bluuebunny/crossref_metadata_2025 huggingface dataset:
Postoperative pain and pain-related health-care contacts after open inguinal hernia repair with Adhesix™ and Progrip™: a randomized controlled trial
Authors: Thölix A.-M. , Kössi J. , Harju J.
Published: January 2022

Purpose

Self-fixed mesh is an alternative to suture mesh fixation in inguinal hernia repair. The aim of this study was to evaluate postoperative pain after open inguinal hernia surgery using self-fixed meshes.

Methods

A randomized clinical trial comparing self-adhesive mesh (Adhesix™) and self-gripping mesh (Progrip™) was conducted from November 2018 through March 2021. Patients included were male, 18–85 years old, and suitable for day case surgery. The primary endpoint was the number of patients needing follow-up visits due to postoperative pain during the first 3 postoperative months. Secondary endpoints included the intensity of pain, the time of return to work and normal daily activities, quality of life measures and postoperative complications.

Results

270 patients were enrolled, 132 received Adhesix™ mesh (A group) and 138 Progrip™ mesh (P group), 231 (85.6%) completed 1- or 3-month follow-up. The number of patients needing follow-up for postoperative pain was significantly higher in the P group (19 vs. 4,p= 0.001). The P group had higher numeric rating scale of pain while coughing (P 0.50 vs. A 0.20,p= 0.024) and during exercise (P 1.02 vs. A 0.60,p= 0.057) at 3 months postoperatively. The time of return to normal activity was 16.6 days in the A group and 22.9 days in the P group, (p= 0.004). The postoperative day being fit for work was sooner for the A group (14.3 days vs 17.8 days,p= 0.009).

Conclusion

This study demonstrated an advantage of self-adhesive mesh over self-gripping mesh with respect to acute postoperative pain and thus faster recovery after surgery.
A Review of Quadrotor Unmanned Aerial Vehicles: Applications, Architectural Design and Control Algorithms
Authors: Idrissi Moad , Salami Mohammad , Annaz Fawaz
Published: January 2022

Over the past decade, unmanned aerial vehicles (UAVs) have received a significant attention due to their diverse capabilities for non-combatant and military applications. The primary aim of this study is to unveil a clear categorization overview for more than a decade worth of substantial progress in UAVs. The paper will begin with a general overview of the advancements, followed by an up-to-date explanation of the different mechanical structures and technical elements that have been included. The paper will then explore and examine various vertical take-off and landing (VTOL) configurations, followed by expressing the dynamics, applicable simulation tools and control strategies for a Quadrotor. In conclusion to this review, the dynamic system presented will always face limitations such as internal and/or external disturbances. Hence, this can be minimised by the choice of introducing appropriate control techniques or mechanical enhancements.
Ecotoxicity and bioremediation potential assessment of soil from oil refinery station area
Authors: Zawierucha Iwona , Malina Grzegorz , Herman Barbara , Rychter Piotr , Biczak Robert , Pawlowska Barbara , Bandurska Katarzyna , Barczynska Renata
Published: January 2022

Purpose

The aim of the present study was to evaluate the toxicity and biodegradation potential of oil hydrocarbons contaminated soil samples obtained from different depths at an oil refinery station area. An approach involving chemical, microbiological, respirometry and ecotoxicity assessment of soil polluted by oil hydrocarbons was adopted, in order to determine the biodegradability of pollutants and ecotoxicological effects of natural attenuation strategy.

Methods

The ecotoxicity of soil samples was evaluated using an ostracod test kit and a seed germination test. The results of the phytotoxicity assay were expressed as a percentage of seedling emergence and as the relative yield of fresh and dry biomass compared to control plants. The intrinsic biodegradation potential of the contaminated soil was examined using a Micro-Oxymax respirometer. Intrinsic biodegradation rates were estimated from the slopes of linear regressions curves plotted for cumulative O2 uptake. The obtained values were then entered in the mass balance equation for the stoichiometric reaction of hydrocarbon decomposition and converted per kg of soil per day.

Results

Although the tested contaminants were biodegradable in the respirometric assay, they were slightly to moderately toxic to plants and extremely toxic to ostracods. The noxious effects raised with the increased concentration of contaminants. The monocotyledonous oat was more tolerant to higher concentrations of oil hydrocarbons than the other test plants, indicating its greater suitability for soil reclamation purposes.

Conclusion

By assessing phytotoxicity and effect on ostracod mortality and progress of soil self-decontamination process, proper approach of reclamation of demoted area can be provided.
Radiometric Dating Sheds Light on Tectonic Debate
Authors: Sidder Aaron
Published: January 2022

The emplacement of the Samail Ophiolite in Oman has been a source of disagreement among geologists. New state-of-the-art research offers a fresh perspective on its timing and geometry.
Rethinking How Valley Fever Spreads
Authors: Sidik Saima
Published: January 2022

Scientists have long assumed that dust storms lead to infections with the desert soil fungus Coccidioides, but new evidence suggests otherwise.
Novel ultra-high-temperature zero-thermal quenching plant-protecting type blue-green dual-emission KAl11O17:Eu2+,Mn2+ phosphors for urban ecological lighting
Authors: Zhu Haifeng , Huang Xu , Li Ya-nan , She Ya-lan , Wang Jing , Wong Wai-Yeung , Liu Min , Li Wei , Zhou Zhi , Xia Mao
Published: January 2022

Super-high-temperature thermal quenching in KAl11O17:Mn2+,Eu2+ phosphor for plant-protecting type light.
Secrecy performance of transmit antenna selection for underlay MIMO cognitive radio relay networks with energy harvesting
Authors: Jiang Xiao , Li Peng , Li Bin , Zou Yulong , Wang Ruchuan
Published: January 2022

