bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence of hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: A meta-analysis and meta-regression
Authors: Orci L , Caballol B , Sanduzzi-Zamparelli M , Sapena V , Colucci N , Torres F , Bruix J , Reig M , Toso C 
Published: May 2021

Abstract

Objective
Nonalcoholic fatty liver disease (NAFLD) may be a risk factor for hepatocellular carcinoma (HCC), but the extent of this association still needs to be addressed. Pooled-incidence rates of HCC across the disease spectrum of NAFLD have never been estimated by meta-analysis.

Methods
In this systematic review, we searched Web of Science, Embase, Pubmed, and the Cochrane library from January 1st, 1950 through July 30th, 2020. We included studies reporting on HCC incidence in patients with NAFLD. The main outcomes were pooled HCC incidences in patients with NAFLD at distinct severity stages. Summary estimates were calculated with random-effects models. Sensitivity analyses and meta-regression analyses were carried out to address heterogeneity. The protocol for this review was registered in Prospero (CRD42018092861).

Results
Eighteen studies, with a total of 470,404 patients were included. In patients with NAFLD at a stage earlier than liver cirrhosis, HCC incidence was of 0.03 per 100 person-years (PYs) (95% confidence interval 0.01-0.07, I2=98%). This rate rose to 3.78 per 100PYs (2.47-5.78, I2=93%) when considering studies that only included patients with liver cirrhosis. Among the latter patients, those undergoing regular HCC screening displayed an incidence of 4.62 per 100PYs (2.77-7.72, I2= 77%).

Conclusion
Patients with NAFLD-related liver cirrhosis have a risk of developing HCC similar to that reported for patients with cirrhosis from other etiologies. Evidence documenting the risk in patients with NASH or simple steatosis is limited, but HCC incidence in these populations may lie below thresholds used to recommend HCC screening. Well-designed prospective studies in these subsets of patients are needed.
Omentin attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice
Authors: Fang Lixin , Ohashi Koji , Otaka Naoya , Ogawa Hayato , Hiramatsu-Ito Mizuho , Kawanishi Hiroshi , Bando Yasuko K , Shibata Rei , Shimizu Yuuki , Kato Katsuhiro , Takikawa Tomonobu , Ozaki Yuta , Takefuji Mikito , Murohara Toyoaki , Ouchi Noriyuki 
Published: May 2021

Abstract

Aims
Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity contributes to an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated in obese complications. Here, we examined whether omentin could modulate angiotensin (Ang) II-induced AAA formation in apolipoprotein E-knockout (apoE-KO) mice.

Methods and results
apoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg mice) to generate apoE-KO/OMT-Tg mice. apoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion by using osmotic mini pumps. apoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA compared with apoE-KO mice. apoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibres in response to Ang II compared with apoE-KO mice. apoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2, and pro-inflammatory genes in aortic walls compared with apoE-KO mice. Furthermore, systemic administration of omentin also attenuated AAA formation and disruption of medial elastic fibres in response to Ang II in apoE-KO mice. Treatment of human monocyte-derived macrophages with omentin protein attenuated expression of MMP9 and pro-inflammatory mediators, and MMP9 activation after stimulation with lipopolysaccharide. Treatment of human vascular smooth muscle cells (VSMCs) with omentin protein reduced expression and activation of MMP2 after stimulation with tumour necrosis factor α. Omentin treatment increased phosphorylation levels of Akt in human macrophages and VSMCs. The suppressive effects of omentin on MMP9 and MMP2 expression were reversed by inhibition of integrin-αVβ3/PI3-kinase/Akt signalling in macrophages and VSMCs, respectively.

