bluuebunny/crossref_metadata_2025 huggingface dataset:
P363 Locally injected allogeneic bone marrow-derived mesenchymal stromal cells for the treatment of refractory proctitis: clinical results of a phase IIa trial
Authors: Ouboter L , Barnhoorn M , van Pel M , Zwaginga J J , Hawinkels L , Maljaars J , Koning F , Verspaget H , van der Meulen - de de Jong A
Published: May 2021

Background

Ulcerative proctitis (UP) can be refractory to treatment, which calls for development of new (local) therapies. Local injection of mesenchymal stromal cells (MSCs) has shown beneficial effects in patients with fistulizing Crohn’s disease and promising results have been obtained when MSCs were locally injected in the bowel of mice with experimental colitis. Our primary aim was to determine the safety, feasibility and tolerability of endoscopically injected allogeneic bone marrow-derived MSCs (bmMSCs) in UP patients.

Methods

UP patients with endoscopic Mayo score (EMS) 2 or 3, who failed on both rectal 5-ASA and corticosteroids for at least 4 weeks, were eligible for inclusion (EudraCT number 2017-003524-75). Rectal therapies were stopped 2 weeks prior to baseline, but other medication was kept stable until at least 6 weeks after MSC injection. MSCs were locally injected in 4 quadrants of the inflamed rectal submucosa if the inflammation was limited to 7 cm. If the length of inflammation was >7 cm, MSCs were injected in another 4 quadrants more proximally as well. Patients in the first cohort (n=7) were treated with 5*106 MSCs/spot and in the second cohort (n=6) with 10*106MSCs/spot. Adverse events, full Mayo score, fecal calprotectin (FCP), histologic activity (Geboes score [GS]) and quality of life (sIBDQ), were assessed at week 0, 2, 6, 12, and 24, and evaluated by non-parametric paired statistical analyses.

Results

All reported adverse events were minor, no patients required interventions and no feasibility issues were reported. Median[interquartile range (IQR)] full Mayo score was 11[9.5-12] at baseline, 9[8-11] at week 2 (p=0.003), 8[6-10] at week 6 (p=0.001), and 4[1.5-7] at week 24 (p<0.001). The FCP improved in 9/13 patients at week 2, in 6/13 patients at week 6 and in 11/13 patients at week 24 compared to baseline. The EMS at baseline was 3 (n=10 patients) and 2 (n=3 patients) and improved in some patients at week 2 and 6 (NS). At week 24 the EMS was 3 (n=2), 2 (n=4), 1 (n=5) and 0 (n=2)(p=0.002). The median[IQR] GS decreased after 6 weeks (7(6.5-12.5);p=0.09) and 24 weeks (4[2-8];p=0.01) compared to baseline (10[6.5-12.5]). Median[IQR] sIBDQ showed improvement during follow-up; week 2 (45[37.5-52];p=0.1), week 6 (47[42.50-55];p=0.02), week 12 (59[39.50-62];p=0.001) and week 24 (56[44.50-63.50];p=0.001) compared to baseline (41[34-49,50]). No dose- response effects were observed in our study when comparing cohort 1 and 2.

Conclusion

Local administration of allogeneic bmMSCs appears safe, tolerable and feasible for the treatment of refractory UP, and shows encouraging indications of clinical efficacy. Further mechanistic and immunological analyses are currently being performed.
P373 Psoriasis and psoriasiform skin lesions in patients with Inflammatory Bowel Disease treated with infliximab: a pharmacokinetic analysis
Authors: Rodrigues I , Damião F , Serrazina J , Fernandes S , Bernardo S , Gonçalves A R , Moura Santos P , Baldaia C , Valente A , Correia L , Tato Marinho R
Published: May 2021

Background

Anti-TNF agents are used to treat a variety of autoimmune conditions, including psoriasis. Paradoxically, new onset of psoriasis or psoriasiform skin lesions (PPSL) can occur in patients treated with these agents. We report a case series of patients featuring PPSL induced by infliximab (IFX) with pharmacokinetic and fecal calprotectin (Fc) correlation.

Methods

One hundred and thirty-five consecutive patients with Inflammatory Bowel Disease under proactive therapeutic drug monitoring (TDM) with IFX were evaluated for PPSL.

Results

Fifteen patients (11.1%) developed PPSL, 12 females (80%), with median age at diagnosis of 52.0 years (38-63). At the onset of PPSL, 6 patients were on 10 mg/kg every 6 weeks, 5 patients on 5 mg/kg every 8 weeks, 2 patients on 10 mg/kg every 4 weeks, 1 patient on 10 mg/kg every 8 weeks, and 1 patent on 5 mg/kg every 6 weeks. In patients with PPSL, IFX trough levels (IFXTL) significantly increased before and after the advent of PPSL: 6.18 µg/mL (3.28-9.91) vs 9.20 µg/mL (5.89-13.91), P= 0.001. At the time of PPSL, all but 2 patients were in Fc remission (< 250 µg/g), median 41 µg/g (30-103). Seven patients improved with topic therapy and 8 patients (53.3%) discontinued IFX (3 switched to ustekinumab) all of which improved. Compared with the overall cohort, IFXTL were higher in patients with PPSL: 7.27 µg/mL (4.02-10.86) vs 6.26 µg/mL (3.37-9.14), P= 0.023. In multivariate regression analysis, female gender [OR 4.84 95%CI (1.23-19.00), P= 0.024], and any IFXTL≥ 10 µg/mL [OR 5.66 95%CI (1.40-22.87), P= 0.015] were independent predictors of developing PPSL.