In this paper, the secrecy performance in a MIMO cognitive radio (CR) relay network with energy harvesting (EH) and transmit antenna selection/maximal ratio combining (TAS/MRC) is invstigated, where the DF relaying protocol and multiple colluding passive eavesdroppers are considered. To improve the security of wireless transmission, two antenna selection schemes are proposed, namely, the optimal transmit antenna selection (OTAS) scheme and suboptimal transmit antenna selection (STAS) scheme. For the purpose of comparison, the space‐time transmission (STT) scheme is introduced as a baseline. The exact and asymptotic closed‐form secrecy outage probability (SOP) expressions for OTAS, STAS and STT schemes are derived over Rayleigh fading channels. An extension of the TAS framework to an artificial noise (AN) aided MIMO network is further presented and an AN aided transmit antenna selection (AN‐TAS) scheme is proposed, in which the unselected antennas at R are used to emit AN for interfering with Es. Numerical results show that the OTAS and STAS schemes perform better than STT scheme in terms of SOP. Meanwhile, the SOP of AN‐TAS scheme is much smaller than that of OTAS, STAS and STT schemes in the high SNR region, indicating the benefit of applying AN in MIMO network.
A novel method for online voltage stability assessment based on PMU measurements and Thevenin equivalent
Authors: Pourbagher Rohallah , Derakhshandeh Sayed Yaser , Golshan Mohammad Esmail Hamedani
Published: January 2022

From the power systems security point of view, determining the voltage stability margin is essential for the operation of systems. An inaccurate determination of the maximum loading factor or voltage collapse point in a power system may cause voltage instability and blackout of the system. So, applying a proper method with high accuracy and high speed is vital in analysing voltage stability in power systems. This article presents a novel method based on Thevenin equivalent of power systems to accurately determine load‐ability margin using phasor measurement units (PMUs) data. The proposed method is based on the fact that at the voltage collapse point, the characteristic curves of ‘the reactive power at the receiving end’ and ‘the reactive power of the load’ in the weakest bus are tangential to each other. Furthermore, online application of the proposed method requires accurate estimation of the ‘ZIP load model’ and ‘Thevenin equivalent’ of the system. The proposed method is designed to determine the load‐ability margin, ZIP load model and Thevenin equivalent of the power system, simultaneously. This characteristic of the method makes it possible to be applied for online voltage stability assessments. To demonstrate the effectiveness of the proposed method, the simulation results for IEEE 14‐bus, 39‐bus New England and IEEE 300‐bus are presented and analysed.
DIET AND ITS MICROENVIRONMENT INFLUENCE THE HEALTH OF COLON
Authors: Thomas Sunil , Mercogliano Giancarlo , Prendergast George
Published: January 2022

Ulcerative colitis (UC) is an autoimmune chronic inflammatory disease of the large intestine that greatly increases risks of colorectal cancer. UC is an idiopathic inflammatory disorder of the colonic mucosa, which starts in the rectum and generally extends proximally in a continuous manner through part of, or the entire, colon. A Western diet, smoking, alcohol abuse, altered circadian rhythm and a dysbiotic microbiome is thought to induce UC. However, it is still not completely understood the factors in the diet that triggers UC. Identification of the factors associated with the diet that induce UC will lead to healthier lifestyle that prevents UC. In animal models we show that standard diet and diet rich in fiber positively influenced the health of the colon. A high fat high protein diet negatively regulated the health of the colon. A high fat high protein diet caused obesity in animals, paradoxically it also reduced the colon length significantly in these animals. Animals feeding on a high fat high protein had no energy in the fecal pellet demonstrating peinosis [hunger-like-condition; peina (Greek) hunger; osis (Greek) condition] of the colon. A high fat high protein diet also induced peripheral neuropathy in animals; whereas animals on a high fiber diet was healthy and had longer colon and no peripheral neuropathy. Bacteria of the family Erysipelotrichaceae that is related to inflammation-related disorders of the gastrointestinal tract is also high in animals fed with a high fat high protein diet; these animals also had low levels of valeric acid and propionic acid in the colon. Overall, a high fat high protein diet negatively impacts the health of the colon due to poor energy metabolism and its associated dysbiotic microbiome and metabolome.

Currently, anti-inflammatory drugs and immune suppressors are prescribed for UC treatment, side-effects and the risk of opportunistic infections limit the quality of treatment. Hence, there is a need for a new class of biologics for efficient UC treatment. Bin1 is a risk factor in UC as determined by the increase in Bin1 expression in the colon of UC patients. In animal models, we showed that attenuation of BIN1 gene protected against UC. We have developed an innovative therapeutic strategy to treat UC that acts by correcting the leaky colonic epithelial barrier function that drives chronic inflammation in this setting. Specifically, we recently showed that administration of our anti-Bin1 monoclonal antibody (Bin1 mAb 99D) is sufficient to mimic the effect of genetic downregulation of Bin1 to preserve the normal colonic mucosa in an established mouse model of UC, in comparison to control-treated mice which exhibited severe lesions and inflammatory cell influx throughout the mucosa. A diet that positively influence the colon may be beneficial during immunotherapeutic treatment of ulcerative colitis.
GENERATION OF ANTIGEN-SPECIFIC REGULATORY T CELLS BYLACTOBACILLUS SPECIES
Authors: Weingarden Alexa , Bousbaine Djenet , Chen Yiyin , Fischbach Michael
Published: January 2022

INTRODUCTION

There is a need for novel treatments for patients with inflammatory bowel disease (IBD) who do not respond to medical therapy. It is likely that IBD arises from dysfunctional interactions between the mucosal immune system and the gut microbiome, and manipulation of this interaction is therefore a promising therapeutic target. Signaling through the T cell receptor (TCR) may have a powerful role in controlling inflammation in IBD, as chimeric antigen receptor regulatory T cells (Tregs) which recognize colitis-associated antigens have been demonstrated to control inflammation in mouse models. We hypothesized that model antigen expression by two potential Treg-inducing organisms, Lactobacillus reuteri and L. plantarum, could stimulate antigen-specific Tregs which may be able to prevent colitis. Here, we demonstrate that expression of the ovalbumin-derived model peptides OT1 and OT2 by these species are recognized in vitro by transgenic CD8 and CD4 mouse T cells specific for OT1 and OT2, respectively. We also demonstrate that OT2 expression by L. reuteri can be recognized in vivo and generate antigen-specific Tregs.