Conclusion
These data suggest that omentin acts as an adipokine that can attenuate Ang II-induced development of AAA through suppression of MMP9 and MMP2 expression and inflammatory response in the vascular wall.
DOP01 Efficacy and safety of the IL-6 trans-signalling inhibitor olamkicept: a phase 2 randomized, placebo-controlled trial in moderately to severely active Ulcerative Colitis
Authors: Chen B , Zhang S , Wang B , Chen H , Li Y , Cao Q , Zhong J , Xie M , Ran Z , Tang T , Yang M , Guo T , Xu B , Cai Z , Schreiber S , Chen M 
Published: May 2021

Abstract

Background
Total inhibition of IL-6 or its receptor represents a potent anti-inflammatory therapy with considerable side effects. Selective targeting IL-6 trans-signalling may have safety advantages that differentiates it from current pan-IL-6 inhibitors. We evaluated the efficacy and safety of olamkicept, a soluble gp130-Fc fusion protein that binds to the IL-6 and soluble IL-6 receptor complex, as induction therapy for active ulcerative colitis (UC).

Methods
This multi-national, randomized, double-blind, placebo-controlled phase 2 trial (NCT03235752) enrolled patients with active UC (full Mayo score ≥5, rectal bleeding (RB) score ≥1, endoscopy score (ES) ≥2) with an inadequate response to at least conventional therapy, in a 1:1:1 ratio to receive either placebo, olamkicept 300 mg or 600 mg biweekly for 12 weeks. Primary efficacy endpoint was clinical response (decrease in Mayo score from baseline ≥3 and ≥30%, including RB ≤1 or RB decrease ≥1) at week 12. Secondary endpoints were mucosal healing (ES 0 or 1) and clinical remission (Mayo score ≤2, with no subscore &gt;1 and RB=0). The efficacy endpoints were analysed by logistic regression. All p-values were 2-sided without adjustment for multiplicity.

Results
Of 91 treated patients (30 in placebo, 31 in olamkicept 300 mg group and 30 in 600 mg group), 88 patients (29:30:29) were evaluable for efficacy. Baseline disease and demographic characteristics were similar among the groups (Table 1). Most patients (94.5%) were bio-naïve. The percentage of patients achieving clinical response at week 12 was significantly greater for olamkicept 600 mg than placebo (58.6% vs 34.5%, P=0.032). Clinical remission at week 12 occurred in 0% (placebo), 6.7% (olamkicept 300 mg) and 20.7% (olamkicept 600 mg, P&lt;0.001) of patients. Mucosal healing at week 12 occurred in 3.4%, 10% and 34.5% (P&lt;0.001) of patients, respectively (Figure 1). Incidence of treatment emergent adverse events (TEAEs) was similar across the groups. The most common TEAEs included upper respiratory tract infection, increased AST levels, and increased urine bilirubin levels, which were mild to moderate and mostly transient. Serious adverse events (SAEs) were reported in 6.7%, 3.2% and 3.3% of patients, respectively. There were no deaths, or other severe AEs associated with current IL-6 inhibitors, such as perforations, severe infections, neutropenia or thrombocytopenia.

Conclusion
Biweekly 600 mg olamkicept induction therapy demonstrated clinical efficacy with respect to achieving clinical response, clinical remission and mucosal healing in patients with active UC. Olamkicept was well tolerated with a favourable safety profile. The positive results of this phase 2 study support further development of olamkicept in IBD.
DOP14 Ultra-high magnification endocytoscopy and molecular markers for defining endoscopic and histologic remission in Ulcerative Colitis
Authors: Iacucci M , Nardone O M , Jeffery L , Acharjee A , Zardo D , Smith S C , Bazarova A , Cannatelli R , Shivaji U N , Williams J , Georgios G , Ghosh S 
Published: May 2021

Abstract

Background
Endoscopic and histological remission are important goals to achieve in patients with ulcerative colitis (UC). We aimed to define deep remission by assessing cellular architecture, expression of molecular markers and their correlation with endoscopic scores by using ultra-high-magnification endocytoscopy and histological indices

Methods
We conducted a prospective study enrolling 29 UC patients (18 males, mean age 41y) referred at a tertiary academic centre for assessing endoscopic remission (ER). All patients underwent colonoscopies with 520-fold magnification endocytoscope. The inflammatory activity was scored using the Mayo Endoscopic Score (MES). ER was defined as MES 0. To assess the grade of inflammation using ECS we set an ECS score (ECSS), whose parameters were summarized in table 1.

