bluuebunny/crossref_metadata_2025 huggingface dataset:
Rh(iii)-Catalyzed allylic C–H amidation of unactivated alkenes with in situ generated iminoiodinanes
Authors: Sihag Pinki , Jeganmohan Masilamani
Published: May 2021

Rh(iii)-catalyzed direct allylic C–H amidation of substituted alkenes by in situ generated iminoiodinanes in a highly atom- and step-economical manner is demonstrated.
Reply to ‘Comment on “Structural characterization, reactivity, and vibrational properties of silver clusters: A new global minimum for Ag16”’ by P. V. Nhat, N. T. Si, L. V. Duong and M. T. Nguyen, Phys. Chem. Chem. Phys., 2021, 23, DOI: D1CP00646K
Authors: Rodríguez-Kessler Peter L. , Rodríguez-Domínguez Adán R. , MacLeod-Carey Desmond , Muñoz-Castro Alvaro
Published: May 2021

The electronic and vibrational properties of the new most stable Ag15 cluster are investigated by density functional theory calculations (DFT) and compared with the results of the original work.
Tako-Tsubo-Syndrom: Stress, Ressourcen und Chancen
Authors: Wimmer Eva , Braunschmied Nina , Eichenberg Christiane , Weihs Valerie , Pogran Editha , Fiegl Jutta , Huber Kurt
Published: May 2021

Das Tako-Tsubo-Syndrom (TTS) ist eine Herzerkrankung, die v. a. postmenopausale Frauen betrifft und oft mit erhöhtem Stresserleben einhergeht. Diese Studie untersucht mittels 19 qualitativer Interviews das Krankheitserleben und psychosoziale Aspekte von TTS. Psychotherapie kann hier von großem Wert sein, da die Erkrankung mit starken Ansprüchen an die Leidensfähigkeit, wenig Selbstfürsorge und problematischem Umgang mit Ressourcen einhergeht.
Wechselwirkungen erkennen: Logistische Potenzialanalyse – effizient, digital und nachhaltig
Authors: Moll Beate , Raida Andrea
Published: May 2021

Die Krankenhauslogistik beinhaltet die Planung, Steuerung, Abwicklung und Kontrolle aller Personen- und Materialströme sowie die damit verbundenen Informationsflüsse entlang der Behandlungsprozesse eines Patienten im Krankenhaus. Die logistische Potenzialanalyse bietet für Krankenhäuser die Chance bisher ungenutzte Potenziale zur Steigerung der Effizienz, Digitalisierung und Nachhaltigkeit unter Berücksichtigung einer ganzheitlichen Logistikvision zu nutzen.
Refractive index and extinction coefficient of hollow microspheres for solar reflection
Authors: Nie Xiao , Yu Ziqi , Jackson Enrique , Lee Jaeho
Published: May 2021

While hollow microspheres and various porous structures have received much attention for solar reflection in the recent literature, their fundamental determinants of optical properties and material selection criteria are relatively little known. Here, we study hollow microspheres with varying refractive index and extinction coefficient and identify their role in determining the solar reflectivity. Our simulations based on finite-difference time-domain method show the effects of refractive index between 1.5 and 100 and extinction coefficient between 10−6–100 in the wavelength region of 0.2–2.4 μm and explain how the reflectivity of hollow microspheres is attributed to a combination of strong backscattering and limited absorption. Our analysis indicates that ceramic materials with a high refractive index and a low extinction coefficient such as Y2O3 are promising. When Y2O3 hollow microspheres are randomly distributed with the diameter ranging from 0.5 to 1 μm, our simulation shows the solar reflectivity reaches 0.97 even at 300 μm thickness, and a diffusion theory-based model predicts the solar reflectivity to exceed 0.98 at 500 μm or 0.99 at 1 mm thickness. Our findings can guide optimal designs of hollow microspheres and related porous structures toward complete solar reflection and enable breakthroughs in thermal management and deep-space applications.
Nonlinear variation of resonant frequency with temperature and temperature-dependent τf in Al2O3–TiO2 microwave dielectric composites
Authors: Li Lei , Yang Shuang , Wu Shu Ya , Chen Xiang Ming
Published: May 2021

The temperature coefficient of resonant frequency (τf) is a key parameter for microwave dielectric ceramics, and it is usually regarded as a temperature-independent constant over a wide temperature range. However, the present theoretical prediction shows that the resonant frequency (f0) first increases then decreases with temperature, and τf decreases monotonously in Al2O3–TiO2 composite with small τf, which fits the experimental data very well. The nonlinear variation of f0 with temperature and temperature-dependent τf are attributed to the temperature-sensitive permittivity (εr) and τf of the constituting phases and also dependent on the dielectric mixing rule that the composite obeys. Such temperature-dependent dielectric behaviors are predicted to be common in microwave dielectric composites with small τf, and the negligence of them probably conceals the real large variation of f0 with temperature and seriously misleads the practical applications. Therefore, it is strongly suggested to understand the real temperature dependence of f0 and τf in microwave dielectric composites by measuring f0 at more temperatures with a smaller interval, so that the central frequency shift can be correctly evaluated for the resonator units and devices where the microwave dielectric composites are utilized. Furthermore, the nonlinear variation of f0 with temperature and temperature dependence of τf are expected to be suppressed by microstructural engineering and adopting more suitable constituting phases.
Impact of parasites on Australian laying hen welfare
Authors: Groves Peter J.
Published: May 2021