METHODS

We generated expression of OT1 and OT2 peptides in L. reuteri and L. plantarum in three subcellular locations: secreted, cell membrane-associated, and cell wall-associated. For in vitro assays, mouse dendritic cells (DCs) were pulsed with heat-killed cell pellets from each of these constructs or culture supernatant from secreted constructs, then incubated with either OT1 CD8+ or OT2 CD4+ T cells pre-stained with CellTrace Violet (CTV) for 3.5 days. For in vivo analyses, mice were gavaged with L. reuteri transformed with either empty vector or wall-associated OT2, or given ovalbumin in drinking water, followed by adoptive transfer of CTV-stained OT2 cells. OT2 cells were recovered from mesenteric lymph nodes (mLN) 7 days after adoptive transfer and stained for Foxp3.

RESULTS

All OT2 constructs induced significant in vitro proliferation (decreased CTV staining) of OT2 cells compared to strains expressing empty vector, while secreted and membrane-associated OT1 constructs induced significant proliferation of OT1 cells. In vivo, L. reuteri expressing wall-associated OT2 induced significant OT2 proliferation in mLN compared to L. reuteri transformed with empty vector. A significantly higher proportion of these proliferated cells were Tregs (Foxp3+) compared to proliferated cells in mice treated with L. reuteri transformed with empty vector.

CONCLUSION

These findings suggest that Lactobacillus species can generate antigen-specific proliferation of T cells in vitro, and that L. reuteri may be capable of inducing antigen-specific Tregs in vivo. Expression of antigens by this species may represent a method of generating tolerance in the intestine, which could lead to novel therapies for controlling inflammation in IBD.
MIRIKIZUMAB REDUCES ABDOMINAL PAIN IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE
Authors: Loftus Edward , Pollack Paul , Hunter Theresa , Shan Mingyang , Chan Lai-Shan , Deckard Deanilee , Cross Raymond
Published: January 2022

BACKGROUND

Mirikizumab (miri), an anti-IL-23p19 inhibitor, has demonstrated efficacy in patients with ulcerative colitis and moderately to severely active Crohn’s disease (CD) in a Phase 2, randomised, double-blind, placebo-controlled study (NCT02891226). This analysis evaluated the effect of miri versus placebo (PBO) on worst abdominal pain (AP) utilising an 11-point AP Numeric Reporting Scale (AP NRS).

METHODS

During induction, patients were randomised 2:1:1:2 to receive PBO, 200mg, 600mg, or 1000mg miri administered intravenously (IV) every four weeks (Q4W). At week (W)12, patients entered a blinded maintenance treatment. Patients who received miri during induction and achieved ≥1 point improvement in Simple Endoscopic Score for Crohn’s Disease (SES-CD) at W12 were randomised 1:1 to either continue induction treatment (IV 200mg, 600mg, 1000mg miri Q4W) or receive 300mg miri Q4W administered subcutaneously (SC) for 40W (maintenance). Because of small patient numbers, the randomised maintenance groups results were combined for those who continued the same IV induction treatment (All IV-C) and those who were randomised to SC treatment (All SC). SES-CD non-improvers (NI/1000mg IV Miri) and patients who received PBO (PBO/1000mg IV Miri) during induction received 1000mg miri IV Q4W during maintenance. Patients recorded “worst AP in the past 24 hours” each day using an 11-point AP NRS (0=no pain to 10=worst possible pain) on an electronic diary. The Pain NRS is a valid, reliable, and responsive patient reported outcome that can be used to assess pain among patients with CD. Weekly average score was calculated and compared to placebo using a mixed model for repeated measures (MMRM) for visits in the induction period. Observed change in Pain NRS is presented for maintenance.

RESULTS

Significant reduction in AP NRS was reported by patients treated with 600mg miri compared to patients treated with placebo at W8 (least square mean difference ± standard error [95% confidence interval]: -1.01 ± 0.4 [-1.87, -0.14], p=0.02) (Table 1) and in all miri treatment groups: 200mg (-0.92 ± 0.4 [-1.80, -0.03], p=0.04), 600mg (-1.23 ± 0.4 [-2.11, -0.36], p=0.006) and 1000mg (-0.86 ± 0.4 [-1.57, -0.15], p=0.02) miri versus PBO at W12 (Table 1). Patients who received miri during induction continued to show improvements at W52 (Table 1). Patients treated with PBO/1000mg IV during maintenance reported similar improvements to patients who received miri from W0-52 (Table 1).

CONCLUSION

Using an 11-point Abdominal Pain Numeric Reporting Scale, mirikizumab treatment was associated with statistically significant improvements in abdominal pain when compared to placebo after 12 weeks in patients with moderately to severely active Crohn’s disease. Additional numeric reductions in abdominal pain were observed through 52 weeks in all mirikizumab treated patient groups.
UTILITY OF FIBROSCAN IN ULCERATIVE COLITIS?
Authors: Jain Shubham , Nair Sujit , Chandnani Sanjay , Junare Parmeshwar , Debnath Prasanta , Rane Siddhesh , Patel Sameet , Rathi Pravin
Published: January 2022

INTRODUCTION

Ulcerative colitis (UC) is associated with liver disorders due to various etiologies. Some are diagnosed on basis of deranged liver function tests, imaging, and/or histology. Data on fibroscan in UC is scarce. A previous study had shown no significant differences in liver stiffness (LS) on fibroscan between the inflammatory bowel disease (IBD) cases and non-IBD control groups.