Biopsies were taken targeting either the worst affected area of inflammation or the most representive area of ER and scored according to Nancy Histopatological Index (NHI) and Robarts Histopatological Index (RHI). Histological remission (HR) is defined as NHI≤1, and RHI≤3 without neutrophils in the epithelium and lamina propria.The correlation between ECSS and MES and with histological scores were determined.
Soluble analytes relevant to inflammation were measured in serum and mucosal culture supernatants using Procartaplex Luminex assays and studied by Partial Least Square Discriminant Analysis (PLS-DA) and logistic model. Mucosal RNA sequencing and gene enrichment analysis (GO, KEGG) were performed to define differentially expressed genes/pathways.

Results
ECSS correlated strongly with RHI (r=0.89 [95%CI 0.51–0.98] and NHI (r=0.86 [95%CI 0.42–0.98] but poorly with MES (r=0.28 [95%CI-0.27–0.70]). We identified that BDNF, MIP-1α and sVCAM-1 predicted HR. Mucosal biopsy cultures also identified sVCAM-1 associated with healed mucosa. RNA-seq analysis identified genes expressed in colonic biopsies that discriminated between healed and non-healed mucosa and overlapped gene expression shared between ECSS, RHI or NHI defined healing. Based on PLS-DA, for healing vs. non healing comparison as defined by RHI, Nancy, Mayo and ECCS we found 32, 83, 127 and 60 differentially genes respectively. These included genes relevant to TGF-b signaling, macrophage recruitment into tissues, neutrophil and plasma cell function and tumour suppressor genes (Fig.1)

A number of those identified were shared by MES and ECSS defined healing as well as histological criteria defined healing.

Conclusion
ECS may sit between endoscopy and histology but closer to the latter and identifies gene expression markers and pathways that are also detected by histology.
*OMN,LJ,AA equal authors
DOP22 Integrative -omic analysis reveals microbiota mediated molecular mechanisms influencing host mucosal gene expression in Crohn’s Disease
Authors: Sudhakar P , Andrighetti T , Verstockt S , Caenepeel C , Ferrante M , Sabino J , Verstockt B , Vermeire S 
Published: May 2021

Abstract

Background
Mechanistic evidence linking gut microbial changes and host mucosal barrier responses in patients with Crohn’s disease (CD) is lacking. In this study, we used a computational approach to integrate gut microbial and intestinal gene expression in CD patients.

Methods
Bacterial species, bacterial genes/transcripts with enhanced abundances/transcriptional activity in CD (t-statistic of &gt; 2 and Q-value &lt; 0.05), as well as mucosal (ileum/rectum) differentially expressed genes (DEGs) between CD (n =43) and non-IBD (n=22) subjects were retrieved from the Inflammatory Bowel Disease Meta -Omics Database (IBDMDB). The impact of bacterial proteins on host gene expression was inferred using MicrobioLink, a computational tool for inferring microbe-host interactions. Drug target information was retrieved from OpenTargets. Paired 16S read-outs from stool samples and gene expression data from ileal biopsies in CD patients (n=20) and non-IBD controls (n=15), cross-sectionally collected at our IBD referral center, were used for independent validation.