Conclusion

Most patients with PPSL presented high IFXTL and low Fc. We hypothesize that high concentrations of IFX in the setting of deep remission may signal aberrant pro-inflammatory pathways potentially responsible for PPSL.
P455 Tofacitinib Therapy is Effective for Arthralgias Associated with Active Inflammatory Bowel Disease
Authors: Silfen A , Cohen N , Traboulsi C , Rodriguez T , Steinberg J , Singer J , Patel S , Cohen R , Dalal S , Micic D , Pekow J , Sakuraba A , Rubin D
Published: May 2021

Background

Tofacitinib is an oral Janus kinase (JAK) inhibitor used to treat ulcerative colitis (UC). It is generally well tolerated and safe with mild to no side effects. Tofacitinib is FDA-approved for use in multiple inflammatory conditions such as rheumatoid arthritis, psoriasis and polyarticular course juvenile idiopathic arthritis as well as for ulcerative colitis (UC). Patients with UC often have extra-intestinal manifestations (EIMs) with up to 20% of patients having arthropathy. There are limited data describing the effect of tofacitinib therapy on EIMs in UC. The aim of this study is to determine whether tofacitinib therapy improves arthralgia in this patient population.

Methods

This retrospective study includes consecutive patients with active UC who initiated tofacitinib at our center since 2014 and remained on the therapy for at least 8 weeks. We reviewed electronic medical records to collect demographic and clinical data. Patients diagnosed with any EIM by the treating physician were included. Improvement in EIM symptoms was determined through patient reports or physician assessment. In the UC patients, a decrease in Simple Clinical Colitis Activity Index (SCCAI) of ≥ 3 was considered response and remission as a score of ≤ 2. In the CD patients, a 3-point reduction in Harvey Bradshaw index (HBI) was considered clinical response and a score of <5 remission.

Results

112 patients were included in this cohort, with 36 (31 UC; 5 CD) having confirmed EIMs (32.1% of total). Basic demographic and clinical data are detailed in Table 1. 35 patients had peripheral arthralgia, 2 patients had primary sclerosing cholangitis (PSC) and 1 had pyoderma gangrenosum. 5 (13.9%) patients discontinued treatment during the induction phase due to lack of response. By 24 weeks, 26 (74.2%) out of 35 patients reported improvement in arthralgias, and 14 (40%) patients reporting resolution of joint symptoms. In terms of gastrointestinal disease activity, at week 24, 17/35 (48.6%) patients achieved clinical response and 11/35(31.4%) patients achieved clinical remission. There was no treatment effect noted on the other EIMs.

Conclusion

In our real world experience, treatment refractory IBD patients with peripheral arthralgia on tofacitinib showed significant improvement in joint symptoms, and this often paralleled improvement in gastrointestinal symptoms. This supports that tofacitinib is a suitable treatment for patients with IBD and concomitant peripheral arthralgia.
P476 Effectiveness and safety of ustekinumab in ulcerative colitis: Real-world evidence from the ENEIDA registry
Authors: Chaparro M , Garre A , Iborra M , Sierra M , Barreiro-de Acosta M , Fernández-Clotet A , de Castro L , Boscá-Watts M , Casanova M J , López-García A , Lorente R , Rodríguez C , Carbajo A Y , Arroyo M T , Gutiérrez A , Hinojosa J , Martínez-Pérez T , Villoria A , Bermejo F , Busquets D , Camps B , Cañete F , Manceñido N , Monfort D , Navarro-Llavat M , Pérez-Calle J L , Ramos L , Rivero M , Angueira T , Camo P , Carpio D , García-de-la-Filia I , González-Muñoza C , Hernández L , Huguet J M , Morales V J , Sicilia B , Vega P , Domènech E , Gisbert J P
Published: May 2021

Background

The development program (UNIFI) has shown promising results of ustekinumab in ulcerative colitis (UC) treatment that should be confirmed in clinical practice.

Aims

Primary: to evaluate the durability of ustekinumab treatment in UC patients in clinical practice. Secondary: to assess the short-term response (at week 16) and the long-term effectiveness (at maximum follow-up) and to assess the safety of ustekinumab in clinical practice.

Methods

Patients included in the prospectively maintained ENEIDA registry who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score (PMS) >2] were included. Clinical activity and effectiveness were defined based on PMS.

Results

95 patients were included (table 1).

At week 16, 53% of patients had clinical response (including 35% of patients in remission) (figure 1).

In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with clinical remission. Long-term remission is represented in figure 2.

36% of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at week 16, 63% at week 56, and 59% at week 72 (figure 3); primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection.

Conclusion

Ustekinumab is effective both in the short and the long-term in real-life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab.
P517 One year effectiveness and safety of ustekinumab in Ulcerative Colitis: a multicentre real-world study from Italy
Authors: Chiappetta M F , Viola A , Mastronardi M , Turchini L , Carparellli S , Orlando A , Biscaglia G , Miranda A , Guida L , Costantino G , Scaldaferri F , Bossa F , Renna S , Cappello M , Orlando A , Armuzzi A , Fries W
Published: May 2021

Background

Efficacy and safety of ustekinumab for the treatment of Ulcerative colitis (UC) has been demonstrated in phase III clinical trials, but real world data are scarce. The aim of this study was to assess effectiveness and safety of ustekinumab in an Italian cohort of UC patients.