AIMS

We aimed to evaluate UC patients for the prevalence of clinically significant liver disease which is defined by an increased liver stiffness measurement (LS) ≥8 kPa using transient elastography (TE) and to evaluate the effect of UC treatment on liver stiffness at 6 months.

METHODS

All individuals (UC and non-IBD) had their LS recorded using FibroScan® (EchoSense, Paris, France) by a single-blinded operator trained in TE.

RESULTS

120 UC patients and 60 non-IBD control subjects were included. All demographic variables were comparable between the two groups. Thirty-five UC patients (29.9%) had an LS over 8 kPa at baseline and 24 had persistently elevated LS at 6 months after treatment. This suggests a significant reduction in TE values among 31.4% of cases after starting treatment. Four patients had LS in the cirrhotic range (>14 kPa). On fibroscan, difference in LS (mean ± standard deviation in group UC = 7.57 ± 2.77 vs non-IBD group = 5.37 ± 2.32, p < .001).

CONCLUSION

TE in UC at the time of diagnosis can detect clinically significant fibrosis. With treatment, TE values regress below <8 kpa in a significant proportion of patients.
LONG TERM OUTCOMES OF PARTIAL ENTERAL NUTRITION THERAPY IN CHILDREN WITH CROHN’S DISEASE
Authors: Vellanki Srisindu , Borcich Anthony , Agawu Atu , Stoner Natalie , Lindsey Albenberg
Published: January 2022

BACKGROUND

Partial enteral nutritional therapy (PEN, defined as 80% of daily caloric intake from formula) has shown similar efficacy in inducing remission for pediatric Crohn’s Disease (CD) in comparison to exclusive enteral nutrition (EEN, defined as 100% of daily caloric intake from formula). Long-term outcomes of PEN are not well defined in the literature We aimed to study the long-term outcomes of PEN as defined by the number of patients still on maintenance PEN at 1 and 2 years after initiation.

METHODS

This was a retrospective cohort study using electronic medical record data at a large pediatric academic center. Patients diagnosed with CD between ages 7-19 years at PEN initiation with available follow-up data were included. Exclusion criteria were diagnoses of ulcerative colitis or indeterminate colitis, concomitant treatment with systemic steroids (prednisone (or equivalent) dose > 20 mg daily), biologics, or immunomodulators. Data collected included demographic and IBD characteristics as well as details of PEN therapy. We calculated the one and two-year PEN persistence rates and used Kaplan-Meier methods to produce survival curves of PEN persistence with adjustment for censoring.

RESULTS

Between 2009 and 2021, forty-nine participants met inclusion criteria (out of 114 assessed for inclusion). Participants were mostly white (n = 38, 77%), and male (n = 30, 61%). The mean age at CD diagnosis was 11.4 years (standard deviation, SD: 2.9 years) and the mean age at PEN initiation was 12.1 years (SD: 2.6 years). The most common reasons for PEN initiation were primary induction (n = 30, 61%), family/patient preference to avoid other medications (n = 26, 53%), and failure of primary medical therapy (n = 10, 20%). The most chosen formula type for PEN therapy was partially hydrolyzed formulas (n = 30, 61%), followed by standard formulas with whole intact proteins (n = 16, 33%). The one-year PEN persistence rate was 51% (26/49) and the two-year persistence rate was 25% (12/49) (table1). The median time on PEN was 1.3 years (IQR: 0.6 – 2.2 years) (Figure 1). The most common reasons for discontinuation were disease relapse/progression (n=32/41,78%) and treatment non-adherence (n =8/41, 20%). A small number of individuals discontinued due to formula intolerance (n = 3/41,7%). The most common medical therapies escalated to were infliximab (n =21/41, 51%), and adalimumab (n = 8/41, 20%) when PEN was discontinued.

DISCUSSION

Our study suggests that PEN therapy can be used as potential long-term treatment strategy for mild pediatric Crohn’s disease while avoiding corticosteroids and side-effects common with other IBD therapies. Secondary analysis is underway to understand predictors of response or failure to PEN therapy such as disease location/ distribution, type of formula, and the amount of calories from food vs. formula.
TOWARDS A COMMON VALIDATED METHODOLOGY FOR HISTOLOGIC MEASUREMENT OF MUCOSAL HEALING IN ULCERATIVE COLITIS: INTRODUCING A NEW PROJECT OF THE BIOMARKERS CONSORTIUM OF THE FOUNDATION FOR THE NIH
Authors: Honig Gerard
Published: January 2022