Results
Across the 8 identified bacterial species enriched in CD, 3.7% (n= 743) of the orthologous groups were identified as being able to bind to human proteins. Network diffusion analysis uncovered bacterial proteins which could cumulatively modulate the expression of 42% of the genes differentially expressed in the ileum of CD patients. Topological and pathway analysis of the inferred signaling network modulated by the microbiota revealed several key hub proteins and immune-related pathways associated with IL-4, IL-2 and IL-13 signaling, receptor tyrosine-kinases, NFkB, and toll-like receptors including TLR4. Seventy-eight percent of the DEGs in our discovery cohort were also differentially expressed in the validation cohort (R2 = 0.907). Bacterial proteins post-translationally modifying host receptors resulted in the up-regulation of several pro-inflammatory cytokines via critical hub proteins such as NFkB (Figure 1). We observed different levels of locational specificity (from 35 to 61%) for the top regulators such as SPI1, STAT1 and NFKB1in terms of genes regulated by them in ileum and rectum. 24 proteins including ITGA4 and JAK1 from the ileal and rectal signaling networks are existing targets of CD drugs such as vedolizumab and tofacitinib, filgotinib and upadacitinib respectively.

Conclusion
Our findings outline the potential mechanisms of microbiome-induced host responses and provide insights into designing microbiome-mediated therapies to prevent and/or treat CD.
DOP47 Real World Evidence on the effectiveness of ustekinumab in Crohn’s Disease: Induction phase results from the prospective, observational RUN-CD Study
Authors: Bokemeyer B , Plachta-Danielzik S , Di Giuseppe R , Mohl W , Teich N , Hoffstadt M , Schweitzer A , von der Ohe M , Gauss A , Atreya R , Krause T , Blumenstein I , Höchstödter J , Hartmann P , Schreiber S 
Published: May 2021

Abstract

Background
Prospective, observational real world studies on the effectiveness and safety of ustekinumab (UST) in Crohn’s disease (CD) are required in addition to RCTs, usually confined to selected patients, which may not represent special treatment patterns and everyday clinical practice. The aim of the present 3-year RUN-CD study was to investigate the induction phase effectiveness of UST vs. other biologics (OB) in CD in terms of clinical and steroid-free remission at week 16. To the best of our knowledge, RUN-CD is currently the largest prospective real world evidence (RWE) study with UST in CD using propensity score adjustment.

Methods
Between 2017–2020, 901 CD-patients starting a new therapy with UST or OB, were enrolled in 44 IBD-experienced centers across Germany. After exclusion of missing outcomes, the final sample consisted of 657 patients. Clinical remission (HBI ≤ 4), and steroid-free remission (HBI ≤ 4 and no systemic use of steroids or budesonide during the last 8 weeks) were considered as outcomes at week 16. To reduce the effect of confounders, propensity score (PS) adjustment with inverse probability of treatment weighting (IPTW) was implemented. A weighted logistic regression was used, and the results were reported as odds ratio (OR) and 95% confidence interval (CI).

Results
339 UST (naïve: 34) and 318 OB CD-patients were included (ADA: 50.3%, IFX: 37.4%, VDZ: 12.3%) (naïve: 203). PS removed systematic differences between both groups (30.8% smokers, 15.1% perianal disease, 36.2% surgical resection, 40.5% EIM). The effectiveness of UST for clinical and steroid-free remission was comparable to that of OB at week 16. Besides, in bio-naïve patients, clinical remission was numerically, though not significantly, higher in UST vs OB (Table 1). Similar results were observed in the bio-experienced UST vs. OB groups [remission: 59.3% vs 55.4%; OR: 1.17 (0.73–1.90)]. For both the remission rates were higher in the bio-naïve than in the bio-experienced groups (p&lt;0.05 for both).

Conclusion
In this prospective RUN-CD study, with propensity score weighted groups, UST showed similar induction effectiveness in comparison with OB therapies. Remarkably higher remission rates were observed in this RWE study than in prior RCTs. An additional favorable safety profile supports consideration of UST as a first-line targeted therapy for CD.
DOP65 Dietary therapy with the Crohn’s Disease exclusion diet induces sustained clinical and endoscopic remission in adults with Mild to Moderate Crohn’s Disease: Results from the CDED-AD trial
Authors: Yanai H , Levine A , Hirsch A , Sigall Boneh R , Kopylov U , Banai Eran H , Cohen N A , Ron Y , Goren I , Leibovitzh H , Wardi J , Zittan E , Ziv-Baran T , Abramas L , Fliss-Isakov N , Raykhel B , Pfeffer Gik T , Dotan I , Maharshak N 
Published: May 2021

Abstract

Background
Crohn’s disease exclusion diet (CDED) with partial enteral nutrition (PEN) is effective for induction of remission in children with mild-moderate Crohn’s disease (CD). Here we evaluated CDED in adults with CD.