Cage housing systems separate the hen from her excreta and, thus, break the transmission cycle for most internal parasites. However, production systems where the birds are on litter or have access to the outdoors allow parasite life-cycle completion and, hence, these systems have seen a resurgence of intestinal parasites (worms, coccidia and histomonads). Effective registered anthelminthics are few in Australia and there are no registered products available to treat tapeworms in hens that are laying eggs for human consumption. Hence, internal parasites represent a challenge to the welfare of free-range and cage-free flocks. This is even more problematic in ‘organic’ production systems, as none of the effective treatments can be used. This is a considerable welfare issue for the organic system of production where the only measure available is lengthy range-area resting. External parasites can infest birds in any production system, although these too are regarded as more likely in extensive systems. Parasites are increasing in the layer industry and this is compounded by the parasites’ ability to infest a variety of bird species, making introduction from wild birds a significant source. New antiparasitic treatments that can be used during egg production for human consumption will be required in future.
Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein
Authors: Hsu Jack Chun-Chieh , Laurent-Rolle Maudry , Pawlak Joanna B. , Wilen Craig B. , Cresswell Peter
Published: May 2021

Significance

To establish infection, pathogenic viruses have to overcome the type I interferon (IFN-I) antiviral response. A previous study demonstrated that the SARS-CoV-2 NSP14 is able to inhibit IFN-I responses. In this study, we report that SARS-CoV-2 NSP14 is a virus-encoded translation inhibitory factor which shuts down host protein synthesis, including synthesis of antiviral proteins. Our finding reveals a mechanism by which SARS-CoV-2 evades host antiviral responses. A comprehensive understanding of the strategies employed by SARS-CoV-2 to subvert host immune responses is critical for the design of next-generation antivirals and to prepare for future emerging viral pathogens.
Smoking Cessation in Tuberculosis Patients and the Risk of Tuberculosis Infection in Child Household Contacts
Authors: Chu Alexander L , Lecca Leonid W , Calderón Roger I , Contreras Carmen C , Yataco Rosa M , Zhang Zibiao , Becerra Mercedes C , Murray Megan B , Huang Chuan-Chin
Published: May 2021

Background

While previous studies have shown that cigarette smoking increases the infectiousness of tuberculosis patients, the impact of smoking cessation on tuberculosis transmissibility has not been evaluated.

Methods

Between 2009 and 2012, we enrolled 4500 tuberculosis patients and followed 14 044 household contacts in Lima, Peru. Tuberculosis patients were classified into 4 categories: never smoked, quit in the distant past (stopped smoking >2 months prior to time of diagnosis), recently quit (stopped smoking ≤2 months prior to time of diagnosis), and active smokers. We used a modified Poisson generalized estimating equation to assess the risk of tuberculosis infection of child contacts at enrollment and by 6 months of follow-up.

Results

In total, 1371 (76.8%) child contacts were exposed to patients who had never smoked, 211 (11.8%) were exposed to distant quitters, 155 (8.7%) were exposed to recent quitters, and 49 (2.7%) were exposed to active smokers. Compared with child contacts of index patients who had never smoked, child contacts of recent quitters had a similar risk of tuberculosis infection at enrollment (adjusted risk ratio, 95% confidence intervals [0.81, 0.50–1.32]) and by six months of follow-up (0.76, 0.51–1.13); and by 6 months of follow-up (aRR, 0.76; 95% CI, .51–1.13); child contacts of recent quitters had a significantly reduced risk of tuberculosis infection compared with contacts of active smokers (enrollment 0.45, 0.24–0.87; 6-month follow-up 0.48, 0.29–0.79).

Conclusions

Our results show that the adverse effects of smoking on the transmissibility of tuberculosis are significantly reduced shortly after quitting smoking, reinforcing the importance of smoking cessation interventions in tuberculosis control.
DOP11 Fibrosis and MAGNIFI-CD activity-index at MRI to predict treatment outcome in perianal fistulising Crohn’s Disease patients
Authors: Van Rijn K , Meima-van Praag E , Bossuyt P , D’Haens G , Horsthuis K , Snijder H , Tielbeek J , Buskens C , Stoker J
Published: May 2021

Background

The aim of this study was to evaluate degree of fibrosis and disease activity using the MAGNIFI-CD index at MRI as predictors of long-term clinical perianal fistula closure in Crohn’s patients who had anti-TNF therapy and/or surgical closure.

Methods

Perianal Crohn’s patients who had anti-TNF and/or surgery between 2013 and 2020 with a post-treatment MRI and long-term clinical follow-up data were retrospectively included. Two radiologists scored the degree of fibrosis and items of the MAGNIFI-CD index at the post-treatment MRI. Long-term clinical closure was assessed 12 months after the post-treatment MRI and was defined as no production on palpation and/or closed external openings and absence of re-interventions. The accuracy of findings at MRI in predicting long-term clinical closure was evaluated in terms of a receiver operating characteristics (ROC) analysis. An area under the curve (AUC) with 95% confidence interval (CI) was calculated.

Results

Forty-nine patients were included; 31 female, median age 33 years (IQR 26–46). Post-treatment MRI was performed at a median of 7 months (IQR 4–14) after treatment. At long-term clinical follow-up, 25 patients showed fistula closure and 24 did not. Fourteen patients showed a 100% fibrotic fistula at post-treatment MRI of which all had a closed fistula at long-term clinical follow-up (Figure 1). ROC analysis showed an AUC of 0.90 (95% CI: 0.81–0.99) for degree of fibrosis in predicting long-term clinical closure. The median MAGNIFI-CD index at post-treatment MRI was 0 (IQR 0–5) in patients with long-term clinical closure and 16 (IQR 10–20) in patients without (Figure 2). ROC analysis showed an AUC of 0.95 (95% CI: 0.89–1.00) for the MAGNIFI-CD index in predicting long-term clinical closure.