Ulcerative colitis is a chronic, debilitating disease characterized by damage to the mucous membrane (mucosa) lining the lower gastrointestinal tract. Endoscopic and histological evidence of healing of the damaged mucosa, referred to as mucosal healing, is increasingly accepted as an important endpoint in clinical practice and in clinical trials due to its association with improved clinical outcomes. In fact, in a draft guidance to industry, the Food and Drug Administration encouraged incorporating histologic evaluation in ulcerative colitis clinical trials. However, there is no community consensus regarding how to define mucosal healing and the field lacks standardized protocols for measuring this treatment target endpoint. Standardized assessment of histologic disease activity in clinical trials is challenging for many reasons, including variability in collection of mucosal biopsies (e.g., number and location), lack of fully validated histology scoring systems, and absence of standard definitions of histologic improvement and remission. The lack of standardized measurement of mucosal healing constitutes a major challenge for drug development and negatively impacts optimization of clinical management for patients. Therefore, the Biomarkers Consortium of the Foundation for the National Institutes of Health recently launched a consortium project, with governmental, nonprofit and industry partners, to address this gap by establishing a common methodology for a histologic measurement of mucosal healing in ulcerative colitis. The project will: 1) Establish the optimum number and locations of biopsies required to determine histological inflammation in ulcerative colitis; 2) Establish a standardized histopathologic measurement of mucosal healing that correlates with clinical outcomes; and 3) Develop an automated machine learning-based methodology for histopathological scoring of mucosal healing. The final results of this project will contribute to a consensus methodology with the goal of establishing a regulatory standard for future industry-sponsored clinical trials, with the potential to contribute to improved tools for clinical monitoring of disease activity in ulcerative colitis.
NON-IMMUNE MEDIATED MUSCULOSKELETAL DISEASE IN INFLAMMATORY BOWEL DISEASE: A SYSTEMATIC REVIEW OF THE LITERATURE
Authors: Schwartzman Monica , Schwartzman Sergio
Published: January 2022

BACKGROUND

Musculoskeletal (MSK) disease is the most common extra-intestinal manifestation of inflammatory bowel disease (IBD); however, the full spectrum of MSK manifestations remains poorly characterized. The published literature is predominately focused on peripheral and axial inflammatory spondyloarthritis (SpA). However, the prevalence of more common, non-inflammatory MSK conditions, such as osteoarthritis (OA) and fibromyalgia (FM), has not been formally reported. In the general population, the prevalence of OA and FM are 10-14% and 2-3%, respectively.

OBJECTIVE

To evaluate the prevalence of OA and FM in the published literature in IBD.

METHODS

A systematic literature review of articles assessing the prevalence of MSK disease in IBD was performed using multiple databases through September 2021. References of included articles were searched for additional pertinent studies.

RESULTS

773 abstracts were screened and 94 studies included. Studies were heterogeneous precluding meta-analysis. Regarding study design, 36% were retrospective, 51% cross-sectional and 13% longitudinal. Median age at the time of the study was 41 years (range 29-51) and 49% (range 31%-100%) were male. The median number of IBD patients in each study was 243 (range 44-56,097). The prevalence of SpA (range) in the reviewed studies was: ankylosing spondylitis (AS) 3.5% (1%-27%), axial SpA 9.2% (1%-46%), and peripheral SpA 15.6% (1%-49%). Only 20/94 studies (21%) stated the term OA in any part of the paper. Of these, 20% excluded OA, 15% used the term OA but did not specifically exclude or identify patients with OA in the results, 5% reported that OA data was unavailable and 60% described the prevalence of OA in the results. In the studies that described OA in the results, median prevalence of OA was 12% (range 0.4%-23.4%). Only 7/94 studies (8%) described FM in any part of the paper, and all described the prevalence of FM in the results with a median prevalence of 2.2% (range 0.8%-12%).

CONCLUSION

While OA and FM are common conditions in the general population, most studies did not formally evaluate for these conditions in patients with IBD. When assessed, the median prevalence of OA was consistent with the general population, and additionally higher than the prevalence of AS and axial SpA in patients with IBD. The prevalence of FM was consistent with the general population. Although both rheumatologists and gastroenterologists need to recognize the importance of SpA, it is as important to understand that the most common MSK disease in IBD may be non-inflammatory. This distinction is critical, as treatment of IBD patients incorrectly diagnosed with inflammatory SpA may subject patients unnecessarily to medication adverse events, while undertreatment of patients with unrecognized SpA may lead to preventable disease morbidity.
MATRIX METALLOPROTEINASE (MMP-9) INDUCED INCREASE IN INTESTINAL EPITHELIAL TIGHT JUNCTION BARRIER IS MEDIATED BY EGFR ACTIVATION
Authors: Al-Sadi Rana , Engers Jessica , Haque Mohammad
Published: January 2022

BACKGROUND

The defective intestinal tight junction (TJ) barrier has a key pathogenic factor in Crohn’s disease (CD) and other inflammatory conditions of the gut. Clinical studies in CD patients have shown that a persistent increase in intestinal permeability is predictive of poor clinical outcome. Matrix metalloproteinase-9 (MMP-9) has been shown to be markedly increased in intestinal tissues of patients with CD and it has been postulated that MMP-9 plays an important role on the pathogenesis of intestinal inflammation in CD. Our recent studies suggested that MMP-9 at clinically relevant concentrations causes an increase in intestinal epithelial TJ permeability in-vitro and in-vivo by inducing intracellular signaling pathways via activating distinct basolateral membrane receptors. However, the specific protein receptors and the intracellular signaling cascades involved have not been fully identified. One of the potential protein receptors that might be a target of MMP-9 on the basolateral membrane of the intestinal epithelial cells is the epidermal growth factor receptor (EGFR), which has been shown to have opposing roles in the pathophysiology of CD.

AIMS

Therefore, our aims in this study were to examine the effect of MMP-9 on EGFR activation and delineate the role of EGRF in MMP-9 induced increase in intestinal epithelial TJ permeability by using Caco-2 monolayers as an in-vitro model system.

