oral Ty21a-immunization.