Methods
This was an open-label prospective randomized controlled pilot trial in patients with mild-moderate CD defined as Harvey-Bradshaw Index (HBI) between 5–14, active disease on colonoscopy, or imaging with calprotectin&gt;200 μ/gr. Group-I received CDED+PEN, and Group-II CDED-alone. A colonoscopy was performed at week-24. Endoscopic remission (ER) was defined as Simple Endoscopic Score for CD (SES-CD)≤3. The primary end-point was corticosteroid (CS) free remission defined as HBI&lt;5 at week-6.

Results
Forty patients were included (median age 30 years [IQR;24–39], 19 patients- Group-I, 21 patients- Group-II). By intention-to-treat (ITT) analysis CS-free remission at week-6 was 62.5% of patients (25/40), comparable between Group-I 68.4%(13/19) vs.Group-II: 57.1%(12/21) (P=.46). Among remitters at week-6, sustained remission was present in 88%(22/25) week-12, and 80%(20/25) week-24. For patients with baseline elevated C-reactive protein (CRP) (n=30), median CRP decreased from 14.5 mg/L [IQR;7.7–37] to 8.4[IQR;5.4–18.5] at week6(P=.006), and to 8[IQR;5.4–20.6] week-24(P=.002). ER at week-24 was present in 14/28 patients (50%) and was 14/40(35%) by ITT. ER week-24 was similar between groups, 8/15(53.3%) vs. 6/13(46.1%) (P=.7). A comparison between baseline and week-24 SES-CD revealed a median of 5-points decrease (IQR; [-6.25]-[-1]), corresponding to 72.8% (IQR;20–100%) decline from baseline (P=.003).

Conclusion
CDED with or without PEN was effective for induction and maintenance of remission in adults with mild to moderate CD and may lead to endoscopic remission.
DOP75 Loss-of-response and immunogenicity following immunomodulator withdrawal from anti-tumour necrosis factor alpha combination therapy: Results from a large retrospective cohort study
Authors: Mahmoud R , Schultheiss J , Louwers J , van der Kaaij M , van Hellemondt B , Mahmmod N , van Boeckel P , Jharap B , Fidder H , Oldenburg B 
Published: May 2021

Abstract

Background
Combination therapy with anti-TNF compounds and immunomodulators (IMM; thiopurine or methotrexate) is superior to IMM or anti-TNF monotherapy in patients with inflammatory bowel disease (IBD). IMMs are frequently discontinued during the maintenance phase to mitigate the risk of adverse events, but long-term consequences of this practice are not well studied. We explored the real-world outcomes after IMM discontinuation, including loss-of-response (LOR), dose escalations, immunogenicity and trough levels.

Methods
This was a multicenter, retrospective cohort study in a general hospital and a tertiary referral center. We included adult patients with IBD, treated &gt;4 months with infliximab (IFX) or adalimumab (ADA) and an IMM at baseline between 2011–2019. The IMM had to be started within 30 days of anti-TNF initiation, or continued for &gt;30 days in case of prior IMM monotherapy. LOR was defined as anti-TNF discontinuation due to disease activity. Adjusted hazards rates (aHR) were calculated using mixed-effects Cox regression analysis with time-varying covariates, accounting for follow-up prior to and after IMM cessation. We adjusted for sex, age, BMI, smoking, Crohn’s disease (CD) vs ulcerative colitis (UC), disease duration, primary sclerosing cholangitis, rheumatological comorbidity, ADA vs IFX, and prior anti-TNF exposure.