Methods

Data of patients with UC who started using ustekinumab were collected. Primary endpoint was steroid-free clinical remission at 24 and 52 weeks of therapy. Secondary endpoints were: treatment response, endoscopic remission, treatment persistence at 12 months and safety.

Results

A total of 68 patients (males 63.2 %; mean age (SD) 31 years (14.5)) were included. All patients were biologics experienced. At 24 and 52 weeks, 32 % and 50 % of patients achieved steroid-free clinical remission, 85% and 81% had clinical response, respectively. (Table 1) At the end of follow-up there were a significant reduction of pMS from baseline (p<0.001) and of steroid use (p<0.001) (Figure 1). Of the available endoscopies at 12 months (18/38), 22.2% showed mucosal healing. The probability to persist in therapy with ustekinumab after 12 months of treatment was of 89.7 %. Only one adverse event occurred (diagnosis of an hypophysis adenoma). No patients required colectomy.

Conclusion

Data from our small real-life cohort of treatment-refractory UC patients suggest satisfactory effectiveness of ustekinumab and an excellent safety. More data assessing mucosal healing after one year of treatment are needed
P543 The role of social support on psychological distress and health-related quality of life in adults with mild to moderately active Crohn’s disease
Authors: Regev S , Goren G , Schwartz D , Sergienko R , Friger M , Nemirovsky A , Greenberg D , Monsonego A , Sarid O , Slonim-Nevo V , Odes S
Published: May 2021

Background

Medical and psychological factors contribute to the heightened psychological distress and reduced health-related quality of life in patients with Crohn’s disease. Whether Social Support plays a role in this scenario is unknown. We used the Multidimensional Scale of Perceived Social Support (MSPSS) to investigate whether Social Support associates with psychological distress and quality of life in Crohn’s disease.

Methods

Consecutive adult patients with Crohn’s disease, presenting at specialist gastroenterology services or recruited by advertising, with mild to moderate disease activity by the Harvey-Bradshaw Index (HBI), were enrolled into the study. Patients completed the 12-item MSPSS questionnaire that measures psychological support in three categories: Family, Friends and Significant Other, and provides individual category scores and a total score (range of all scores 1–7; a higher score indicates more social support). Patients also completed the following questionnaires: psychological distress (Brief Symptom Inventory, with Global Severity Index, GSI), quality of life (Short Inflammatory Bowel Disease Questionnaire, SIBDQ), satisfaction with life (SWLS), family stress (Family Assessment Device, FAD), coping strategies (Brief-COPE), and presenteeism and work activity (WPAI). Statistics: Spearman rho. *p<0.05, **p<0.01.

Results

The cohort comprised 126 patients, mean (SD) age 33.7 (10.6) years, females 79%, HBI 8.4 (2.5), CRP 1.2 (2.3), calprotectin 394 (674). MSPSS scores were as follows: Total score 5.72 (1.14), Friends 5.36 (1.34), Family 5.73 (1.14), and Significant Other 6.07 (1.15); Cronbach’s α ≥ .877. MSPSS scores correlated negatively with family stress measure FAD: Friends -.258**, Family -.732**, Significant Other -.401**; and with GSI psychological stress measure: Friends -305**, Family -.352**, Significant Other -.245**. MSPSS correlated positively with SIBDQ quality of life: Friends .300**, Family .188*, Significant Other .200*; and with satisfaction with life SWLS: Friends .379**, Family .333**, Significant Other .245**. MSPSS correlations with emotion-focused coping were: Friends -.337**, Family -.263**, Significant Other -.329**. MSPSS Family score correlated negatively with WPAI presenteeism -.270*, and WPAI work activity -.294**.

Conclusion

In mild to moderate Crohn’s disease, strong social support was associated with better quality of life, more satisfaction with life, and better performance in the work arena. Social support was associated with reduced psychological distress, reduced family stress, and less use of emotion-focused coping. This research shows the importance of social support in improving the psychological condition of patients with Crohn’s disease.
P576 Ustekinumab levels correlate with induction fecal calprotectin drop-slope and discriminate the need for intensification at week 52 in Crohn’s Disease patients
Authors: Mateos B , Sáez-González E , Iborra M , Moret I , Cañada A , Tortosa L , Bastida G , Aguas M , Cerrillo E , Nos P , Beltrán B
Published: May 2021

Background

Ustekinumab (UST) intensification during Crohn’s Disease (CD) treatment is becoming common in clinical practice. Little is known about early intensification maintenance regimens and their drug levels utility in discriminating CD-response and the need for further intensification. We aim to analyze UST levels’ evolution in an intensified maintenance regimen, their capacity to discriminate response according to inflammatory parameters and indicate the need for further intensification.

Methods

This is a retrospective study with 43 moderate/severe active CD patients (Harvey-Bradshaw Index [HBI] ≥4 and Fecal Calprotectin [FC] >250 µg/g) who received UST induction treatment (induction dose of 6mg/kg IV, plus dose of 90mg SC at week 8). Patients received maintenance treatment (90mg SC/8 weeks) and were followed for 52 weeks. They were classified according to the response obtained at the first year in responders (R), HBI <3 and FC <200µg/g; non-responders (NR), HBI ≥4 and FC >250µg/g; and intensification group (IG), partially responders that needed UST intensification to every 4 weeks. HBI, FC, C-Reactive Protein (CRP), and UST levels data were collected at baseline (w0), week 8 (w8), week 16 (w16), and 52 weeks (w52) of maintenance. IG was followed 12–26 weeks after intensification (aI).