Abstract DOP11 – Figure 1: Degree of fibrosis at the post-treatment MRI in relation to long-term clinical closure.

Abstract DOP11 – Figure 2: MAGNIFI-CD index at the post-treatment MRI in relation to long-term clinical closure.

Conclusion

Degree of fibrosis and MAGNIFI-CD index at post-treatment MRI are accurate in predicting long-term clinical closure of perianal fistulas in Crohn’s patients and can be valuable parameters for radiological follow-up. A completely fibrotic tract at MRI seems a robust indicator for long-term fistula closure.
N06 Patient perspectives on the role of the IBD nurse and telemedicine during COVID-19 pandemic: results from a Belgian tertiary IBD unit
Authors: Dewitte G , Geldof J , Truyens M , Lobaton T
Published: May 2021

Background

Many inflammatory bowel disease (IBD) patients experienced additional stress due to the COVID-19 pandemic. Concerns for COVID-19 disease increased the risk of immunomodulatory or biologic treatment discontinuation. Furthermore, lockdown threatened the continuity of chronic care delivery. To guarantee the continuity of care our IBD unit rapidly adapted and developed new ways of remote communication. This included telephonic clinics and telephonic pre-admission screening before every appointment at the dayclinic. In this process the IBD nurse played a pivotal role.

The aim was to assess patients’ concerns during the first COVID-19 wave and their acceptance of telemedicine.

Methods

A cross-sectional study was performed using an anonymous electronic questionnaire (REDCap®) to assess IBD patients’ satisfaction regarding care delivery at the IBD unit of the Ghent University Hospital during the first COVID-19 wave.

Results

A total of 274 patients participated. Mean age was 47.5 years (SD ± 15.4). According to patients’ answers, 57.2% had Crohn’s disease, 34.5% ulcerative colitis and 8.3% reported ‘other’.

During the first wave, 43.6% of patients contacted their IBD nurse; usually questions regarding medication (20.6%), appointments (18.4%) or SARS-CoV2 infection risk (6%). For the majority of patients (96.5%) these contacts were sufficient.

In person follow-up consultation was scheduled for 178 patients. From those, 31 considered cancelling their consultation due to the pandemic and 18 effectively cancelled (Fig 1).

Half of the population (51.6%) received intravenous therapy at the day clinic. Telephonic pre-admission screening the day before was done for all patients and well received in most of them (98.5%).

During the first wave, endoscopy was planned in 31.5% of the responding patients. A minority (11.1%) postponed or cancelled endoscopic appointments. From those, 55.6% reported that the main reason was fear of the coronavirus.

Ninety-four (39.2%) of responders had a telephonic consultation during the first wave. Different aspects regarding satisfaction and acceptance of telemedicine were also assessed (Fig 2–3).

For further follow-up, 60.2% preferred balanced combination of telephonic and face-to-face consultations.

Conclusion

Remote ways of care delivery were generally well received during the first wave of the pandemic. Only a minority of patients cancelled appointments without discussion with the medical team. The most frequent patient concerns were about medications and appointments. The challenges in continuity of care during the pandemic created a window for new ways of care delivery in the future.
OP35 Effect of maintenance ustekinumab on corticosteroid-free endoscopic and clinical outcomes in patients with Crohn’s Disease - Week 48 analysis of the STARDUST trial
Authors: Danese S , Vermeire S , D’Haens G , Panés J , Dignass A , Magro F , Nazar M , Le Bars M , Lahaye M , Ni L , Bravatà I , Gaya D R , Peyrin-Biroulet L
Published: May 2021

Background

The STARDUST study demonstrated that ustekinumab (UST), using either a treat-to-target (T2T) or standard of care (SoC) strategy, may induce and maintain endoscopic and clinical response and remission in Crohn’s disease (CD). Primary endpoint, safety, and efficacy have been reported previously.1 Because corticosteroid (CS) sparing is an important aim of CD management, we compared the efficacy of UST T2T vs SoC in achieving CS-free clinical remission and endoscopic response.

Methods

Adult patients (pts) with moderate–severely active CD who were CDAI 70 responders after 16 weeks (W) of induction, comprising a single dose of UST 6 mg/kg iv followed by UST 90 mg SC at W8, were randomized to either T2T or SoC arms. In the T2T arm, choice of UST maintenance dosage (q12w or q8w) was based on endoscopic improvement at W16, followed by clinical and biomarker-directed dose escalation up to q4w; in the SoC arm, UST q12w or q8w dosage was based on EU SmPC. Primary endpoint was endoscopic response (Simple Endoscopic Score in CD [SES-CD] decrease from baseline [BL] ≥50%) at W48. For pts on CS at W16, CS tapering was mandatory. At W48, CS-free clinical remission (CDAI <150 and no CS for ≥30 days) and CS-free endoscopic response (reduction from BL in SES-CD ≥50% and no CS for ≥30 days) were evaluated.

Results

Of 500 pts enrolled, 441 achieved a CDAI 70 response at W16 and were randomized to T2T (n=220) or SoC (n=221); 79.1% and 87.3%, respectively, completed W48. Among clinical remitters and responders at W16 (start of CS tapering), in both T2T and SoC arms more than 70% were still in remission or response at W48 (Figure 1). CS use throughout 48 weeks of treatment is summarized in Table 1. At W48, in T2T and SoC arms similar rates were noted for CS-free endoscopic response (33.6% and 28.5%, respectively) and CS-free clinical remission (56.4% and 63.3%, respectively). Notably, in T2T and SoC arms the CS-free clinical remission rate among pts on CS at BL was 44.1% and 45.1%, respectively (Figure 2). Among W48 endoscopic responders (T2T, n=83; SoC, n=66), CS-free endoscopic response rate was 89.2% and 95.5%, respectively; among W48 clinical remitters (T2T, n=135; SoC, n=154), CS-free clinical remission rate was 91.9% and 90.9%, in T2T and SoC arms, respectively.