RESULTS

MMP-9 (400 ng/ml) caused a time-dependent increase in EGFR activation as assessed by EGFR phosphorylation, and by in-vitro kinase activity measurement of EGFR in filter-grown Caco-2 monolayers. Inhibition of EGFR by pharmacologic inhibitor, PD 153035, prevented the MMP-9 induced increase in Caco-2 TJ permeability measured by trans-epithelial resistance (TER) and mucosal-to-serosal flux of a paracellular marker dextran 10kd. MMP-9 caused a decrease in the TJ protein occludin expression. Inhibition of EGFR by PD 153035 prevented the MMP-9 induced degradation of occludin expression. In addition, the effect of EGFR activation by a known activator, NSC 228155 25, in the absence of MMP-9, caused an increase in Caco-2 TJ permeability and a decrease in occludin expression.

CONCLUSION

Our data showed that MMP-9 induced increase in intestinal epithelial TJ permeability is mediated in part by the activation of EGFR and the subsequent degradation of occludin expression. Identifying the specific membrane receptors that mediate the MMP-9 induced increase in intestinal TJ permeability could be important in developing future therapeutic strategies in IBD.
GENETIC OVERLAP BETWEEN INFLAMMATORY BOWEL DISEASE AND PARKINSON’S DISEASE IMPLICATES THE ROLE OF ADAPTIVE IMMUNE RESPONSE IN THEIR COMORBIDITY
Authors: Otten Thomas , Ayash Jonathan , Lee Wonjun , Cheng Haoxiang , Debebe Anketse , Hao Ke , Peters Lauren , Björkegren Johan , Kalash Olivia , Picker Mellissa , Rendon Alexa , Colombel Jean-Frederic , Saunders-Pullman Rachel , Unger Marcus , Peter Inga
Published: January 2022

BACKGROUND AND AIMS

Patients with inflammatory bowel disease (IBD), Crohn’s disease (CD), and ulcerative colitis (UC) have been shown to be at up to a 40% increased risk of developing Parkinson’s disease (PD), a progressive neurodegenerative disorder. Even though a genetic link between IBD and PD was established through shared causal mutations in the LRRK2 gene, it cannot fully explain the observed comorbidity. The goal of this study was to further explore the genetic overlap between these two diseases.

METHODS

The polygenic risk scores (PRS), representing estimated genetic determinants for IBD, CD, UC, and PD from previously reported respective genome-wide association studies, were computed using a linear combination of the estimated effects across multiple disease-associated variants in the Parkinson’s Progression Markers Initiative (PPMI, www.ppmi-info.org/data) cohort consisting of 413 PD cases and 195 healthy controls (HC) of predominantly European ancestry. We applied a generalized linear regression model to determine the relationship between IBD-related PRS and PD status while adjusting for sex, age, ethnicity, and principal components (PC1-5). A gene-set enrichment analysis was then conducted using Enrichr to examine the biological pathways associated with the genes regulated by variants intersecting between PRS-IBD and PRS-PD in various tissues relevant to IBD and PD (whole blood, visceral adipose fat, brain, and skeletal muscles).

RESULTS

As expected, PRS-PD was significantly elevated in PD patients (odds ratio (OR) 1.76 [95% confidence interval 1.39-2.26], adjusted p=5.34e-06). We also found that PRS-IBD, PRS-CD, and PRS-UC were significantly positively associated with PD case status (OR 1.37 [1.07-1.76], adjusted p=0.01, OR 1.46 [1.15-1.87], adjusted p=0.002, OR 1.36 [1.05-1.76], adjusted p=0.02, respectively, Figure 1). Gene-set enrichment analysis of the intersecting genes between PRS-IBD and PRS-PD across the 4 different relevant tissue types consistently identified the pathways implicating susceptibility to immune-mediated diseases and infections and immune cell differentiation and processing (Figure 2).

CONCLUSION

These results further support the genetic link between IBD and PD and emphasize the role of immunity, particularly pertaining to the adaptive immune system in the pathogenesis of both diseases. This is in line with the established role of autoimmunity in IBD etiology and is consistent with recent studies implicating the autoimmune system in PD development. Moreover, our findings suggest that PRS-IBD could serve as an early biomarker of PD and help stratify high-risk IBD patients for future PD prevention interventions.
CHRONIC COLITIS ALTERS BRAIN ACTIVITY BY INDUCING HMGB1-MEDIATED PYROPTOSIS IN MICE
Authors: Mitchell Jonathon , Kim Su Jin , Howe Cody , Patel Marisa , Kim Gayoung , Heo Gwangbeom , Im Eunok , Rhee Sang
Published: January 2022

BACKGROUND AND AIM

Chronic gut inflammation such as inflammatory bowel diseases is thought as being associated with neurodegenerative diseases in humans. The direct evidence for and the underlying mechanism of this brain-gut interaction, however, remain elusive.

METHODS

We used manganese-enhanced magnetic resonance imaging (MEMRI) to assess brain functional activity from awake and freely moving mice. As a mouse model of chronic colitis, mice were treated with three cycles of dextran sulfate sodium. We performed the passive avoidance test, which is a fear-motivated test that assesses short-term and long-term memory. Mouse hippocampus tissues and microglial cells were subjected to GC-MS, immunofluorescence staining, ELISA, and immunoblotting analysis to examine how the inflamed gut is linked to the brain pathology.

RESULTS

We found that manganese ion uptake, indicative of Ca2+ influx into neuronal cells, and accumulation are dramatically reduced in the hippocampus of chronic colitis mice compared to control mice. Long-term memory is declined in chronic colitis mice. Neuroinflammatory signals, including IL-1β production and the activation of Caspase-1, Caspase-11, and Gasdermin (GSDM), are induced in the hippocampus of chronic colitis mice. High-mobility group box 1 (HMGB1) level is elevated both in the serum and in the hippocampus of chronic colitis mice; however, lipopolysaccharide (LPS) levels remain at low levels without significant changes in these samples. The blood-brain barrier permeability is increased in chronic colitis mice. In the presence of LPS, accordingly, HMGB1 treatment induces the activation of Caspase-11 and GSDM in mouse microglial cell line SIM-A9.