Results

Half of the patients (48.8%) were male. Most of them (97.7%) have received previous anti-TNF-α treatment (53.49% ≥2 anti-TNF-α). Patients’ median age at the moment of starting UST was 51 (37.5, 58.5) years. Median disease duration was 11 (7.5, 23) years. Location of disease was ileal in 30% of patients and ileocolic in 53%. One-third of patients suffered perianal disease, and 41 % were smokers. The only demographic factor associated with non-response was ileocolic location.

Table 1 shows the evolution of inflammatory parameters and UST levels according to the response. A Pearson correlation (r=0.62) between higher FC drop (baseline-w16) and higher drug levels at w16 was observed. The evolution of biological markers discriminates NR during induction; however, neither biological markers nor UST level can distinguish between R and those who will need intensification. R shows higher UST levels at w52 compared to IG. IG showed a significant increase of UST levels (mean of 5.39 points) and a substantial drop of FC and HBI (mean of 115.62 and 2.27 points, respectively) after intensification. Those patients reported clinical improvement; however, they could not reach a FC <250µg/g, which could need a more extended period to decrease.

Conclusion

FC drop-slope is associated with higher levels of UST at the end of induction. UST levels at w52 are useful for discriminating patients who will benefit from UST intensification every 4 weeks.
P610 Fear of COVID-19 among persons with Inflammatory Bowel Disease according to employment status, educational background and residential setting, as compared to persons with other gastrointestinal conditions
Authors: Lo B Z S , Mokrowiecka A , Mikocka-Walus A , Bernstein C N , Trindade I A , Burisch J , Barreiro-de Acosta M , Ferreira N , Gearry R B , Knowles S R
Published: May 2021

Background

Although several studies have reported the impact of fears relating to COVID-19 on several chronic illness populations, there are few studies focused on gastrointestinal (GI) conditions. The aim was to compare how fear of COVID-19 is manifested in people living with Inflammatory Bowel Disease (IBD) compared to other GI conditions; and, how fear of COVID-19 is manifested across different demographic backgrounds (employment status, education level and country of residence) among IBD respondents using a large international sample.

Methods

Participants with a GI condition (≥18years of age) were recruited from 22 countries through a web-based questionnaire. Demographic, clinical, and psychosocial information was collected in relation to the COVID-19 pandemic. An adaptation of the scale developed for IBD by Trindade & Ferreira (2020) measuring fear of COVID-19 (FoC; original items 1–9) and GI specific fear of COVID-19 (GI-FoC; new items 10–14) was used.

Results

In 831 participants (312 IBD), there were no significant differences in FoC between IBD and other GI conditions; whilst significant increases in GI-FoC were found in IBD respondents (mean [SD]: 13.5 [5.5] vs. 10.9 [5.0], p<0.01). The greatest fears of IBD respondents were: their condition would get worse; impact on access to medical support;

being at increased risk of getting COVID-19; and being at increased risk of death if they got COVID-19.

Among IBD respondents, persons on sick leave had significantly more general FoC than those who were employed, and significantly more GI-FoC compared to the employed or respondents outside of the labour market (Figures 1a and 1b). Persons living in a rural setting had significantly more general FoC and GI-FoC (Figures 2a and 2b). These persons were fearful of contracting COVID-19, having contact with someone with respiratory symptoms, having contact with healthcare professionals, going outside, meeting people, having contact with someone who was in contact with an infected person, having contact with someone infected with COVID-19, and that their IBD means being at increased risk of death if they got COVID-19.

There were no differences in general FoC and GI-FoC according to educational background. However, respondents with higher education were less afraid of dying from COVID-19.

Conclusion

Respondents with IBD are more afraid of the consequences of COVID-19 due to their disease compared to other GI diseases; especially, persons on sick leave or persons living in a rural setting. Persons with higher education were less afraid of dying from COVID-19. These findings should be taken into consideration to personalise the support health-care providers can offer in mitigating fear related to COVID-19 in IBD patients.
P635 Assessment of sarcopenia and nutritional status in a cohort of patients with Crohn’s disease
Authors: Nardone O M , de Sire R , Ponsiglione A , Rispo A , Testa A , Villani G , Camera L , Castiglione F
Published: May 2021

Background

Altered body composition may negatively impact on the clinical outcome and quality of life of patients with IBD. Sarcopenia, defined as a progressive loss of skeletal muscle mass and function, is commonly observed in patients with IBD and can be reliably assessed by computed tomography (CT) which allows accurate and reproducibile quantification of both abdominal adipose tissues (subcutaneous and visceral), as well as skeletal muscles. We aimed to assess the prevalence of sarcopenia in Crohn’s disease (CD) patients undergoing contrast-enhanced CT(CECT). We further investigated the associations of sarcopenia with visceral fat parameters, disease severity and surgery

Methods

40 CD patients (22F, aged 44±16 yrs; BMI 20.8±3.7) who underwent CECT for clinical assessment were retrospectively enrolled. CECT was performed using a 64-rows multi-detector equipment after i.v. injection of non ionic iodinated contrast media with a tailored scan delay.