Conclusion

Pts treated with UST under T2T or SoC strategies achieved similar rates of CS-free clinical remission and endoscopic response over 48 weeks. Overall for pts on CS at BL, UST reduced the need for CS while achieving response/remission. Most (>89%) pts with endoscopic response/clinical remission at W48 were also CS-free responders/remitters.

Reference
P016 SZN-1326, a Wnt signal activator, is more efficacious than cyclosporine A in an acute DSS model
Authors: Xie L , Baribault H , Lu C , Handa P , Newman M , Le L , Liu A , Mutha D , Deshmukh S , Shah D , Tun C , Le T , Fletcher R , Chen H , Ye J , Tibbitts J , Srinivasan U , Li Y , Vanhove G , Yeh W C
Published: May 2021

Background

Current Inflammatory bowel disease (IBD) treatments focus on inhibition of excessive inflammation, and clinical remission rates have reached a plateau. There is a clear unmet need for agents that directly repair and regenerate the intestinal epithelial barrier as mucosal healing has been associated with reduced hospitalizations and long-term remission. Wnt/β-catenin signaling promotes intestinal stem cell renewal and is crucial for intestinal epithelial homeostasis and regeneration. Fzd5, a Wnt receptor, is highly expressed in intestinal epithelium. We have engineered a FZD5,8 and LRP6 bi-specific IgG1 antibody, SZN-1326, which potently induced Wnt signaling in a Super Top Flash (STF) Luciferase reporter assay, stimulated intestinal organoid growth, increased Wnt target gene Axin2 expression in the colon tissue and ameliorated Dextran Sulfate Sodium (DSS)-induced colitis in mice. The objective of the current studies was to compare the efficacy of SZN-1326, a Wnt signal activator, to Cyclosporine A, which has been shown to have activity in an acute DSS-induced colitis mouse model.

Methods

To induce acute colitis, 7- to 8-week-old female C57BL/6 mice were given drinking water containing 4.0% (w/v) DSS for 7 days followed by 1.0% DSS for 3 days. Groups of mice were treated either with an isotype control antibody (anti-GFP), one intraperitoneal (IP) injection of SZN-1326 at 2, 6, 20 mg/kg on day 4 or two injections of SZN-1326 at 1, 3, 10 mg/kg on days 4 and 7, or treated daily with Cyclosporine A by oral gavage at 80 mg/kg on days 0–9, and the mice were taken down on day 10.

Results

Mice subjected to DSS developed severe colitis characterized by profound and sustained weight loss and bloody diarrhea, resulting in the increase of disease activity index (DAI). SZN-1326 treatments improved body weight, decreased fecal score, and reduced DAI much more effectively than Cyclosporine A. Histological evaluation showed SZN-1326 treatments repaired the damaged colon epithelium, decreased colon histology scores of inflammation, mucosal erosion, and goblet cell loss, at doses as low as 1 mg/kg dosed twice or a single dose of 2 mg/kg. In addition, SZN-1326 treatments significantly decreased serum levels of inflammatory cytokines, Lipocalin-2, IL-6 and IL-8, while Cyclosporine A treatment led only to a reduction of Lipocalin-2.

Conclusion

In an acute mouse IBD model, SZN-1326 at various dosing regimen stimulated intestinal epithelial regeneration, induced mucosal healing and restored the epithelial barrier resulting in reduced inflammation, improved body weight and reduced disease activity. In contrast, Cyclosporine A showed only a mild effect on reducing DAI and lipocalin-2.
P028 The Apa I polymorphism in the Vitamin D receptor gene is associated with a stricturing behaviour in Crohn′s disease patients
Authors: Gisbert-Ferrandiz L , Llau J , Cosin-Roger J , Coll S , Bauset C , Ortiz-Masia D , Hinojosa J , Calatayud S , Barrachina M D
Published: May 2021

Background

Vitamin D receptor (VDR) is a member of the nuclear receptor family of transcription factors that plays an immunomodulatory role in the gastrointestinal tract through binding Vitamin D. Single-nucleotide polymorphisms (SNPs) in the VDR gene have been related to inflammatory bowel disease. Indeed, Crohn′s disease (CD) patients carrying the Taq I polymorphism in VDR gene run a higher risk of developing a penetrating behaviour. We analyse here the association between the VDR SNPs Taq I, Bsm I, Apa I and Fok I and the clinical characteristics of CD.

Methods

DNA was extracted from blood samples from 80 patients diagnosed with CD from the Hospital of Manises (Valencia). Four polymorphisms identified in the VDR gene (Bsm I, Fok I, Apa I and Taq I) were genotyped using PCR-RFLP. Clinical data for each patient, including the Montreal classification was collected. Statistical significance was done using contingency tables and measured by Chi-squared or Fisher test.

Results

Results reveal a strong linkage disequilibrium between Apa I, Bsm I and Taq I polymorphisms. Apa I appears next to Bsm I and it is negatively associated with Taq I. The presence of at least a risk allele for Apa I is significantly associated with a stricturing behaviour in CD patients (P=0.014, Table 1), while the ancestral genotype (WT) of Apa I was significantly associated with a penetrating behaviour (P=0.062, Table 2). Finally, the presence of the risk genotype of Apa I is associated with a non-colonic location of the disease (P=0.059, Table 3). Fok I was not significantly associated with any of the parameters analysed.