Results
We included 615 episodes of combination therapy (543 individual patients; CD, n=382, 70%). The IMM was discontinued in 296 (48%) episodes after a median of 0.9 (IQR: 0.6 – 2.1) years, at which point 252 (85%) patients were in clinical remission. IMM withdrawal was performed as part of a de-escalation strategy (n=158, 53%), for intolerance (n=86, 29%) or for miscellaneous reasons (n=52, 18%). During a median follow-up of 1.7 (IQR 0.8 – 3.5) years after IMM withdrawal, 46 (16%) patients experienced LOR, 79 (32%) required dose-escalation and 31 (10.3%) developed anti-drug antibodies. Compared to IMM continuation, withdrawal did not significantly increase the risk of LOR (aHR 1.10, 95%CI: 0.74 – 1.64), but more patients required dose escalations (aHR 1.42, 95%CI 1.02 – 1.97) or developed anti-drug antibodies (aHR 2.22, 95%CI 1.21 – 4.08). Among patients who stopped the IMM, clinical remission at IMM withdrawal was the only predictor of LOR (aHR 0.48, 95%CI 0.23 – 0.99), while higher BMI (aHR 1.09, 95%CI 1.01 – 1.17) and shorter duration of combination therapy (Figure 1, aHR 0.57 per year, 95%CI 0.33 – 0.96) increased the risk of immunogenicity. IFX, but not ADA, trough levels decreased significantly after IMM withdrawal.

Conclusion
Withdrawal of immunomodulators is not associated with higher risk of LOR, but does increase the risk of dose-escalation and unfavorable pharmacokinetics.
DOP79 Primary hypogammaglobulinemia with IBD-like features: An ECCO CONFER Multicenter Case Series
Authors: Albshesh A , Eder P , Ribaldone D G , Oldenburg B , De Boer N K , Mantzaris G J , Savarino E V , Dragoni G , Weisshof R , Truyens M , Festa S , Maillard M H , Capirchio L , Filip R , Kopylov U 
Published: May 2021

Abstract

Background
The most commonly recognized clinical feature of hypogammaglobulinemia is recurrent infections with high prevalence of gastrointestinal manifestations. In some cases, clinical and endoscopic features are indistinguishable from those of inflammatory bowel disease (IBD).

Methods
This was a multicenter case series performed as a part of the Collaborative Network of Exceptionally Rare case reports (CONFER) project.

Results
This report includes 25 patients with primary hypogammaglobinemia and IBD-like features [20 males and 5 females, mean age 50 years (±21.7 SD)]. Crohn’s disease-like features were noted in 22 patients, three patients had ulcerative colitis-like features. The diagnosis of hypogammaglobulinemia preceded IBD-like features diagnosis in 20 patients (mean of 7.7 years prior, range 0.3–35 years), and followed IBD-like features appearance in 5 cases (mean of one year after, 0.4- 9.1 years).
Hypogammaglobinemia etiologies were common variable immunodeficiency (72%), Agammaglobulinemia (8%), selective IgA-deficiency (8%), Goods syndrome (8%), IgG subclass deficiency with IgA deficiency (4%). In addition to antibiotics and intravenous immunoglobulin (IVIG) as a treatment for hypogammaglobinemia, fifteen patients received IBD treatment during the follow-up period, of whom two were on 5-aminosalicylic acid, five on corticosteroids, three on immunomodulatory, four on anti-tumor necrosis factor, and one on vedolizumab. By the end of the follow-up [35.5 months (Interquartile range 18–75)], 20 of 25 (80%) patients were in clinical remission.

Conclusion
This case series illustrates a strong male and CD-like features predilection. The diagnosis of IBD-like features mainly occurs after that of hypogammaglobulinemia, the majority of cases successfully recovered after appropriate treatment.