Demographic and clinical data were collected at the date of abdominal CT. Clinical outcome included the rate of surgery within one year. The skeletal muscle index (SMI) at the level of third lumbar vertebra was used to assess sarcopenia defined as a SMI<38.5cm2/m2 in women and <42cm2/m2 in men (Fig1).Clinical malnutrition was defined by a BMI<18.5 kg/m2, while visceral obesity as a visceral fat area ≥130cm2

Results

Mean duration of disease was 117 months ± 84. Most patients 60% had a moderate-severe clinical activity based on Harvey Bradshaw index (HBI) >8, whereas 35% had a mild activity (HBI 5–7) and 5% were in remission (HBI<5). Overall, 17(42.5%) patients were sarcopenic. In detail, 14 out of 22 (63.6%) females and only 3 out of 18 (16.6%) males (p=0.04). The majority (65%) had moderate activity of inflammation with a mean of HBI 9.2 ± 1.6. Malnutrition occurred in 41,2% sarcopenic patients with a mean BMI of 16.5±3.75. A significant correlation was observed between BMI and sarcopenia (r=0.4,p<0.001). A total of 25 (62.5%) patients underwent surgery within one year. Among them, 40% patients were sarcopenic, while 60% non sarcopenic (p=0.7). In the total population the mean of visceral fat was 48,03±58.04 and only 4 patients had a visceral fat area ≥104 cm2. The ratio between visceral fat and subcutaneous fat area (VFA/SFA) was 0,57±0.5. The correlation between SMI and visceral fat was significant (r=0.4,p=0.02),while it was not significant with VFA/SFA (p=0.7). For all IBD patients, univariate analysis revealed that female sex (p=0.002) and low BMI (p=0.003) were significantly associated with sarcopenia

Conclusion

Approximately 42.5%CD patients were sarcopenic. Female sex and low BMI were significantly associated with sarcopenia but this latter did not correlate with the clinical outcome
P671 Effect of genetic polymorphisms in the folate pathway on the efficacy and safety of methotrexate in Crohn’s disease
Authors: Salazar J , Gordillo Abalos J , Fernández A , Esteve M , Pérez Gisbert J , Busquets D , Lucendo A , Márquez L , Guardiola J , Martin M D , Iglesias E , Monfort D , Villoria A , Cañete F , Bell O , Ricart E , Zabana Y , Domènech E , Garcia-Planella E
Published: May 2021

Background

Methotrexate (MTX) is currently used in steroid-dependent patients with moderate-to-severe Crohn’s disease (CD) when thiopurines have failed or are contraindicated. Although its efficacy has been proved for both induction and maintenance of remission, its use is limited due to the rate of associated adverse events. Polymorphisms in the folate pathway might predict the efficacy and toxicity of MTX. Our aims were to evaluate the predictive value of these polymorphisms of MTX efficacy and safety in CD.

Methods

Patients from ENEIDA registry of GETECCU who were treated with MTX on monotherapy and of whom genomic DNA was available, were identified. Clinical efficacy and MTX-related toxicity were collected, and 10 variants from ATIC, DHFR, MTHFR, RFC1, ABCB1 and ABCC3 genes were genotyped with TaqMan assays.

Results

One hundred and twenty nine patients were included, 55% were female and 31% active smokers. MTX was used as first and second-line therapy in 10% and 60% of patients, respectively, at a mean dose of 22 mg and for a median time of 14 months. Thirty-seven per cent of patients achieved clinical remission, whereas 34% were non-responders (MTX failure). Forty patients (30%) developed MTX-related toxicity, with nausea and vomiting, myelotoxicity and hepatotoxicity as the most frequent adverse events (37%, 15% and 15%, respectively). MTX was discontineud in 19% of the patients due to toxicity. In the multivariable analysis, patients with the AA genotype for the rs408626 DHFR variant was predictive of a higher efficacy as compared to the G allele carriers (RR 0.372, p=0.026), and smoking was associated with a higher risk of MTX therapy failure (RR 2.676, p=0.015). Moreover, the CC genotype for the rs1476413 MTHFR variant and the TT genotype for the rs4793665 ABCC3 variant were independently associated with a higher risk of MTX toxicity (RR 2.357, p=0.038 and RR 2.368, p=0.044, respectively).

Conclusion

Genetic polymorphisms related to the folate pathway (mainly the variant rs408626 of DHFR, rs1476413 of MTHFR and rs4793665 of ABCC3) seem to impact on MTX efficacy and toxicity in CD. Smoking could also influence MTX efficacy.
P677 Fungal abundance is related to inflammatory status in Ulcerative Colitis
Authors: Herrera De Guise C M , Sarrabayrouse G , Varela E , Robles V , Borruel N , Mayorga L F , Casellas F , Ibarz A , Perez Z , Robles M , Guarner F
Published: May 2021

Background

Fungi account for approximately 0.1% of the total microorganisms in the gut. Despite the vast body of literature on the bacterial component of the gut microbiota, little has been published on the fungal microbiota. Fungal-bacterial interactions may be significant in inflammatory bowel disease (IBD), with several lines of evidence linking fungi and IBD. Our study aimed to explore and compare the fungal and bacterial loads in fecal samples from different ulcerative colitis (UC) patients’ groups.

Methods

Using two qPCR systems to amplify the ITS2 sequence from fungi and the 16srRNA gene from bacteria, we characterized and compared fungal and bacterial loads in 3 groups: 1) UClr: UC patients in long-term remission (≥5 years of flare-free disease, clinical, endoscopic and histological remission at inclusion); 2) UCsr: UC patients in short-term remission (3 months in clinical remission at inclusion and previously more than one relapse/year); 3) UCfl: UC patients with active disease (CAI >4 at inclusion). We obtained two frozen fecal samples from all subjects, except for the UCfl group from which we obtained 1 sample at flare onset. Results were expressed in copies/g of feces.