Conclusion

Our results in CD patients reveal that the presence of the risk allele of Apa I in the VDR genotype is associated with a stricturing behaviour and tends towards a non-colonic location of the disease. This suggests that the analysis of this polymorphism may be useful for clinicians as a prognostic factor.
P039 New molecular markers of the development of ulcerative colitis
Authors: Iakovlev A A , Volkov A , Tarasova G , Zubova A
Published: May 2021

Background

The mechanisms of ulcerative colitis (UC) progression require detailed study. Modern achievements of proteomic methods of analysis are ideal for research that is free from hypotheses and allows us to define molecular characteristics of inflammation in colon mucosa of UC patients.

Methods

The study was comparative cohort with parallel design and included 88 patients (range from 22 to 35 years, 37 men and 51 women): 53 (60.2%) pancolitis and 35 (39.8%) left-sided UC, mild and moderate activity. The control group included 30 healthy individuals. Biosamples of colon mucosa in patients with UC in the active stage and in healthy persons were received by ileocolonoscopy with colon mucosa biopsy. The separation of individual proteins of colon mucosa was based on technologies of IEF, SDS-PAGE, 2DPAGE, by standard sets (MB-HIC C8 Kit, MB-IMAC Cu, MB-Wax Kit, «Bruker», USA). Automated mass spectrometry imaging was performed by MALDI-TOF-MS/MS, Ultraflex II, «Bruker», USA). The data of the molecular interactions and functional features of proteins were received with STRING 10.0 database.

Results

We identified following functional groups of peptides and proteins in molecular patterns of colon mucosa in UC patients: SMAD family member 2 (SMAD2) activates the transcription of TFG1β, that leads to specific regulation of the CCN2 gene in cells and the development of fibrosis in colon submucosa in UC patients; the stimulation of the expression of apoС-III in affected colon mucosa in UC is associated with the activation of the FOXO1 signaling pathway that supports inflammatory processes in colon mucosa; the second small heat shock protein (HSP2) controls the apoptosis of colonocytes, is also responsible for the mucosa resistance to therapeutic strategies; caspase 8 protects colonocytes from TNFα-induced cell death through a necroptosis mechanism via the blockade of the RIP3 expression; the expression of prohibitin maintains optimal activity of the electronic transport chain through the activity of transcription factor STAT3 and the decrease in the TNFα expression; significant decrease of the PPARγ expression promotes the activation of STAT and AP-1 signaling pathways, which promotes the activity of immune and inflamation processes in colon mucosa and a significant increase in the NF-kB expression in colon mucosa is associated with the activation of TNFα and IL-1, which promotes the increase of immune processes in colon mucosa.

Conclusion

Bioinformatics analysis revealed the presence of molecules that are the participants in the universal pathways of UC in the active stage, and the molecular interactions involved. This information may provide new avenues for the development of novel diagnostic tests for UC.
P068 The combination of JAK1 and TPL2 or IRAK4 inhibitors is more effective than single agents in reducing TLR-mediated cytokine responses in human monocyte populations
Authors: Hornsby E , Yadon A N , Clarke A , Grant E , Lindsay J O , Stagg A J
Published: May 2021

Background

Dysregulated Toll-like receptor (TLR)-mediated responses in intestinal monocyte-derived cells contribute to pathology in inflammatory bowel disease (IBD). JAK inhibitors regulate the production of inflammatory mediators and are an emerging therapy in IBD. Recent data suggest that combination therapies may be more effective than single agents, and therapies targeting aspects of TLR signalling pathways are being developed. We assessed the impact of inhibitors of IRAK4, TPL2 and JAK1 (IRAK4i, TPL2i and JAK1i, respectively) either alone or in combination on TLR-mediated cytokine responses and associated signalling pathways in classical (CD14+CD16-), intermediate (CD14+CD16+) and non-classical (CD14lowCD16+) human blood monocyte subsets.

Methods

Peripheral Blood Mononuclear Cells (PBMCs) or CD14+ monocytes from healthy volunteers were pre-incubated with TPL2i, IRAK4i or JAK1i individually or with JAK1i in combination with TPL2i or IRAK4i for 1 hour at 37°C. Cells were then stimulated at 37°C with agonists of TLR4 (E.coli lipopolysaccharide; LPS) or TLR2 (Pam3CYSK4). Intra-cellular staining and flow cytometry were used to measure phosphorylation of signalling molecules (NF-kappaB p65, p38 MAPK and ERK) or cytokines (TNF-alpha and IL-1-beta) in the three monocyte subsets after stimulation for 15 minutes or 3 hours respectively.

Results

Pre-incubation of PBMCs or CD14+ monocytes with IRAK4i, TPL2i or JAK1i individually led to a significant dose-dependent reduction in TLR-stimulated cytokine production (the frequency of TNF-alpha+ cells and the per cell level of IL-1-beta) within the classical, intermediate and non-classical monocyte subsets. The combination of JAK1i with IRAK4i or TPL2i had an additive effect. TPL2i reduced LPS-stimulated ERK phosphorylation, but p65 and p38 phosphorylation in response to LPS was not affected by any of the inhibitors.