CONCLUSION

Our findings suggest that HMGB1 released from the inflamed intestine may move to the brain through the blood circulatory system; in conjunction with a low level of endogenous LPS, elevated HMGB1 can subsequently activate Caspase-mediated inflammatory responses in the brain. This study implies that chronic gut inflammation may alter brain activity in mice.
NOVEL FUNCTION OF MYELOID METHYLTRANSFERASE SMYD5 IN INFLAMMATORY BOWEL DISEASE PROGRESSION
Authors: Hou Yuning , Guan Xiaoqing , Sharma Shaligram , Li Chunying
Published: January 2022

Background and Aims

SET and MYND domain-containing protein 5 (SMYD5) is a lysine methyltransferase and broadly expressed across various tissues, including immune cells. However, the myeloid SMYD5 in inflammatory bowel disease is entirely unknown. Here, we interrogated the role of SMYD5 in IBD pathogenesis and progression.

METHODS

Colitis was induced in myeloid-specific Smyd5 knockout (Smyd5fl/flLyz2+/-) and floxed control (Smyd5fl/fl) mice through DSS administration in drinking water for 7 days followed by regulator drinking water for 1 day. The induction of colitis was evaluated by measuring relative body weight loss, disease activity index, and histological as well as morphological changes in the colon. The infiltration of macrophages and neutrophils was examined by immunohistochemical staining. Smyd5 depletion in the myeloid cells in Smyd5fl/flLyz2+/- mice was confirmed by quantitative real-time PCR (RT-PCR). The formation of neutrophil extracellular traps (NET) was observed by immunofluorescence microscopy in vitro and in vivo.

RESULTS

Smyd5fl/flLyz2+/- mice administered with DSS displayed a significantly worsened colitis reflected by profound body weight loss and an exaggerated disease activity compared to Smyd5fl/fl mice that received DSS. Meanwhile, Smyd5fl/flLyz2+/- mice receiving DSS exhibited severer tissue damages and immune cell infiltration compared to Smyd5fl/fl mice. In addition, more infiltrated neutrophils were observed in the colon tissues of Smyd5fl/flLyz2+/- mice than in Smyd5fl/fl mice that received DSS. However, the infiltration of macrophages was comparable between these two groups. Moreover, we also observed exaggerated NET formation when Smyd5 was silenced both in vitro and in vivo.

CONCLUSION

Our findings suggest that SMYD5 depletion in myeloid cells leads to exaggerated disease in acute experimental colitis. Furthermore, these data revealed that SMYD5 might play a critical role in suppressing inflammatory response and could serve as a potential therapeutic target in IBD.
INCREASE IN MK2 ACTIVITY IN CROHN’S DISEASE: ROLE IN THE INFLAMMATORY ACTIVATION OF FIBROBLASTS
Authors: Chulkina Marina , McAninch Steven , Ehudin Melanie , Dovat Sinisa , Koltun Walter , Yochum Gregory , Valentine John , Beswick Ellen , Pinchuk Irina
Published: January 2022

INTRODUCTION AND HYPOTHESIS

Mesenchymal cells known as myo-/fibroblasts (MFs) are critical immunosuppressors under gut mucosal homeostasis. Expression of immune checkpoint PD-L1 by MFs plays a key role in the control of T cell inflammatory responses. In Crohn’s disease (CD), MFs switch their activity from immunosuppressive to pro-inflammatory, where they are also known as Inflammatory Fibroblasts. However, the mechanisms responsible for these pathological changes in MF activity are unknown. Map-kinase-activated protein kinase 2 (MK2) is a major regulator of inflammation in the gut. MK2 is downstream of p38 signaling, it evokes a sub-pathway that directly regulates the production of key inflammatory cytokines implicated in CD (such as TNF-α, IL-1, and IL-6). Thus, we hypothesized that activation of MK2 signaling is critical to the pathological changes in MFs during the immunopathogenesis of CD.

METHODS

Human normal and CD tissues and derived MFs, as well as animal models relevant to CD, were used in this study. MF signaling/activity was analyzed using RNAseq, qRT-PCR, western blot (WB), cytokine/chemokine multiplex arrays, and confocal microscopy.

RESULTS

In situ analysis demonstrated an increase in MK2 activity within the inflamed compared to the non-inflamed CD and healthy control intestinal tissues, which was confirmed by WB and multiplex signaling array analysis. In situ increase in MK2 activity in CD intestinal mucosa was greatly associated with mesenchymal stromal cells that bear a “myofibroblast” phenotype (positive for α-SMA expression). An increase in MK2 activity was also observed in primary MF cultures isolated from CD (CD-MFs) when compared to normal (N-) MFs. MK2 activity within CD-MFs was also associated with a significant decrease in the expression of the immunosuppressive checkpoint PD-L1 and an increase in the expression of inflammatory CCL2 and IL-6. Inhibition of MK2 activity within CD-MFs through using the MK2-specific inhibitor PF-3644022 (10 μM) reversed the inflammatory activity of MFs. Remarkably, we observed a differential role of p38 and MK2 in the regulation of PD-L1 expression in MFs: while p38 was required for basal expression of PD-L1, activation of MK2 downregulates PD-L1 expression. These data indicate a unique role of MK2 activation in pathological reprogramming of MFs in CD. Use of MK2 inhibitor in a therapeutic modality in chronic DSS and IL-10 KO murine models of CD also significantly reduce MF-linked inflammatory responses in vivo.