Results

We included 87 UC patients, 29 in UClr, 20 in UCsr, and 38 in UCfl groups. Median age was 39 years, women comprised 52%. Fecal samples contained a significantly lower number of ITS2 gene copies (median 9.27E+05) than 16srRNA gene copies (median 4.28E+11). 16s rRNA gene copies were similar among the different groups with a median 3.88E+11 for UClr, median 5.29E+11 for UCsr, and median 4.315E+11 for UCfl patients (FDR p=0.65). In contrast, copies of ITS2 gene were increased in UCfl (median 1.95E+06) when compared to UClr (3.68E+04, FDR p=0.0036) but not significantly different to UCsr (5.24E+05 copies, FDR p=0.20). We analyzed the variation between samples over time; we compared the number of copies of ITS2 and 16s rRNA genes in fecal samples collected at two different time points: basal versus 8-weeks. We calculated overall fold changes that reflect stability over time. We found a trend for a more significant variation in the quantity of the ITS2 gene than the 16srRNA gene, but this was not significant. Analysis of the ITS2/16S rRNA ratio assessing the frequency of fungi compared to bacteria showed that this ratio was higher in UCfl (median 6.94E-06) when compared to UClr (median 2.63E-07, FDR p=0.0005) and UCsr patients (median 5.60E-07, FDR p=0.0072), there were no differences between UClr and UCsr patients.

Conclusion

Fungal abundance was increased in UC flare patients compared to UC patients in long remission, while there were no differences in bacterial abundance. This high number of fungi could be involved in the inflammatory response of UC patients.
P459 Expression of SerpinE1, a potential new disease activity marker, reflects therapeutic response in Inflammatory Bowel Disease
Authors: Jójárt B , Molnár T , Szabó V , Varga Á , Resál T , Szántó K , Kata D , Földesi I , Molnár T , Maléth J , Farkas K
Published: May 2021

Background

Inflammatory Bowel Disease (IBD) occurs as a consequence of abnormal immune response generating unbalance between pro- and anti-inflammatory signalling. Analysis of cytokine profiles in view of different cytokine targeting or immunosuppressive therapy may open up new therapeutic targets and may reveal biological profiles that distinguish responders from non-responders before initiating therapy.

The aim of present study was to determine cytokine profile of IBD patients and identify cytokines with predictive potential.

Methods

IBD patients with clinically active disease were enrolled in study. Blood and biopsy samples were obtained from 22 IBD patients and 5 healthy controls. Biopsies were taken from inflamed and non-inflamed part of colon of IBD patients. Total protein and mRNA were isolated from biopsy samples. Cytokine Array was used to analyse cytokine expression patterns. Serum and mucosal SerpinE1 levels were measured by ELISA and qRT-PCR.

Results

In samples from IBD patients, remarkable discrimination between inflamed, or non-inflamed areas was observed, whereas no pro-inflammatory cytokines were detected in control samples. SerpinE1 was presented in every inflamed biopsy samples, which was analyzed in more details. Mucosal expression of SerpinE1 differed significantly in healthy subjects compared to IBD patients with active disease (0 vs 24.06 pg/mg, p=0.02). After therapy induction a remarkable decrease was observed in the mucosal SerpinE1 concentration in responders (45.5 vs 9.7 pg/mg, p=0.02) versus non-responders (45 vs 61.2 pg/mg, p=0.3). Moreover, mean value of mucosal SerpinE1 did not differ significantly in healthy subjects compared to responders (5.7 vs. 0 pg/mg, p=0.12). In non-responders the fold changes of SerpinE1 gene expressions were significantly (p=0.001) higher than in responders. Lowest expression of SerpinE1 gene was measured in control samples, whereas the highest in untreated, inflamed biopsy samples. Serum and mucosal SerpinE1 concentrations were significantly higher in patients with active disease compared to inactive (tissue: 5 vs 47.4 pg/mg, p=0.00003; serum: 22.4 vs 25.94 mg/ml, p=0.022). Correlation analysis revealed that serum SerpinE1 correlates with disease activity (p<0,01, cut-off value: 22 mg/ml, sensitivity=80%, specificity=60%, accuracy=74%), whereas no correlation was observed between the mucosal SerpineE1 concentration and the disease activity (p>0.1, sensitivity=72%, specificity=77.8%, accuracy=73.5%).

Conclusion

These results suggest that serum and mucosal SeprinE1 expression reflects endoscopic activity of IBD. Correlation of SerpinE1expression between the blood and the bowel mucosa would open up new possibilities in non-invasive disease monitoring of IBD.
Wave propagation in the poro-viscoelastic orthorhombic two-phase media: plane-wave theory and wavefield simulation
Authors: Cheng Shijun , Mao Weijian , Zhang Qingchen , Xu Qianru
Published: May 2021