Conclusion

Small molecule inhibitors of TPL2, IRAK4 and JAK1 dampen TLR4- and TLR2- mediated inflammatory responses in human monocyte subsets, by affecting pathways independent of p65 or p38. This is due to a cell intrinsic effect on CD14+ monocytes. TPL2 inhibition may in part act to dampen cytokine production in monocytes through the reduction of ERK phosphorylation. Combining JAK1i with IRAK4i or TPL2i may be more effective in reducing inflammatory responses than single agents. Further work is required to elucidate the mechanisms by which IRAK4i and JAK1i dampen TLR-mediated inflammation in monocyte subsets.
P163 The impact of the COVID-19 pandemic on Health-Related Quality of Life of Patients with Inflammatory Bowel Disease in The Netherlands
Authors: Paulides E , Pasma A , Erler N S , van Eijk R L A , de Vries A C , van der Woude C J
Published: May 2021

Background

To learn from the current crisis caused by the COVID-19 pandemic and be prepared for future pandemics, it is important to investigate the impact of this extraordinary period on the wellbeing of patients with inflammatory bowel disease (IBD). Therefore, the aim of this research was to describe the self-reported Health-Related Quality of Life (HRQoL) and disease control of patients with IBD from the start of the COVID-19 pandemic and measures in The Netherlands.

Methods

This was a prospective study initiated on March 17, 2020 until July 1st, 2020. All patients aged 18 years and older with IBD that visited the Erasmus MC (Rotterdam, The Netherlands) outpatient clinic between March 2019 to February 2020 received up to date information on COVID-19. Patients were invited to complete online questionnaires at week 0, 2, 6 and 12. The Inflammatory Bowel Disease Questionnaire (IBDQ), the Inflammatory Bowel Disease control-8 (IBD-control-8 and the Numeric Rating Scale (NRS) on fatigue were used. The evolution of the different outcomes over time was measured using mixed models.

Results

Of 1151 invited patients, 851 participants (67% had CD and 33% UC or IBD-U) completed one or more questionnaires (response rate 74%). Median age of the participants was 41 years, with 57% being female. No relevant changes in total scores were found over time for the IBDQ (effect estimate 0.006, 95% CI [-0.003–0.015]) and IBD-control-8 (effect estimate 0.004, 95% CI [0.998–1.011]). There was a slight, increasing trend in fatigue scores over time (effect estimate 0.011, 95% CI [0.004, 0.019]).

Conclusion

This first lock down due to the COVID-19 pandemic in The Netherlands did not impact on the HRQoL and disease control of patients with IBD. Up to date information may have contributed to a stable HRQoL in IBD patients even in an extreme period with restrictions and insecurities.
P168 Depression and fatigue dependent variation of gut microbiome in patients with active Inflammatory Bowel Disease
Authors: Reindl W , Wuestenberg T , Knoedler L , Ebert M , Wirbel J , Zeller G , Thomann A
Published: May 2021

Background

Fatigue and depression are highly prevalent extraintestinal symptoms in IBD, especially during active disease. The underlying mechanisms are still poorly understood, but an involvement of the microbiota-gut-brain-axis seems likely. The aim of this study was to examine associations between the gut microbiota and symptoms of fatigue and depression in patients with active IBD.

Methods

We included 62 patients with active IBD. Blood and stool samples were collected before a change of therapy and patients completed questionnaires regarding fatigue (WEIMuS) and depression (HADS). Fecal microbiota were analyzed by means of shotgun metagenomic sequencing.

Based on taxonomical and functional metagenomic annotations of gut microbiome, we investigated the correlation between functional modules and psychometric scores as well as the nature of co-occurrence networks on the genus level using Bayesian statistical methods and analyzed modulating effects of fatigue and depression on genera co-occurrence. CRP levels as well as age, gender, diagnosis and medication were included as nuisance variables.

Results

Half of the patients (n=31) were fatigued (WEIMuS >/= 32P.), and 18 patients reported symptoms of at least mild to moderate depression (HADS D >/=10P.). Co-occurrence of genera that is influenced by depression or fatigue in this active IBD-sample with is displayed in Figure 1 (Log10(BF10) ≥ 1.0, strong evidence for H1).

Evidence for an influence of depression severity was found for 10 genera combinations, with the strongest effects on the Dorea-Butyrococcus-association (Log10(BF10) = 1.41, increase of association strength with higher depression score) and the association between an unknown genus of the Coriobacteriaceae family with Arabia (Log10(BF10) = 1.00, decrease of association strength with higher depression score). Modulatory effects of fatigue severity was present in 10 genera combinations, most pronounced for the Azospirillum-Akkermansia- (Log10(BF10) =2.39, increase of association strength with higher fatigue-score) and Odoribacter-Actinomyces-association (Log10(BF10) =1.58, decrease of association strength with higher fatigue-score) (Figure 2).

Conclusion

This study is the first to address the relationship between extraintestinal symptoms like fatigue and depression and microbiota parameters in patients with active IBD by means of network analysis with Bayesian methods. Our results show strong associations between these symptoms and co-occurring genera in a sample-specific network, indicating a role of the microbiota-gut-brain-axis in the development of fatigue and depression during active disease.
P260 An analysis of non-melanoma skin cancer rates in the tofacitinib Ulcerative Colitis clinical programme
Authors: Sands B E , Cohen R D , Ha C , Reinisch W , Salese L , Mundayat R , Lawendy N , Panés J
Published: May 2021

Background

Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We present an updated analysis of non-melanoma skin cancer (NMSC) events in the tofacitinib UC clinical programme, including final data from the open-label, long-term extension (OLE) study (as of 24 Aug 2020).