CONCLUSION

Our data suggest that an increase in MK2 activity in CD is critical to the reprogramming of the MF from immunosuppressive toward pathological Inflammatory fibroblasts. Targeting MK2 activity within MFs could be a desirable strategy for improving the efficacy of current IBD therapeutic approaches.
LACTOBACILLUS MURINUS ACTIVATES THE ARYL HYDROCARBON RECEPTOR TO ATTENUATE TNF-ALPHA-INDUCED PRO-INFLAMMATORY RESPONSES IN HUMAN INTESTINAL EPITHELIAL CELLS
Authors: Ahmed Husnain , Bell Julia , Mansfield Linda
Published: January 2022

BACKGROUND

Anti-TNF-alpha therapy is an established treatment modality for inflammatory bowel disease (IBD). Yet up to 30% of patients do not respond to anti-TNF-alpha therapy (primary non-responders), and almost 50% of responders lose clinical efficacy over time (secondary non-responders). Furthermore, numerous safety concerns are associated with the long-term use of anti-TNF-alpha agents. Anti-TNF-alpha therapy safety concerns and the increased incidence of non-responders have driven the need to develop innovative strategies to treat IBD.

OBJECTIVE

A potential alternative to anti-TNF-alpha therapy is the use of novel probiotics capable of attenuating the damaging effects of TNF-alpha on the intestinal epithelium. We hypothesized that Lactobacillus murinus attenuates TNF-alpha induced pro-inflammatory responses and decreases barrier disruption in human intestinal epithelial cells (Caco-2) by activating the aryl hydrocarbon receptor (AhR).

METHODS

We used Caco-2 cells grown on Transwell inserts to model the human intestinal epithelial barrier. Transepithelial Electrical Resistance (TEER) was measured to evaluate the formation of tight junctions. Once TEER reached 500 ohms per cm2, the cells were considered to have formed tight junctions. To induce pro-inflammatory responses, Caco-2 cell monolayers were treated with increasing doses of TNF-alpha (0.1, 1 and 10 ng/ml). Caco-2 cell monolayers were also treated with L. murinus to test its ability to activate AhR. Two defined ligands for AhR were used as controls i.e., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 6-formylindolo[3,2-b] carbazole (FICZ). Next, we pre-treated the Caco-2 cells with either L. murinus or defined AhR ligands for 12 hours. After pre-treatment, monolayers were stimulated with TNF-alpha for 24 hours. IL-8 and TEER were quantified as endpoints to determine treatment efficacy.

RESULTS

TNF-alpha stimulation decreased the TEER and induced the secretion of IL-8 in a dose-dependent manner thus, providing a model of intestinal inflammation. AhR was significantly activated in monolayers treated with L. murinus as well as with defined AhR ligands. Furthermore, pre-treating the cells with L. murinus or with endogenous AhR ligand attenuated the TNF-alpha induced pro-inflammatory response and decreased epithelial barrier disruption in Caco-2 cells.

CONCLUSIONS

These results indicate that TNF-alpha induced damage to the gut wall can be attenuated using novel probiotics such L. murinus or endogenous AhR ligand. These data suggest that AhR could be a novel drug target for treating IBD. These results also indicate that L. murinus may be a potential therapeutic to mitigate or treat IBD without the use of anti-TNF-alpha agents.
LONG TERM ADVERSE HEALTH OUTCOMES IN OFFSPRING FROM MOTHERS WITH INFLAMMATORY BOWEL DISEASE: A NATIONWIDE POPULATION BASED STUDY IN KOREA
Authors: Ahn Hyeong Sik , Kim Hyun Jung
Published: January 2022

BACKGROUND

The research on reproductive women with inflammatory bowel disease (IBD) has focused on short-term outcomes and the studies on the long-term health outcomes of the children of parents with IBD are scarce. Therefore, there is a gap in understanding the influence of parental IBD on long-term outcomes especially in growth and development of their children. The objective of this study is to assess the long-term influence of maternal IBD on disease, growth and development of their offspring.

METHODS

Using National Health Insurance Service (NHIS) which covers total population in Korea (n=50 million), we constructed a mother-child database to track healthcare utilization of their offspring. We linked National Health Screening for Infant and Children database which include growth and development information to NHIS data for subset of population. From the database, we identified IBD patients who had given live singleton births and their offspring by linking personal identification number, providing all children born alive in Korea between 2002 and 2018. Through follow-up until the age of 15, we investigated the association between maternal IBD and selected disease categories in the offspring that include neurodevelopmental disorders, metabolic, autoimmune and allergic conditions. We also assessed association to growth and development such as height and weight of the children up to 71 months of age.

RESULTS

From study database of 3 million woman who gave birth during study periods, we identified 5191 women with IBD who had 7230 children, and 1:10 matched non-IBD control. Mortality rate between IBD and non-IBD offspring was not significantly different between two groups (p>0.05). We could confirm the higher risk of autoimmune diseases (risk ratio (RR); 1.5), but no significant increased risk was identified in neurodevelopmental disorders, and metabolic diseases in IBD offspring compared to non-IBD offspring. In multivariate analysis, children born to IBD mothers had an higher risk (RR: 8.1) of IBD development compared to children with non-IBD mother with but no increased risk was observed in other conditions including autism spectrum disorder, bronchial asthma, or juvenile rheumatoid arthritis. Growth failures defined as less than 3 percentiles in weight and height at 71 months of age were more prevalent in IBD offspring compared to non-IBD offspring (RR 1.53 in weight and 1.25 in height). Among IBD offspring, 5.14% and 4.25% children showed growth failure in weight and height, respectively, compared to 3.40% and 2.78% children in non-IBD offspring.

CONCLUSIONS

From the largest study that ever researched on the health offspring of IBD parents, we found the evidence of poor long-term morbidity regarding autoimmune diseases, but not in neurodevelopmental disorders. Offspring have a higher risk of developing IBD and growth failure up to age of 6.