Most researches on the Biot-squirt (BISQ) model are limited to the poroelastic transverse isotropic (TI) media. Actually, the poro-viscoelasticity and the orthorhombic anisotropy are closer to the realistic properties of many reservoir media. Therefore, we expand the BISQ model theory to the poro-viscoelastic orthorhombic media and develop the corresponding constitutive relation and 3-D wave equations in the time domain. Here, the generalized Zener linear body model is introduced to describe the relaxation effect of the solid skeleton, and the pore fluid is assumed to be saturated. The expressions of the complex and phase velocities for two quasi-compressional waves qP fast (qP1) and qP slow (qP2), and two quasi-shear waves qS1 and qS2 are obtained from the homogeneous plane-wave analysis, respectively. While introducing the viscoelasticity to our model, the attenuation value predicted by the conventional quality factor is not accurate, and the group velocity representing the position of the wave front in the poroelastic model becomes meaningless. So we derive the novel quality factor and the energy velocity expression by invoking the energy balance equation and the Poynting theorem. Two examples are implemented. First, the 3-D multicomponent wavefield is simulated. The snapshots show the orthorhombic anisotropy and viscoelastic effects lead to significant changes in the wavefield. The comparison to the synthetic seismogram in the poroelastic model indicates that the relaxed skeleton can describe the strong attenuation of seismic waves in the seismic exploration band. Secondly, the variations in the velocities and the quality factor curves with propagation direction, frequency and porosity are analysed. Both examples present the characteristics of wave propagation in the poro-viscoelastic orthorhombic media and validate the correctness of the proposed theory and equations.
The mysterious meeting between Carl Schmitt and Josef Redlich
Authors: Bassok Or
Published: May 2021

In 1934, Carl Schmitt, then the crown jurist of the Third Reich, wrote in an essay titled “National Socialist Legal Thought” about “[a] conversation with a world-famous, world travelled, experienced scholar of more than seventy years of age from the United States [which] belongs to the major experiences and encounters which led me as a jurist to National Socialism.” Schmitt never disclosed the identity of the scholar whom he met. Based on Schmitt’s diaries, I reveal that the scholar was Josef Redlich. Born to a Jewish family in 1869, Redlich was the Fairchild Professor of Comparative Public Law at Harvard Law School at the time he met Schmitt in 1931. According to Schmitt’s 1934 essay, the conversation focused on the indeterminacy of legal norms and on a nihilist understanding of the era. Even after discovering the identity of the scholar to whom Schmitt refers in his essay and analyzing the ideas discussed in their meeting, the story of the encounter between Schmitt and Redlich remains mysterious. For some reason, the ideas of a scholar of Jewish descent, who believed in an Austrian multi-national, federal state, inspired and played a profound role in the formulation of a blatantly antisemitic essay promoting National Socialist legal thought by the crown jurist of the Nazi regime. Schmitt repeated the tale of his meeting with an American scholar—without disclosing his identity—in a lecture he gave in Italian, two years after publishing his essay. Based on an analysis of this obscure lecture, his 1934 essay, and various other materials written both by Schmitt and Redlich, I offer three possible explanations for why Schmitt viewed his encounter with Redlich as so influential on his road to National Socialism.
Consistency analysis of the Grünwald–Letnikov approximation in a bounded domain
Authors: Sousa Ercília
Published: May 2021

The Grünwald–Letnikov approximation is a well-known discretization to approximate a Riemann–Liouville derivative of order $\alpha>0$. This approximation has been proved to be a consistent approximation, of order $1 $, when the domain is the real line, using Fourier transforms. However, in recent years, this approximation has been applied frequently to solve fractional differential equations in bounded domains and the result proved for the real line has been assumed to be true in general. In this work we show that when assuming a bounded domain, the Grünwald–Letnikov approximation can be inconsistent, for a large number of cases, and when it is consistent we have mostly an order of $n-\alpha $, for $n-1<\alpha <n$.
Effect of a novel consensus bacterial 6-phytase variant in grower pigs fed corn-soybean meal-based diets formulated with a full nutrient matrix and no added inorganic phosphorus
Authors: Velayudhan D E , Gracia M , Casabuena Rincón O , Marchal L , Dersjant-Li Y
Published: May 2021

The capacity of a novel consensus bacterial 6-phytase variant (PhyG) to entirely replace dietary inorganic phosphorus (Pi) source in grower pigs fed diets with reduction of calcium (Ca), net energy (NE), and digestible amino acids (AA) was evaluated, using growth performance and apparent total tract digestibility (ATTD) of nutrients as outcome measures. A total of 352 mixed-sex pigs (initial BW 23.4 kg) were randomized to 4 treatments, 8 pigs/pen, and 11 pens/treatment. Diets were corn-soybean meal-based and formulated by phase (grower 1, 25 to 50 and grower 2, 50 to 75 kg BW). The positive control diet (PC) provided adequate nutrients and a negative control diet (NC) was formulated without Pi (1.2 g/kg ATTD P) and reduced in Ca (-0.12 to -0.13 percentage points), NE (-32 kcal/kg), and digestible essential AA (-0.004 to -0.026 percentage points) vs. PC. Two further treatments comprised the NC plus 500 or 1,000 FTU/kg of PhyG. Data were analyzed by ANOVA, mean contrasts and orthogonal polynomial regression. Nutrient reductions in the NC reduced (P < 0.05) average daily gain (ADG) during grower 1 and overall (73 to 136 d of age), increased (P < 0.05) feed conversion ratio (FCR) during grower 1 and overall and tended to reduce (P < 0.1) average daily feed intake (ADFI) during grower 2 and overall, vs. PC. Phytase supplementation improved (P < 0.05) FCR during grower 1, ADG during grower 2 and overall, ATTD of DM and P, and tended to improve DE (P = 0.053) in a linear dose-dependent manner. PhyG at 1,000 FTU/kg resulted in growth performance (all measures, all phases) equivalent to PC. The findings demonstrate that PhyG at 1,000 FTU/kg totally replaced Pi in complex grower pig diets containing industrial co-products, compensated a full nutrient matrix reduction and maintained performance.
Identification of Chemicals AssociatedGambusia affinis(Cyprinodontiformes: Poeciliidae), and Their Effect on Oviposition Behavior ofCulex tarsalis(Diptera: Culicidae) in the Laboratory
Authors: Why Adena M , Choe Dong-Hwan , Walton William E
Published: May 2021