Methods

NMSC events were evaluated from 3 randomised, placebo (PBO)-controlled studies (2 Phase [P]3 induction studies [NCT01465763; NCT01458951]; 1 P3 maintenance study [NCT01458574]) and an OLE study (NCT01470612), as 3 cohorts: Induction (P3 induction studies [patients (pts) receiving tofacitinib 10 mg twice daily (BID) or PBO]); Maintenance (P3 maintenance study [pts receiving tofacitinib 5 or 10 mg BID or PBO]); Overall (pts receiving tofacitinib 5 or 10 mg BID in P3 or OLE studies). Analysis was by predominant dose (PD) 5 or 10 mg BID, based on average daily dose <15 or ≥15 mg, respectively (82% of pts received PD 10 mg BID). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique pts with events per 100 pt-years of exposure) were evaluated for NMSC. A Cox proportional hazards model was used for risk factor analysis.

Results

1124 pts were evaluated for NMSC (2809.4 pt-years of tofacitinib exposure; up to 7.8 years of treatment; median duration 685.5 days). NMSC events in Induction and Maintenance were previously reported (Table 1).1 In Overall, NMSC occurred in 21 pts (IR 0.73 [95% confidence interval (CI) 0.45, 1.12]): PD tofacitinib 5 mg BID n=5, IR 0.63 (0.21, 1.48); PD tofacitinib 10 mg BID n=16, IR 0.77 (0.44, 1.25) (Table 1); 2 new cases since May 2019.1 Eleven pts had squamous cell carcinoma and 15 pts had basal cell carcinoma; 5 pts had both. No NMSC was metastatic or led to discontinuation. IRs by time interval and subgroup are reported (Table 2). Prior NMSC (hazard ratio [HR] 12.08 [95% CI 4.20, 34.76]) and age (per 10-year increase, HR 2.01 [1.38, 2.93]) were significant risk factors for NMSC in the multivariable analysis. Prior immunosuppressant use was not a significant risk factor in either the multivariable or univariate analyses.

Conclusion

In this analysis, NMSC IRs for tofacitinib were similar to those in pts with UC treated with biologics2 and those previously reported in the tofacitinib UC clinical programme.1 NMSC events were more likely to occur in pts with recognised NMSC risk factors: prior NMSC and increasing age.3 Dose dependency of NMSC IR could not be concluded here, as dose changes were permitted. NMSC IRs remained stable over time, up to 7.8 years of exposure.

References
P269 Real-world impact of biological therapies on work impairment and quality of life in Inflammatory Bowel Disease patients
Authors: Thomas P , Den Broeder N , West R , Russel M , Jansen J , Römkens T , Hoentjen F
Published: May 2021

Background

Randomised controlled trials have reported improvement of work productivity and activity impairment (WPAI) as well as quality of life in biological-treated inflammatory bowel disease (IBD) patients. However, data beyond clinical trials are limited.

Methods

This multicentre prospective cohort study evaluated the effect of initiating biological or small molecule therapy on work impairment in IBD patients. Subjects completed the WPAI questionnaire and Short IBD questionnaire (SIBDQ) at biological therapy initiation and at week 26. Clinical disease activity was assessed using the Harvey Bradshaw Index and Simple Clinical Colitis Activity Index. Biochemical disease activity was assessed using C-reactive protein and faecal calprotectin. Data are presented as mean ± standard deviation.

Results

In total, 156 IBD patients were included for analysis (median age 40 years, 55% male, 55% Crohn’s disease). Of these patients, 28% started infliximab, 33% adalimumab, 19% vedolizumab, 18% ustekinumab, 1% tofacitinib and 1% golimumab. Concomitant medication use at baseline included 28% prednisone, 12% budesonide, 34% mesalamine, and 46% immunomodulator. At baseline, 58% had clinical disease activity and 58% had biochemical disease activity. In our cohort, 111 (71%) were employed and 17 (11%) patients reported partial or full occupational disability. The mean total work impairment at baseline was 52% ± 36%. During follow-up, 7 patients lost their job and 8 patients started employment. For the entire cohort, improvements in all WPAI domains were observed: mean 11%-points decrease in missed working hours, 4%-points decrease in impairment while working, 15%-points decrease in total work impairment and 15%-points decrease in total activity impairment. Parallel improvements were seen in SIBDQ scores (mean improvement 7.6 ± 11.3). At week 26, 66 (42%) patients achieved the minimal clinical important difference in total work impairment (improvement ≥7%-points). Patients with clinical disease activity at baseline and clinical response to the biological (n=32) showed a larger improvement in total work impairment compared with other subjects (n=86) (mean difference 29%-points versus 10%-points; p=0.036 (T-test)). Similarly, these patients showed greater improvement in SIBDQ scores compared to other subjects (mean 13.8 versus 5.4, respectively; p<0.001 (T-test)).

Conclusion

IBD patients experienced substantial work impairment prior to initiating biological treatment. Improved work impairment scores were seen after initiation of biological therapy and patients with clinical response showed even greater improvements. These results underline the importance of IBD disease control to improve work productivity and participation.
P281 Evaluation of trough level and disease activity after switch from adalimumab originator to biosimilar in patients with Inflammatory Bowel Disease
Authors: Deprez N , De Somer T , Baert D , Deceuninck M , Huys I , Mattens V , Sterckx A , Vanden Branden S , Vanderstraeten E , Vandervoort J , Vanheddegem N , Dewint P
Published: May 2021

Background

SB5 is approved as a biosimilar to the adalimumab (ADA) originator. Bio- and efficacy equivalence, as well as comparable safety and immunogenicity have been demonstrated in Phase I and III randomised clinical trials. In this study we want to describe the trough levels and effectiveness of switch to a biosimilar in a real-life Inflammatory Bowel Disease (IBD) population.

Methods

In 2 Belgian IBD centres, patients in clinical remission or stable response and treated with ADA originator were offered to enter a phase IV, interventional trial of switch to biosimilar SB5. Assessments were done at baseline, at 8 weeks, 6 and 12 months post-switch. Therapy type and dosing regimen remained unchanged the first 8 weeks; after week 8, dose adjustments could be made based on trough level and/or at the discretion of the treating physician. Trough serum ADA concentrations were measured by enzyme-linked immunosorbent assay (ELISA). The primary outcome measurement was the description of ADA trough level over time after the switch. The secondary outcome measurements were secondary loss of response (SLOR) (defined at physician’s discretion), disease activity scores and biochemical assessments (faecal calprotectin (fCal), leukocyte count (LC) and C-reactive protein (CRP)).

Results

In the study, 110 patients were enrolled from whom 84 had Crohn’s disease and 26 had ulcerative colitis. By 12 months, SB5 was stopped in 5 patients because of high ADA antidrug antibodies at both baseline and at week 8. Nine patients presented with SLOR of whom 3 discontinued treatment with SB5, the remaining 6 patients received treatment optimisation. Table 1 displays the core results concerning the ADA trough levels over time. Table 2a and 2b display disease activity scores and biochemical parameters at the different time points.

Conclusion

In this pragmatic, interventional phase IV trial, ADA trough levels remain within the therapeutic range after switch from originator to SB5. The proportion of patients in our study with SLOR is in line with what is described in literature. In patients persisting on SB5, no change in disease activity over time is observed, based on both disease activity scores and biochemical parameters.
P288 Vedolizumab May Be An Effective Option For The Management Of Postoperative Recurrence Of Crohn’s Disease
Authors: Macaluso F S , Cappello M , Crispino F , Grova M , Privitera A C , Piccillo G , Magnano A , Ferracane C , Belluardo N , Giangreco E , Fries W , Viola A , Di Mitri R , Mocciaro F , Camilleri S , Garufi S , Renna S , Casà A , Maida M , Orlando A
Published: May 2021

Background

The role of Vedolizumab (VDZ) as therapeutic option for the postoperative recurrence of Crohn’s disease (CD) following ileocolonic resection is currently unknown.

We aimed to assess the effectiveness of VDZ in this setting.

Methods

All consecutive CD patients with an available baseline colonoscopy at 6-12 months from the ileocolonic resection and treated with VDZ for the postoperative recurrence after the baseline colonoscopy were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD). The primary outcome was endoscopic success, assessed at the first colonoscopy following initiation of VDZ. In patients with Rutgeerts score i0 or i1 at baseline, endoscopic success was defined by maintenance of Rutgeerts score i0 or i1; in patients with Rutgeerts score ≥ i2 at baseline, it was defined as reduction of at least one point of Rutgeerts score. The secondary outcome was clinical failure, assessed at one year and at the end of follow-up.

Results

Seventy patients were included (median follow-up: 23.5 months). All 9 patients without endoscopic recurrence at baseline (Rutgeerts score i0 or i1) and available post-treatment colonoscopy maintained a Rutgeerts score i0 or i1 (treatment success: 100%). In patients with endoscopic recurrence (Rutgeerts score ≥ i2 at baseline), a reduction of at least one point in the Rutgeerts score was obtained in 20 out of 42 patients (47.6%). By combining the two subgroups, the overall endoscopic success was achieved in 29 out of 51 patients (56.9%). Furthermore, 14 out of 42 patients (33.3%) with endoscopic recurrence at baseline achieved a Rutgeerts score i0 or i1 at the subsequent colonoscopy. Clinical failure was reported in 13/70 patients (18.6%) at one year, and in 23/70 patients (32.9%) at the end of follow-up. A new resection was required in 7/70 patients (10.0%).

Conclusion

VDZ may be a therapeutic option for the management of postoperative recurrence of CD. Further studies are needed to confirm these results.
P292 Effect of drug therapy on the lipid profiles of patient with Inflammatory Bowel Disease: a systematic review and meta-analysis
Authors: Sleutjes J A M , Roeters van Lennep J E , Boersma E , de Vries A C , van der Woude C J
Published: May 2021

Background

Increases of lipid levels associated with inflammatory bowel disease (IBD) medication have been previously reported. However, it is unknown whether this effect is similar for all IBD drug classes.

Methods

We performed a systematic literature search of randomized controlled trials and observational cohort studies of IBD treatment with corticosteroids, anti TNFα agents and tofacitinib that assessed total cholesterol (TC) before and after short-term (≤8 week) and long-term (≥12 week) treatment. Data of 11 studies (1,663 IBD patients) were pooled using a random effect model with as primary outcome TC levels. Lipid changes were reported as mean difference on the log2-scale (MDlog2) with 95% CI. The effect of patient and disease characteristics on TC changes were analyzed in 6 studies with individual patient data of 1,211 patients.

Results

A significant increase in TC was observed after treatment with corticosteroids, anti TNFα agents and tofacitinib (short-term +0.370, +0.197 and +0.190; long-term: +0.452, +0.068 and +0.162, respectively). (Figure 1) After correcting for age, sex, BMI and CRP, increases of TC levels after start of corticosteroids and tofacitinib treatment were higher (short-term: +0.293 and +0.161; long-term: +0.090 and +0.127, respectively) as compared to anti TNFα agents (short-term: -0.059, long-term: +0.041). (Figure 2)

Conclusion

Changes in lipid levels differ between IBD drug classes. TC levels increase was strongest for corticosteroids followed by tofacitinib but not observed for anti TNFα agents. Whether TC change associated with IBD treatment has effect on CVD risk requires further study.