The western mosquitofish, Gambusia affinis (Baird & Girard), has been used worldwide for the control of larval mosquitoes for more than 100 yr. We found that the western encephalitis mosquito, Culex tarsalis Coquillett (Diptera: Culicidae), can detect the presence of G. affinis in oviposition sites based on associated chemicals, leading to a decrease in the number of egg rafts laid. Three volatile chemical compounds were identified in the headspace above the water where G. affinis had been held for 24 h. Oviposition bioassays conducted using standards of the volatile compounds identified (dimethyl disulfide [DMDS], dimethyl trisulfide [DMTS], and S-methyl methanethiosulphonate) found that females reduced oviposition only when low concentrations of DMTS were present, but this response was not consistent across all trials and concentrations tested. DMDS, DMTS, and S-methyl methanethiosulphonate are known bacterial metabolic waste products and may be the source of the compounds. Two nonvolatile compounds of interest were found to be present in the Gambusia-exudate water. After tasting Cx. tarsalis were deterred from ovipositing onto Gambusia-treated water from which the bacteria had been removed by filtration, indicating that the kairomone may consist of nonvolatile compound(s). One of the nonvolatile compounds isolated from the Gambusia-treated water has a benzene ring structure similar to that of cholesterol but the structure of the two nonvolatile deterrents remains to be fully characterized. Our research shows that three volatile compounds and two nonvolatile compounds are present in water associated with G. affinis (Poeciliidae: Gambusia) and affect the oviposition behavior of Cx. tarsalis in laboratory bioassays.
Towards realistic estimates of solar global oscillation mode-coupling measurement noise
Authors: Woodard M F
Published: May 2021

Time series of the medium-l spherical-harmonic decomposition of SOHO/MDI Doppler images were used to investigate the noise of solar-oscillation mode-coupling measurements and to reveal the coupling signatures of global-scale Rossby-waves and magnetic activity. A theoretical model of mode-coupling noise was developed starting from the assumption that the Doppler oscillation signal obeys Gaussian statistics. The measured coupling noise was found to agree with the model noise at the level of 20 per cent. The noise of mode-coupling measurements obtained from MDI data turns out to be considerably larger than that of hypothetical, ‘ideal’ measurements, which could only be obtained from observations with more coverage of the Sun’s surface than current instruments provide. The noise analysis was carried out for a simple suboptimal mode-coupling estimation procedure which is described in some detail. A more rigorous, maximum-likelihood, approach to mode-coupling measurement, which generalizes a method currently used to extract global oscillation mode information, is also described and its relationship to the simple mode-coupling analysis is discussed.
Cosmology from weak lensing alone and implications for the Hubble tension
Authors: Hall Alex
Published: May 2021

We investigate the origin of Lambda cold dark matter parameter constraints in weak lensing, with a focus on the Hubble constant. We explain why current cosmic shear data are sensitive to the parameter combination $S_8 \propto \sigma _8 \Omega _{\rm m}^{0.5}$, improving upon previous studies through use of the halo model. Motivated by the ongoing discrepancy in measurements of the Hubble constant from high and low redshifts, we explain why cosmic shear provides almost no constraint on H0 by showing how the lensing angular power spectrum depends on physical length-scales in the dark matter distribution. We derive parameter constraints from galaxy lensing in KiDS and cosmic microwave background weak lensing from Planck and SPTpol, separately and jointly, showing how degeneracies between σ8 and Ωm can be broken. Using lensing and big bang nucleosynthesis to calibrate the sound horizon measured in projection by baryon acoustic oscillations gives $H_0 = 67.4 \pm 0.9 \,\, \mathrm{km} \, \mathrm{s}^{-1} \, \mathrm{Mpc}^{-1}$, consistent with previous results from Planck and the Dark Energy Survey. We find that a toy Euclid-like lensing survey provides only weak constraints on the Hubble constant due to degeneracies with other parameters that affect the shape of the lensing correlation functions. If external priors on ns, the baryon density, and the amplitude of baryon feedback are available, then sub-per cent H0 constraints are achievable with forthcoming lensing surveys.
Neutrino propagation in winds around the central engine of sGRB
Authors: Morales G , Fraija N
Published: May 2021

Since neutrinos can escape from dense regions without being deflected, they are promising candidates to study the new physics at the sources that produce them. With the increasing development of more sensitive detectors in the coming years, we will infer several intrinsic properties from incident neutrinos. In particular, we centralize our study in those produced by thermal processes in short gamma-ray bursts (sGRBs) and their interactions within the central engine’s anisotropic medium. On the one hand, we consider baryonic winds produced with a strong magnetic contribution, and on the other hand, we treat only neutrino-driven winds. First, we obtain the effective neutrino potential considering both baryonic density profiles around the central engine. Then, we get the three-flavour oscillation probabilities in this medium to finally calculate the expected neutrino ratios. We find a stronger angular dependence on the expected neutrino ratios, which, incidentally, contrast from the expected theoretical ratios without considering the winds’ additional contribution. The joint analysis of this observable, together with the sGRB ejected jet angle, might lead to an effective mechanism to discriminate between the involved merger progenitors (black hole-neutron star (BH-NS) or neutron-star neutron-star(NS-NS)), acting as an additional detection channel to gravitational waves.